Hello friends 👋
In this episode, Ben and Daphna cover a range of neonatal topics, starting with a review of recent research on monkeypox (mpox) in pregnancy and neonates. They discuss a case report of neonatal mpox infection and review current understanding of risks, transmission, and treatment options.
The hosts then examine a study on vaccine administration in preterm infants, finding that giving multiple vaccines on a single day did not increase adverse events compared to spreading them out. They also explore research on iron deficiency in extremely preterm infants, which revealed surprisingly high rates despite supplementation, especially in formula-fed babies.
Other topics covered include PICU admissions of former NICU patients in the first two years of life, and innovative approaches to reducing non-actionable alarms in intensive care units.
The episode concludes with insights from Dr. Rivara's 24 years as a medical journal editor-in-chief, touching on key aspects of research publication.
Throughout, Ben and Daphna provide expert commentary on the clinical implications of these studies, making complex research accessible to listeners while emphasizing areas needing further investigation in neonatal care.
----
----
The articles covered on today’s episode of the podcast can be found here 👇
Abdelmessih E, Desai PV, Tracy J, Papadopoulos J, Bashqoy F.J Perinatol. 2024 Sep 10. doi: 10.1038/s41372-024-02111-1. Online ahead of print.PMID: 39256613
Nachega JB, Mohr EL, Dashraath P, Mbala-Kingebeni P, Anderson JR, Myer L, Gandhi M, Baud D, Mofenson LM, Muyembe-Tamfum JJ; Mpox Research Consortium (MpoxReC).N Engl J Med. 2024 Aug 28. doi: 10.1056/NEJMp2410045. Online ahead of print.PMID: 39197097 No abstract available.
Ramnarayan P, Mitting R, Whittaker E, Marcolin M, O'Regan C, Sinha R, Bennett A, Moustafa M, Tickner N, Gilchrist M, Kershaw A, Rampling T; NHS England High Consequence Infectious Diseases (Airborne) Network.N Engl J Med. 2022 Oct 27;387(17):1618-1620. doi: 10.1056/NEJMc2210828. Epub 2022 Oct 12.PMID: 36223535 No abstract available.
Barr H, Morrison L, Kulkarni K, Ghotra S.J Perinatol. 2024 Aug 29. doi: 10.1038/s41372-024-02103-1. Online ahead of print.PMID: 39210023 No abstract available.
van Hasselt TJ, Gale C, Battersby C, Davis PJ, Draper E, Seaton SE; United Kingdom Neonatal Collaborative and the Paediatric Critical Care Society Study Group (PCCS-SG).Arch Dis Child Fetal Neonatal Ed. 2024 Apr 18;109(3):265-271. doi: 10.1136/archdischild-2023-325970.PMID: 37923384 Free PMC article.
Sharma P, King B.Acta Paediatr. 2024 Jul 29. doi: 10.1111/apa.17361. Online ahead of print.PMID: 39073191 No abstract available.
HIP Trial Investigators; Blakely ML, Krzyzaniak A, Dassinger MS, Pedroza C, Weitkamp JH, Gosain A, Cotten M, Hintz SR, Rice H, Courtney SE, Lally KP, Ambalavanan N, Bendel CM, Bui KCT, Calkins C, Chandler NM, Dasgupta R, Davis JM, Deans K, DeUgarte DA, Gander J, Jackson CA, Keszler M, Kling K, Fenton SJ, Fisher KA, Hartman T, Huang EY, Islam S, Koch F, Lainwala S, Lesher A, Lopez M, Misra M, Overbey J, Poindexter B, Russell R, Stylianos S, Tamura DY, Yoder BA, Lucas D, Shaul D, Ham PB 3rd, Fitzpatrick C, Calkins K, Garrison A, de la Cruz D, Abdessalam S, Kvasnovsky C, Segura BJ, Shilyansky J, Smith LM, Tyson JE.JAMA. 2024 Mar 26;331(12):1035-1044. doi: 10.1001/jama.2024.2302.PMID: 38530261 Clinical Trial.
Yang JK, Su F, Graber-Naidich A, Hedlin H, Madsen N, DeSousa C, Feehan S, Graves A, Palmquist A, Cable R, Kipps AK.J Pediatr. 2024 Aug 29:114278. doi: 10.1016/j.jpeds.2024.114278. Online ahead of print.PMID: 39216620
Rivara FP.JAMA Pediatr. 2024 Sep 3. doi: 10.1001/jamapediatrics.2024.3288. Online ahead of print.PMID: 39226042
----
The transcript of today's episode can be found below 👇
Ben Courchia MD (00:00.598)
Hello everybody, welcome back to the incubator podcast. is Sunday, we're doing another episode of Journal Club and we have a bunch of exciting articles for you today. Daphna, how are you?
Daphna Yasova Barbeau, MD (00:09.484)
doing well. You know, I preparing for journal club is not always the easiest thing that we do. it's the hard it is it is definitively the hardest thing. But I missed it. I don't know why I feel like I feel like we
Ben Courchia MD (00:15.478)
The hardest.
Ben Courchia MD (00:22.124)
Yeah, because the last episode of Journal Club, had recorded a bit ahead of schedule. And so it's been a few weeks, I would say, since we actually got on to record Journal Club. So that makes sense. And we have an interesting episode today. We are going to be joined later on by Dr. Brian King, accompanied by one of the fellows at Harvard Medical School and Boston Church Hospital, Dr. Puneet Sharma.
Daphna Yasova Barbeau, MD (00:27.105)
That's right.
Yeah.
Daphna Yasova Barbeau, MD (00:36.428)
Mm -hmm.
Ben Courchia MD (00:49.278)
They're going to be giving their commentary on the recent trial that was published on the impact of timing of inguinal hernia repair on outcomes in preterm infants. was a very interesting trial that we already reviewed a couple of weeks back. It's been a while. So if you forgot some of these outcomes, then it's a great refresher. We recently actually just got around to reviewing it on the French podcast with Gabriel. So yeah, so this is good.
Daphna Yasova Barbeau, MD (01:05.996)
Mm -hmm.
Daphna Yasova Barbeau, MD (01:13.794)
And it's been very clinically relevant, right? Like in our units. Yeah, exactly.
Ben Courchia MD (01:16.232)
I mean, immediate application of that paper into practice. As this episode airs, we are about one week away from the Delphi Innovation Conference. It's a really exciting conference, people, like we're working really hard on an amazing lineup of speakers. So if you are in the area, please feel free to join us. And if you cannot make it, please reach out to us. There are opportunities to watch the conference virtually.
Daphna Yasova Barbeau, MD (01:25.026)
Mm -hmm.
Ben Courchia MD (01:46.249)
So yeah, this is very exciting. Don't forget to register, and especially for the people in person, like we're really getting close to being full and sold out. just be mindful of that.
Daphna Yasova Barbeau, MD (01:57.634)
Well, and actually, mean, anybody who wants to register virtually can just go to the website, the -incubator .org slash or backslash, backslash, backslash Delphi 2024.
Ben Courchia MD (02:01.612)
Yeah, for sure.
for sure.
Ben Courchia MD (02:09.622)
Yeah. All right. So I wanted to maybe take a different turn today with the Journal Club because I've been reading some interesting articles that are not the typical stuff I would usually read, but I think that are quite current when it comes to what's in the news. And the first article is something that was published two years ago, but it's a case report of neonatal monkeypox or neonatal pox infection.
Daphna Yasova Barbeau, MD (02:37.058)
Mm -hmm.
Ben Courchia MD (02:38.53)
I mean, it's been in the news. think it's coming up and down the trend and mention of Mpox in the news. think it used to be known as monkeypox. And I believe the WHO called it Mpox that people would not really think this is like a monkey disease and that this is also something that could affect humans. So, I mean, I'm to call it Mpox. But I was reading this paper and there was another paper in the New England about that I'm going to go over about reviewing some of these findings. And I thought this would be very helpful for Journal Club as people are trying to keep up with what's going on out there.
So this is a case report that's published out of the Imperial College in London. And I'm just going to go through the case so that we can go over this together. And then we'll talk a little bit about -pox. So this was something where obviously they mentioned that young children are at risk for a severe disease related to -pox and that early recognition and prompt treatment are obviously very important. Perinatally acquired -pox virus infection and adenovirus infection were noted.
in a baby that was 10 days old. And basically after an uneventful birth, there was a rash that developed on day nine of life. I will link the paper, obviously, in the show notes, but you will see the rash. is quite impressive and in my opinion, fairly, fairly typical. The rash was initially vesicular, starting on the palms and soles and subsequently spreading to the face and trunk and gradually became pustular. Nine days before the birth, the infant's father had a febrile illness followed by a widespread rash.
The rash resolved before the infant's birth and four days after the delivery, a similar rash developed in the mother. So and interestingly enough, and that's why I thought the case was interesting, the family lived in the UK, in the United Kingdom, and there was no history of travel to Africa or of any contacts with any travelers. So I think this is something that it feels quite relevant. So the infant eventually clinically got worse, so was transferred.
to the regional pediatric intensive care unit on day 15 for evolving hypoxic respiratory failure. And a number of diagnoses were entertained basically like neonatal varicella, herpes, coccyx, or enterovirus infection, staph, staphylococcal skin infection, scabies, syphilis, gonorrhea, et cetera. But they're mentioning that the presence of axillary lymphadenopathy, the nature of the skin lesions, and the atypical timeline of the intrafamilial infection aroused concerns for potentially human MPOX.
Ben Courchia MD (05:02.626)
So they did a PCR chain reaction of the blood urine and vesicular fluid and throat swabs. And they got from the baby, from the mother, and that led to the diagnosis of MPOX infection clad 2B. Adenovirus was also identified, of course. There's always something else in the infant's respiratory secretions and in the blood. And the infant condition continued to worsen, actually requiring intubation, mechanical ventilation. And eventually they gave the baby a two week course of
TECOVIRIMAT with a combination of CIDOFIVIR. After four weeks in intensive care, 14 days on invasive ventilation, the baby eventually recovered, discharged home. And they're basically sharing with us in supplemental material Q2, believe, the timeline of the infection of the entire family.
They mentioned obviously that this case of neonatal MPOX after peripartum transmission within a family cluster, that transpositional transmission can't really be rolled out. And that really MPOX should be considered, especially when you have that very typical vesicular rash. So I thought this was quite interesting. Just to review, mean, this is the things obviously that you're never really prepared for. And then in the New England, I don't know, in the past couple of weeks, there's been an article called MPOX in Pregnancy.
Daphna Yasova Barbeau, MD (06:13.974)
Mm -hmm. Mm -hmm.
Ben Courchia MD (06:23.816)
risks, vertical transmission, prevention, and treatment. The first author is Jean Nachega, and this is a paper that's coming out of a team in the US. And basically, it's a review of MPOC. So I'm just going to go over some of the notes that I took down on the paper. It's not very long, but it helps us summarize. believe that I was reading this with particular interest because I wouldn't be surprised, for example,
if a mother was diagnosed with MPOX and then suddenly they consult you in the NICU and they say, hey, what to expect and so on and so forth. Like I wouldn't have known. And so I thought, let me read a little bit about that so that I could be a bit more informed. some of the things I noted is that obviously they're mentioning the alarming surge in human to human transmission of MPOX infections, particularly in high risk sexually active and reproductive age populations, along with the known association between MPOX virus and
adverse obstetrical outcomes, there's a need to highlight the data that is available, as we just said, to enhance our understanding and mitigate the risk of .pox during pregnancy. .pox is a zoonotic disease caused by the .pox virus. It's a DNA virus of the orthopoxvirus genus in the family of the poxviridae and is closely related to smallpox, which we're all familiar with.
Now they're saying that there's two types of -Pox virus, right? And they're basically divided into clads. There's clad one and clad two. Clad one is actually more virulent. And there's a case fatality ratio that is as high as 10 % compared to clad two, which only has a fatality ratio that can go from zero to like 3 .5%. So very important to differentiate which clad you're dealing with. -Pox data from the Democratic Republic of the Congo
reported to the World Health Organization between January 1st and May 26th indicates that the case fatality ratio among children under the age of one is 8 .6%. So you can see that for children, the mortality rate is quite high. And in the case that we presented, the baby got quite sick compared to really 2 .4 % among people who are 15 years of age or older. And they mentioned that if...
Ben Courchia MD (08:40.312)
God forbid there's also a co -infection with HIV, the fatality ratio actually can be higher. So historically, EMPOX cases have predominantly arisen from a zoonotic spillover in central and West African country where the EMPOX virus circulates among wild rodents and non -primate host. In 2022, a human -clad 2B outbreak linked to sexual transmission led to global epidemic with a case fatality ratio of less than 0 .2%, primarily affecting men who are having sex with other men.
Recent reports have raised concerns about outbreaks of the more lethal EMPOX -CLAD1 in the Congo. And in 2023, more than 12 ,000 cases and 600 deaths were reported by the WHO. So EMPOX Research Consortium documented a substantial outbreak of 241 CLAD1 cases in Kamituga, a gold mining town in Eastern Congo, affecting a highly mobile population of migrant workers. I think another reason to think of how this disease can spread, obviously, with people moving back and forth between
the necessity to find employment. Genomic analysis identified a new mutation pattern in the isolated MPOX virus, now considered a distinct clad strain with the proposed designation 1B. Now, the median age of infection was found to be about 22 years of age. 52 % of patients were female, and it's quite prevalent in sex workers with an incidence of about 29%, again, highlighting that sexual transmission.
Now, there's alarmingly, there's infections that have now been reported in various countries in Africa, Rwanda, Uganda, Burundi and Kenya. And given this recent upsurge, the WHO declared mpox a public health emergency of international concern on August 14th. Historical data on smallpox during pregnancy, which again, we said is related to the mpox virus, reveals high rates of miscarriage, premature birth and maternal death.
When they're looking at 15, they were looking at 15 studies involving 830 pregnant patients with smallpox. 40 % had miscarriage or premature birth. And 1 ,074 pregnant patients in 16 studies, 368 died with a case fatality ratio of 34%. So it's very scary to deal with any virus related to smallpox, it looks like, during pregnancy. A 2024 systemic review of seven studies identified 32 pregnant women with clad
Daphna Yasova Barbeau, MD (10:42.55)
Wow.
Ben Courchia MD (11:02.776)
two B poxvirus infection, between six and 31 weeks of gestation, three of the 12 pregnancies with reported gestational outcome have resulted in intrauterine fetal demise.
I'm going to say that again. So of the 12 pregnancy with reported gestational age, gestational outcomes have led to intrauterine fetal demise. So like smallpox, -pox can be transmitted from mother to fetus with high viral loads. The potential for intrauterine transmission is further supported by data from non -human primates. There was a macaque model showed vertical transmission six to 14 days after infection followed by short followed shortly by fetal demise. The interesting question that remains is
What about breastfeeding? Like, is it a bit like HIV where we really have a big concern? And they're saying that transmission from breastfeeding mothers with MPOX to their infants can occur potentially by means of close contact. Whether MPOX is present in breast milk, it's not really clear. Breast milk from one MPOX infected woman tested negative for MPOX DNA on PCR. The outcomes were reported on three breastfeeding infants in studies of MPOX infected mothers. All infants were infected and one of them died.
So because of the broad cross immunity observed within the orthopox virus family, the WHO Strategic Advisory Group on Immunization recommends administering smallpox vaccine for -pox prevention. And that's what's been really mentioned in the news. And the problem with that is that there are only two potential vaccines. And the one that's actually available in pregnancy, there's some developmental toxicity studies that have shown in female rats and rabbits that there was no concerns.
for harm to the fetus, but there's no real human study that could potentially completely resolve these concerns about developmental toxicity. So that could be something that obviously parents might want to bring up and want to have a discussion about. The last thing I want to bring up before I wrap this up is obviously treatment. So in the US, the antiviral agent Tecovirimat is approved by the FDA for smallpox and is available for treating severe -pox under an expanded access investigational new drug authorization from the CDC.
Ben Courchia MD (13:10.328)
And although there's no pharmacological data related to pregnancy or breastfeeding in humans, there's no embryo toxic or teratogenic effect that were found when to take over. Matt was administered to mice and rabbits at doses that were very high, 20 times or more greater than what is the recommended human dose. Tico Vira Matt was detected in animal breast milk, but whether it crosses into human breast milk is actually quite unknown or whether it crosses through the placenta is not really known.
Because of the increased risk of severe disease during pregnancy and the possibility of severe infection in newborn, tecovirimat has been recommended in the US as therapy for MPOX infected persons who are pregnant or who are breastfeeding. In a study of 23 US pregnant women with MPOX, 11 received tecovirimat and no medication -related adverse events were reported, which is really, really good news. I'm going to wrap this up by talking about the POM007 trial, which sounds like such a James Bond type of trial.
in the Congo in partnership with the NIH and the National Institute for Biomedical Research in the Congo wants to evaluate the safety of tecovirimat and the efficacy in 600 children and adults, including pregnant women with laboratory confirmed pox virus. There was an NIH press release on preliminary results from this study that was published on August 15th. And it says that though the study didn't meet the primary endpoint of statistically significant improvement in the time to lesion resolution,
They said that there was no difference from the placebo to the placebo control group in terms of adverse events. So at the very least, they are not worse off. And they're saying additional analyses are planned and other trials are evaluating tecovirimat use in mpox in the US, Canada, UK, Switzerland, and Brazil, some of which allow enrollment of pregnant or lactating persons. So it's an active field. And I thought this was a great review of sort of this topic that has been in the news.
Daphna Yasova Barbeau, MD (14:58.806)
Hmm.
Ben Courchia MD (15:02.274)
God knows, maybe whoever's listening right now might end up seeing somewhere in their perinatal unit.
Daphna Yasova Barbeau, MD (15:05.644)
For sure. Now I really appreciate how thorough your review was. I know you're exhausted, but I mean, truthfully, I mean, okay. With rashes, vesicular always bad, right? But like our mind goes to some very specific path, know, pathologies, causative agents for vesicular rash, all of which are scary, all of which are dangerous, all require immediate treatment. But if you don't get the treatment right.
Ben Courchia MD (15:17.697)
Yeah.
Ben Courchia MD (15:28.172)
Mm -hmm.
Daphna Yasova Barbeau, MD (15:33.842)
I mean, the kid's not going to get better. And obviously the morbidity and mortality is high with this,
Ben Courchia MD (15:35.34)
Yeah. You might need to get your ID team involved. I don't want to speak out of terms here. But the Tecovirimat, I think you have to request it from the CDC. So your pharmacist is definitely going to tell you it's non -formulary.
Daphna Yasova Barbeau, MD (15:40.83)
I don't want to manage this Tico business by myself.
Daphna Yasova Barbeau, MD (15:50.187)
God, that's right. That's right. Can't put in that miscellaneous order.
Ben Courchia MD (15:56.906)
If your pharmacist has been stifling you for the IV Tylenol, they might be much nicer if you start asking for a takeover. might be like, I'll give you IV Tylenol, just leave me. All right.
Daphna Yasova Barbeau, MD (16:06.356)
As much Tylenol as you want. Yeah. Okay. All right. Well, on that note, on Tylenol, I have a paper not about Tylenol, but it does talk about Tylenol. This one's entitled, Don't Wait, Vaccinate, Evaluation of Routine Vaccination, Administration, and Reactogenicity in Preterm Infants. Lead author, Emily Abdelmese, and this is in the Journal of Perinatology. It's coming from Hassenfield Children's Hospital at NYU.
Ben Courchia MD (16:15.168)
Okay.
Ben Courchia MD (16:20.248)
Hmm.
Daphna Yasova Barbeau, MD (16:35.906)
Langone Health. So basically what happened is the group, the team, underwent a practice change in January 2021. So they went from administering, three, the, the, the three vaccine series on separate days to administering all three on a single day at two months postnatal age. Right. So I think this is a very interesting study. Admittedly, almost every institution I've ever been at
Ben Courchia MD (16:55.842)
Ho
Daphna Yasova Barbeau, MD (17:03.81)
does them over the course of Q12 to Q24 hours with concern for events, right? Some sort of cardiorespiratory events. So I thought this was an excellent paper to review. So it was a single center retrospective cohort study. It's a level four, December 2019 to September 2022. They included all preterm infants born before 37 weeks gestation that received the two month vaccines in the NICU.
Ben Courchia MD (17:08.247)
Mm -hmm.
Ben Courchia MD (17:12.696)
Yeah.
Daphna Yasova Barbeau, MD (17:33.346)
And then just to clarify the third three shot series, they do a combo DTaP, HEPB and polio. They do the pneumococcal and the Hib. Then to limit variation, patients were only included as the vaccine series was administered on the one day or the multi -day administration, but it had to be that the patients got one vaccine every 24 hours for three days. So for some reason the baby got
one vaccine, waited a week, got another vaccine, they weren't included. Okay, so then the patients were categorized either to the pre -practice change, so across three days, or those who were in the post -practice change are all on one day. Patients had to be quote unquote medically stable to receive vaccination and they use the AAP definition for medically stable, not requiring significant ventilator support or ongoing management for debilitating infection, metabolic disease, or renal cardiovascular
or respiratory instability and appear to be maintaining a pattern of steady growth. I actually thought that was a very nice definition of quote unquote medically stable. And then the outcomes they looked at, the primary outcome was the incidence of cardiorespiratory events. So they included prolonged apnea, prolonged bradycardia and other severe type events. They looked at time from initial vaccine administration up to 48 hours after the final administration.
The other outcomes they looked at were vaccine interruptions, a fever, incidence of sepsis workups, that required initiation of antibiotics, daily median of neonatal pain using the N -PAS scores, the need for a seed -administered administration within 24 hours of vaccination, respiratory support, incidence of enteral feeds being held for more than one day, vaccine interruption, and time to complete series.
So they had a total of 146 infants admitted to the NICU and eligible for the two month vaccines. They excluded 19 infants who were either too old or who did not receive vaccines on the correct regimen. And so they had 127 infants in the pre, what do they call it? pre, pre -practice change, the PPC, the pre -practice change. They had,
Ben Courchia MD (19:54.594)
They call it the pre -practice.
Daphna Yasova Barbeau, MD (20:02.21)
52 infants, in the post -practice, she had 75 infants. The population, was 48 % male, the median gestational birth, the median gestational age, was 28 .6 weeks and the, they were.
Ben Courchia MD (20:16.632)
Yeah, they were quite small. They didn't give it to like, they're not talking about like the 30 -weekers, they?
Daphna Yasova Barbeau, MD (20:22.186)
Right. Well, I mean, these were all babies who were now two months, you know, post postnatal age. So,
Ben Courchia MD (20:26.296)
Yeah. And they all had about like 50 % BPD almost.
Daphna Yasova Barbeau, MD (20:31.19)
Yeah, they had a moderate to severe group of infants. Very important, yeah. Because I think those are the kids you want to hold off on potentially. So infants in the pre -practice change group. So there were differences between the two groups, the two cohorts. So I'll just highlight those. In the pre -practice change group, they were smaller at birth, both by weight in kilograms and in length.
Ben Courchia MD (20:36.886)
Which, the purpose of answering this question, is great. if they were all like... It's exactly right.
Daphna Yasova Barbeau, MD (20:58.498)
Other baseline characteristics were similar between the groups except that more infants in the pre -practice change group also had a history of positive culture. So they were a little bit smaller and more likely to have had a positive blood culture. The median weight at the time of vaccination was 2 .59 kilograms and was not different between the two groups. Now at baseline, so the 48 hours prior to the vaccination, 26 infants,
had greater than or equal to one episode of apnea or bradycardia prior to the vaccination. There were nine in the pre -practice change group and 17 in the post -practice change group. So the post -practice change group was already having more events prior to their vaccination, but they went for it anyways. And then, so let's look at the outcomes. Out of the total cohort, 37%. That's a lot, I thought.
Anyways, had greater than or equal to one episode of apnea or bradycardia, 36 .5 % in the pre -practice change group versus 28 % in the post -practice change group, but this was not statistically significant. There were a total of eight episodes of prolonged apnea, 7 .7 in the pre -practice change, 5 .3 in the post -practice change, also not statistically significant. There were 40 episodes of prolonged bradycardia.
Ben Courchia MD (21:53.004)
Yeah.
Daphna Yasova Barbeau, MD (22:20.386)
That's 28 % in the pre -practice change group, 33 % in the post group, not statistically significant, and 18 episodes of severe events. 17 .3 in the pre and 12 % in the post, also not statistically significant. So I want to highlight that there were a number of events surrounding vaccination, but they were not significantly different between the two groups. The overall patient core...
cohort had a median end pass score of zero. There were no differences. The incidence of fever, number of patients on respiratory support, escalation of respiratory support, and median FI2 is not different between groups. I told you that infants in the pre -practice change cohort were more likely to have a sepsis workup done within the 48 hours of immunization, but there were no significant differences in sepsis workup after vaccination.
internal feeds were not held in any infants. That was great. The median time to vaccine series completion was five days in the prior to practice change group. and there was, a significant reduction in vaccine schedule interruptions, in the post practice change group. They looked at Tylenol, commonly used as supportive, care among the whole cohort.
30 % of the cohort received a one -time dose of Tylenol and 27 % received scheduled doses. There were significantly, a lot more. interesting. But you don't pre -medicate. Okay.
Ben Courchia MD (23:50.54)
It would have been higher for me. think I give I'm very I'm very loose with the title and I'll post vaccination.
Ben Courchia MD (24:00.906)
I don't pre -medicate, if there's a, I think I almost ordered PRN after the vaccine just so that, yeah, so that we have that.
Daphna Yasova Barbeau, MD (24:04.386)
Yeah, just to have, I see. There was significantly greater use of single dose Tylenol in the post -practice change groups, the kids who got them all at once, but no difference in scheduled Tylenol use. They looked at a univariate analysis to look at the predictors for severe events within the 48 hours of vaccination. Not surprisingly, predictors of severe events included younger gestational age, a smaller birth weight, smaller birth length,
and higher number of apnea or bradycardia events at baseline. So in conclusion, the study found that the single day administration of these routine two month vaccines to preterm infants, again with a median gestational age of 28 weeks, resulted in a shorter time of vaccine series completion with no significant differences in cardiorespiratory events.
Ben Courchia MD (24:56.79)
Yeah, I think it's interesting, know, because it might help alleviate some of the concerns that we have and that prevent sometimes the complete series to be done. Because if there's a mild event, but the parents obviously are, I these are parents that are basically getting over the hump of the of the hospitalization. And if God forbid they have one shot and the kid needs a little bit of nasal cannula, the parents have this, they have this PTSD of like, my God, we're going backwards.
Daphna Yasova Barbeau, MD (25:06.593)
Mmm.
Daphna Yasova Barbeau, MD (25:12.706)
Mm -hmm.
Daphna Yasova Barbeau, MD (25:16.492)
Mm hmm. They're done. Yeah.
Ben Courchia MD (25:22.442)
And guess what? They will not sign consent or approve for the rest of the series. And so.
Daphna Yasova Barbeau, MD (25:27.708)
Yeah, and I imagine this is, and I think there's data to support this, but it probably changes their opinions about vaccinations long term, right?
Ben Courchia MD (25:37.024)
yeah. And I think that at the very least, if you do it, if the number of events are relatively the same between the two groups that they presented, and it gets you to complete the series, and then maybe there's an event or not, doesn't really matter, but at least the series is complete. Yeah, that's a good, that would be kind of nice.
Daphna Yasova Barbeau, MD (25:46.774)
Mm -hmm.
Daphna Yasova Barbeau, MD (25:51.242)
It's over with, right?
All right, boss, you had to tell us if we're making a practice change in our head.
Ben Courchia MD (25:56.842)
Alright.
Ben Courchia MD (26:01.27)
Well, I'm almost ashamed to say this, but basically in the paper that we just talked about, they're using the PDRX. I don't have any ties to PDRX, but they have this three in one shot. And we recently were told that this was not available. Yeah, so basically the PDRX for us has become three separate shots. And I don't have the heart to subject our babies to whatever that is now. has five shots for our kids, six shots. It's insane. So if.
Daphna Yasova Barbeau, MD (26:07.243)
Mmm.
Mmm.
Yeah, was a shortage, yeah.
Daphna Yasova Barbeau, MD (26:19.703)
Mm -hmm.
Daphna Yasova Barbeau, MD (26:23.5)
Mm -hmm. Yeah, it's off.
So we're working on that. That's what we're busy doing. All right.
Ben Courchia MD (26:31.094)
Well, yeah. OK, so maybe we'll take a quick break now, and then we'll come back with Brian and Puneet right after the break to talk about the paper on inguinal or hernia repair. Sounds good?
Daphna Barbeau (00:05.651)
Okay, for our EB-Neo segment today, we are so grateful to be joined by Dr. Brian King, neonatologist at Beth Israel Deaconess Medical Center and the social media lead for EB-Neo, and Dr. Puneet Sharma, a third-year fellow at the Harvard Neonatal Perinatal Medicine Fellowship. You can follow Dr. King on X with the handle at Brian King Neo. They will be reviewing the effect of early versus late inguinal hernia repair and serious adverse event rates in preterm infants.
a randomized clinical trial, which was published this year in JAMA. Thank you both so much for joining us today.
Puneet Sharma (00:39.935)
Thank you, Daphna, for inviting us on and giving us a chance to talk about this really great study.
Brian (00:47.826)
I'm glad to be here.
Daphna Barbeau (00:49.453)
Perfect. Well, I'll let you get started. Give us the basics. Tell us what is going on in this study.
Puneet Sharma (00:56.521)
So essentially the core question that the study was hoping to address is, and preemies born less than 37 weeks who have inguinal hernia repair diagnosed during their NICU stay, does repair before going off from the NICU when compared to repair after NICU discharge lead to differences in adverse events that the child experiences in the immediate 10-month follow-up period after the surgery itself? So essentially it was a multi-center randomized clinical trial that the primary intervention was either
prior to discharge versus repair after discharge. And they really first randomized the children about two weeks prior to their anticipated NICU discharge. And either those that were in the quote unquote early repair group, the prior to NICU discharge group underwent repair of their inguinal hernia at an appropriate time course and developed by the clinical team. Or in the late repair group, they waited till after NICU discharge and preferentially till after 55 weeks corrected post-menstrual age. And what they were hoping to really assess from our primary outcome.
point of view was the proportion of infants with at least one serious adverse event in the 10 month follow-up period afterwards. And they had a whole host of adverse events, but they categorized them into specific categories. There was either pulmonary events, cardiac events, surgical events, events specific related to the hernia like incarceration, et cetera, or of course death being a serious adverse event. And the secondary outcome they were interested in was the number of days in the hospital led to. So it's obviously a little bit different because you're talking about
staying in the NICU versus a discharge home and then additional days after that. They just wanted to look at the absolute number of days in the hospital between the two different groups. So they looked at a period of between September 23 and April 2021, and they essentially randomized the eligible infants in a one-to-one ratio. Obviously, blinding wasn't really feasible because we're talking about different timing of interventions, but when they assessed the serious adverse events in both groups, those...
committee that assigned that was blinded to which group the child was in. But obviously the proceduralists knew when the procedure was being performed. And then in addition to the 10 month follow up period for the primary outcome, they're still undergoing their long term follow up at two years of age at this point. So essentially, the authors hoped to initially enroll about 615 infants. And where that came from was they were hoping to get 80% power to detect their
Puneet Sharma (03:19.029)
early repair group would have about a 10% higher adverse event rate than the late repair group. So that's where they got the 615 infants, assuming about a 5% loss. But interestingly enough, this study was actually, enrollment in the study was actually stopped at 50% enrollment because they found a pretty significant difference, a 97% probability of decreasing rate of severe adverse events in the late group versus the earlier group. So at that point, they had previously determined a 95% threshold for stopping the trial. So
they did stop the trial. So only 330, 338 infants were randomized instead of the initial plan, 615. And despite that, about 308 of them were included in the primary analysis. So they had about 91% of the initial and randomized group in the primary analysis. And ultimately, what the structure of the study is, I kind of let the cat out of the bag a little bit when I talked about the early stop rate, but essentially they found that delayed.
repair group did have increased events. So for the primary outcome, I'm sorry, the late repair group had less adverse events. In the primary outcome for the late group, only 27 of the 149 had adverse events, and then 44 of the 159 of the early repair groups. That's a difference between 18 and 28 percent, which is a relative risk of 0.68. And as I alluded to, the posterior probability of benefit of primary outcome was 97 percent, so that's why they ended up stopping it.
just to fill up a little bit more of the kind of information about the results. So the population was primarily male. It was 86% male and the median birth weight of the patients were 820 grams. And they're really between the early repair and the late repair group. There was no significant difference between the two other than the early repair group had slightly more apnea requiring intervention. Um, but also notably the early repair group has by the design of the study was younger and smaller essentially. So.
The PMA at repair for the early repair group is 41 weeks and the weight was 3.1 kilos, versus the late repair group is 57 weeks, which is the goal to be after 55 weeks, and the weight was correspondingly 5.9 kilos. So also as such, more of the early repair group was done laparoscopically and the procedures were therefore shorter just because of the technical difficulties from a smaller infant versus a larger infant.
Puneet Sharma (05:37.817)
And then the secondary outcome, which I kind of alluded to, is that the median number of days in the hospital was actually also longer for the early repair group than it was for the late repair group. So it was 19 days in the early group versus 16 days in the late group. And that computed a 82% posterior probability of benefit for the late repair as well. And interestingly, when they did the subgroup analysis looking at two specific vulnerable populations, we think of in the NICU, the BPD, and the less than 28 weeks population.
the effect was actually magnified to the effect. So that it showed that there was even more benefit for late repair in those groups than there were for infants older than 28 weeks who did not have BP diagnosis. So in conclusion, the study showed that in preemptive infants with inguinal hernia, late repair led to less advanced, a serious adverse events. And it also led to less stays in the hospital as well. That was magnified in those two vulnerable populations I talked about. So, you know, I found the study
really quite compelling. I thought it was extremely well designed and very thoughtful. And it's obviously something we think about a lot in the NICU, just because there is a lot of competing concerns around the timing of surgery for neonates. There's obviously the anesthesia risk that we try to minimize in any neonate, but especially the vulnerable patients we care for in the NICU. But there's also, you have to balance that with the potential risk of things like incarceration if you wait too long to repair the hernia, which obviously is something we would want to avoid to try to protect Bowen overall.
health as a child. So it really kind of brings me to the point, and I'd love to kind of have Brian hop in a little bit as well, which, you know, it's very clear conclusion, very well designed study. But one of the things that they use is an outcome, which is not unique to the study. We do a lot in NICU research is the use of a composite outcome. So essentially these serious events, serious adverse events, is a big umbrella term. And that really fell into a lot of different things that, you know, depending on the context could be.
different clinical significance, but also could have different potential meanings for the families as well. Mathematically, I guess you could say that they fit an equivalency of any of all of these adverse events, but you could argue that one of the adverse events being incarceration or another one being acne requiring intervention may not have the same clinical significance to a population. So it's just something that we found, it's kind of a necessary thing we do in NICU research, but something that provided a little bit of interest. And we thought about...
Puneet Sharma (08:02.021)
maybe there's a better way to kind of represent some of these composite outcomes in a way that risk stratifies or kind of gives a hierarchy, so to speak, on the clinical importance of that. And really one thing we looked to was a recent group did the essentially door is what it was called or desirability of outcome ranking to kind of assess the situation. So the katheria at all did.
in the umbilical cord milking study, a similar approach to their composite outcomes. So we found it would be kind of interesting how that would look like in this study, given the kind of differences in the, in the overall adverse event. Right. But I know Brian, if you had any specific, uh, thing to contribute regarding that.
Brian (08:46.11)
Yeah, I think you mentioned at one point the anesthesia risk and incarcerated hernia. I think if you really asked why was this study important, it was because of those two key competing risks, and the long-term risks of anesthesia. Like anesthesiologists say, wait six months to do elective surgeries for babies. And so there's that risk. But then if you wait six months, are you going to have incarcerated hernias where you have very serious injury?
Daphna Barbeau (08:58.035)
Mm-hmm.
Daphna Barbeau (09:01.392)
night.
Brian (09:14.454)
Those, that's the two outcomes that are competing that I think we all really care about. I think the problem here is that the majority of the composite outcome wasn't those two things, necessarily, you know, the most frequent adverse event, as you mentioned, was AFNI requiring intervention and by and large, the most frequent event. There are 28 out of the 44 babies in the early group had a AFNI requiring intervention and nine out of the...
27 in the late group had an apnea requiring intervention. And yet when you look at table one, 80% or so of both groups had these prior to enrollment. So these are kids who've already had apneas requiring intervention, they've had more. Do we know that that's really clinically significant? It may be, there is work being done about the burden of apneas and the burden of desaturations long-term, but if these are babies that have been having them frequently in the hospital,
and have had them again now because they've had surgery, that may not mean nearly as much as a baby who had incarcerated hernia, or two or three babies in the late group had cardiac arrest. Those are outcomes that truly matter. So this DOOR approach, which as you mentioned, a new sort of applied as a sort of a secondary analysis post-hoc to his milking trial, I believe it was, basically ranks these, right? It says, what's most important?
and apply a higher favorability to those. And you can even go so far as to ask families what's most important and say, what's the most important thing that you want to avoid? We'll count that as number one and then we'll do second and third and fourth. That's that desirability component to it. Because I do think you may get different results. You may not because I think another important outcome that
Daphna Barbeau (10:48.307)
Mm-hmm.
Brian (11:09.282)
the study identified, which they mentioned briefly in the discussion, and you can see in the flow sheet is how many babies actually had a resolution of their inguinal hernia, right? So by waiting, you actually avoid surgery in a decent number of patients, which I think if you ask families, what's the best outcome you could have want from your baby in terms of an inguinal hernia, it would be to not need the surgery at all. And 11% of them in the late group didn't need surgery versus 4% in the early group.
Daphna Barbeau (11:30.794)
Mm-hmm.
Brian (11:39.478)
So that right there is an outcome that is highly desirable probably to families, would be to not require surgery at all. I think the other issue with the composite outcome is it's these events were during the whole 10 month period, right? Which also makes you wonder like, okay, the AFNI requiring intervention, how many of those were even related to surgery? Or were these events that required enrollment? It happened, I think, one to two weeks before discharge. Maybe some of these babies just had another A and B before going home.
Daphna Barbeau (11:58.724)
Mm-hmm.
Brian (12:07.658)
And that gets counted as an adverse event for the study. So the challenge of course, is if you've got rid of all these more common events, you end up with a much rarer outcome needing to enroll many more babies. But that's why I think some of these more novel techniques might be able to kind of bridge that gap. And I think we'll see probably more studies applying it as we move forward. It's just going to take some time lag to catch up.
Puneet Sharma (12:32.173)
Yeah, good.
Daphna Barbeau (12:32.615)
Well, I think that speaks to how the community is changing about what's important, I mean, to us as a community, but like you said, especially to families. I think that's great.
Puneet Sharma (12:45.413)
I was just going to say it would be very interesting as Brian kind of alluded to, and you kind of alluded to Daphne, about how the paradigm might change going forward with these kinds of composite outcomes and not only approaching this more outcome ranking methodology, but what input does the family put into that output, that outcome ranking methodology? Is it determined by just the clinicians or is there an input from the enrolled family members as far as what do they feel is more important or not for their child?
Daphna Barbeau (13:12.347)
Yeah, I appreciate that. I'm hoping you guys can speak a little, oh, go ahead.
Brian (13:14.662)
One of the, I was going to say what in terms of family preferences, et cetera, one of the other things that we talk about in our commentary is the, one of the exclusions for participation was families not being able to reliably follow up for the surgery. And I think it makes sense from a study standpoint to exclude those patients, but that does sort of bring in that element of
of equity here, like what is the right approach for the babies versus what is most feasible for families. And obviously, that's going to vary depending on where they're located, how far away they live in the hospital, all these sorts of things, which I think is another really important element to this study.
Daphna Barbeau (14:00.615)
Thank you for that. As kind of an educational point, I'm hoping you can speak a little bit to stopping trials early, like occurred you alluded to in this trial, since they met the pre-specified Bayesian stopping rule for effectiveness.
Brian (14:17.682)
Yeah, I think most trials have these sorts of interim analyses, and it's very ethical, and it's the right thing to do to set up sort of pre-specified stopping rules, both for benefit or harm. Oftentimes, we see stopping rules meant for harm, like the sustained inflation trial, but here for benefit. I think my...
Brian (14:45.842)
I think what's unfortunate here is that what was met was a pre-specified stopping rule for a composite outcome that again, as we've been talking about, may not be the most clinically relevant across the board. And of course, enrolling more babies would have allowed us to tease out, I think the secondary outcomes a bit more, like the individual adverse events, right? If they had really enrolled twice as many babies, we would have had...
a bit more certainty if we wanted to play around with, you know, how many incarcerated hernias do you avoid, et cetera. Whereas here the numbers are just get to be so small. Many of the, if you exclude apneas requiring intervention, pretty much, you know, and then prolonged intubation had six babies, you very quickly get down to events that happened one or two times per group, which just makes it really hard to, you know, tease things out. And obviously enrolling more babies would have, would have helped to tease that out. But I think when you set up the composite outcome as the primary
then you have to follow that. And if you meet the stopping rule, then you stop appropriately.
Daphna Barbeau (15:48.399)
Yeah, and to your point, I'm not sure we mentioned, I think a lot of people are interested in what was the incarceration rate. So that was two in the early inguinal hernia repair, 1.3%, six in the late inguinal hernia repair, 4%. But yeah, I wonder if we had more babies, what would we have seen? Very interesting. And I guess my most important question is how do you think this will change practice then?
Puneet Sharma (16:17.893)
It's a great question. You know, it sounds like I'm in a very unique space in my training career experiences. An outgoing fellow, soon to be brand new attending where I've been thinking a lot more about not just this study, but...
in general, how it would change my own individual practice. And yeah, my immediate response is that I would probably put a little bit more preference on trying to not do repair unless it felt, you know, completely immediately necessary at the point. But I think it's a lot more of a complex decision than just, oh, the children, if we wait, have less virtuous events than not, as we've kind of been talking about. And I think there is a really, really real, patient basis, per case basis analysis that would still need to be done where
If this is a family that has a hard time, you know, follow up or if this is a family that is a referral from out of state or whatever the circumference may be, or if there's a real financial difference to continue, you know, one or two more days in the NICU from their first admission versus a readmission and surgical thing, I think I'm not so moved by the difference in adverse event rates that I would say absolutely not. We have to delay every single angle on hernia repair. And I think there is a room for us to kind of...
don't inform families and take a case by case basis.
Daphna Barbeau (17:34.55)
Brian, any thoughts?
Brian (17:34.634)
Yeah, I think I agree. Yeah, I think, I mean, these discussions were probably already starting with the families and I think they're going to continue to start with the families about what makes the most sense. I think it's helpful to have data to frame that discussion. For me, honestly, I think the two numbers that would stick out the most when I talk to families would be that incarceration risk versus the spontaneous resolution risk. And I actually think those are the ones that I would like, maybe sometimes even specifically mentioned. Like, look, we...
We know from this study that there's a 4% chance of incarceration. If you go home with the incognito hernia, these are the signs to look for. However, there's an 11% chance that maybe it resolves on its own prior to needing surgery and you wouldn't need to have a surgery. And those are still competing risks and benefits to both of them. And then also add in, as Puneet was saying, the elements of like, depending on where they live relative to the hospital and what their transportation needs are like,
Some families are just done. If it's a four or five month hospital stay, they might say, hey, yeah, like, yes, it's going to keep us three more days, five more days here. But then when we're done, we're done. And other families will weigh things differently.
Daphna Barbeau (18:47.963)
And how do you think this changes things for babies who do have a really prolonged hospital stay? You know, what marker do we use in terms of timing for them?
Puneet Sharma (19:02.269)
It's a good question. I mean, the study investigators used kind of two weeks prior to anticipated discharge as the point of randomization, which as we all know, anticipated discharge and actual discharge can often be very different things. I think there's a serious conversation where it needs to be had as far as
If this is going to keep a child who's been in the hospital for five months, three more days, like the difference in length of stay to do it now, and then that family doesn't have to follow up versus if the child is there briefly, then maybe it makes more sense to wait till after discharge. Ultimately, I don't know if I have a great answer to that question. I'd be interested to see what you think, Brian, as far as how it would affect your thought process.
Brian (19:46.666)
I don't know if this is capturing exactly what you're asking, Daphna, but I think the other thing that we talk about in the commentary that we wrote was, which we've kind of alluded to, which is sort of a health insurance issue here, which is cost sharing that families have to participate in for their hospitalization. And you know,
It doesn't take very much for a NICU hospitalization to reach. We don't like to talk about this a lot, but I think it's important to talk particularly around what the family experiences. And for most families and most health plans that have an out-of-pocket maximum, it doesn't take a lot of NICU days to reach that out-of-pocket maximum. And then at that point, everything else in the hospital stay, they don't, every day that they stay, society is paying money to keep them in the NICU, but the family do not pay more out-of-pocket.
Daphna Barbeau (20:34.963)
Mm.
Brian (20:40.042)
And so when you have these long hospital stays, you know, that added three to five days. Yes, that costs us all sort of in a societal way, but the individual family may not pay out of pocket. However, if you tell them to go and come back and they're coming back six months later. Right. And most plans, you know, out of pocket maximums reset every year. So if this baby gets discharged in November and they're out of pocket maximum resets in January, you may be asking them to come back for a new hospitalization that while short.
Daphna Barbeau (21:03.527)
Hmm.
Brian (21:08.414)
might incur a fairly substantial cost sharing component. 20% is a common rate, like cost sharing for inpatient hospitalizations. So if that baby stays for the inguinal hernia for a day or two, they're paying out of pocket again, versus if they had stayed and did it before discharge. There's obviously a lot more nuance to that, depending on where you are and different Medicaid plans, if families are on Medicaid, but I think...
This study really highlights this interesting difference between what might be beneficial to society or cost-effective to society. That's what the secondary outcome is really kind of trying to get at, I think, is fewer total hospital days implies lower costs as a surrogate, right? But this may be a situation where the cost-benefit to society is different than what families experience. That we may be saying, hey, this costs less. To us all.
Daphna Barbeau (21:49.043)
Mm-hmm.
Daphna Barbeau (21:55.649)
Hmm.
Brian (22:07.69)
as a society because the babies will be in the NICU less, but you may pay slightly more out of pocket. And if that's the case, right? I don't think it's fair to be putting that burden on families to be like, it's beneficial to society, but you get to pay more. Which I don't know if this study had a pre-specified economic evaluation of, but I think this is a really important element is the perspective that parents experience in terms of.
Daphna Barbeau (22:27.849)
Mm-hmm.
Brian (22:36.687)
what an acute state costs to them.
Puneet Sharma (22:39.228)
Yeah, I think not all.
Daphna Barbeau (22:39.791)
I think that's such an important point, especially given our current system. I wonder for some parents or some infants, it will really prolong that time to surgery if they maybe can't pay for it. It's an interesting concept.
Brian (23:00.446)
Yeah, they might hesitate to come back.
Daphna Barbeau (23:04.343)
Mm-hmm. Puni'i we're going to say.
Puneet Sharma (23:05.781)
Oh yeah, I was just going to say, just to kind of summarize exactly, not all hospital days are created the same. And I think, you know, we often use it like Brian was saying, as a surrogate, as an absolute number that 16 is less than 19, therefore the benefit is improved. But what kind of hospital day are we talking about? Are we talking about the readmissions that Brian has alluded to? So I think it's just important going forward, not just for this study, obviously, but for any kind of consideration of length of stay as an outcome. Does that mean?
Daphna Barbeau (23:12.463)
Mm.
Puneet Sharma (23:32.173)
multiple states, does that mean just one state in a different duration?
Daphna Barbeau (23:38.203)
And just as a clinical tidbit, you know, I like to think about the outliers. That's the opposite of what we do in research. I wonder if there are babies that you don't think we can apply the data to.
Puneet Sharma (23:53.701)
You know, one of the populations they excluded, which obviously is, you know, the nature of the design is all the infants that had an inguinal hernia repair as a secondary procedure to another procedure. So going through your trach, and then you're going to get your hernia repaired then, or going through your G-tube and getting your hernia repaired. I think that's a, that's a major population that obviously we can't translate the results of this study to direct, you know, it's honestly in my limited
clinical experience, a lot of the inguinal hernia repairs I see in the NICU are usually that degree of kind of, oh, he's going to the OR, she's going to the OR for X, Y, and Z procedures. So while we're in there, we can go ahead and just close up that hernia. So I think at least from my initial review, that was one population that stuck out to me as far as those add-on surgery patients.
Daphna Barbeau (24:46.368)
Brian, any thoughts?
Brian (24:47.95)
Yeah, I'm just, as he's talking, I'm even looking through again. I think it's honestly for this question is a, it's a pretty representative population, I think. I mean, obviously, if you know if it's a less premature infant with an inguinal hernia that may, if you're talking about a 32 week or with an inguinal hernia, that may be a slightly different element, element there. But I think
I think they captured it well. The biggest exclusion for me is that population of people who they identified as unable to follow up or weren't going to be able to follow up. And that's a bit of a black box for me. It is a bit about like who is in that group. And you almost think like, you know, if this truly is the beneficial decision to like do a late repair, that shouldn't be a barrier, right? That should be an opportunity for us.
to find ways to help these families to give their child the same outcome and same benefit of anyone else.
Daphna Barbeau (25:51.815)
This was excellent. Thank you both so much. Dr. King, Dr. Sharma, it was lovely having you on.
Puneet Sharma (25:59.369)
Thank you so much, Daphne, for having us.
Brian (25:59.618)
Great to be here.
Ben Courchia MD
All right, and we're back. It's always pleasant to have our friends at the eBneo team. They're doing such a good job. like I always say, the senior level at eBneo are super nice. They're really good people to connect. If you are a fellow, you should sign up for one of these commentaries because it is such a good experience. Number one, and I'll leave the best part for last, obviously, number one,
Daphna Yasova Barbeau, MD (27:10.326)
Mm -hmm.
Ben Courchia MD (27:16.3)
You'll get to work on reviewing a paper quite critically. You'll get paired with one of these EBNEO guys. It could be Brian that we just saw. It could be Dr. Abdul Razak. It could be Ravi Patel. You never know. So you might get paired with a very interesting mentor to work with. You'll get to write your paper.
Daphna Yasova Barbeau, MD (27:32.107)
who really understands the workup of a paper. Such a good exposure.
Ben Courchia MD (27:36.918)
Yeah, and you'll get to write that commentary. It will get published. So that's kind of like, like that's a publication and you know, and fellowship, how important these publications are. So that's a publication. And guess what? And you get to come on the podcast and talk about what you wrote. So. This is my favorite part. I'm going to go for this next paper to the Journal of Perinatology, a paper out of Canada that I thought was quite interesting.
Daphna Yasova Barbeau, MD (27:40.47)
Mm -hmm
Daphna Yasova Barbeau, MD (27:44.758)
Mm -hmm.
Daphna Yasova Barbeau, MD (27:48.802)
Which is our favorite part.
Ben Courchia MD (28:01.154)
called prevalence of iron deficiency and extreme preterm infants at four to six months corrected age despite prophylactic iron supplementation. I must say that most of the papers we're reviewing today you can see basically caught our eye with a very good title. I really liked, I think my favorite so far is the one that you just presented earlier, Don't Wait, Vaccinate. That's kind of a good one, but yeah. So.
Daphna Yasova Barbeau, MD (28:13.9)
Mm -hmm. Mm -hmm.
Mm -hmm.
Ben Courchia MD (28:21.836)
The background, is by Hudson Barr and colleagues. It's coming out of Canada, as I mentioned, iron deficiency during early infant infancy we know has adverse impact on the Neurodevelopment and behavioral outcomes of young children. Now, preterm infants are particularly vulnerable to the development of iron deficiency due to number one, lower iron reserves at birth due to their rapid growth and due to frequent blood draws. That's a board questions. If you're subscribed to the Neonatology Review Podcast, this is something we go over, but these are...
Good things to remember. Another example of how in these papers you can have great tidbits. Now the group of investigators that we're talking about here in Canada reported already in a different paper that one third of very preterm infants, those born before 31 weeks of gestation, develop iron deficiency by six months of age despite prophylactic iron supplementation.
So we can go and review that paper. But this study specifically wanted to establish the prevalence and risk factors of iron deficiency in extremely preterm infants. So this was a retrospective cohort study that's conducted based on population -based provincial perinatal follow -up database that basically they have in Nova Scotia. And they looked at this database from 2005 to 2018. They excluded babies with congenital malformation, chromosomal issues, or blood disorder. All eligible infants were the ones who received iron supplementation.
either between two and four milligrams per kilo per day, starting at two to four weeks of chronological age in accordance with the recommendations from the Canadian Pediatric Society. Now, for the babies who are on formula, what they did is that the dieticians from each team took into account the iron content that was present in the formula and calculated whatever supplemental iron dosage was needed. The iron supplementation dose was further adjusted to
potentially a max of six mg/kg/day per day based on serum ferritin levels during the hospitalization. Discharge instructions that they give to parents, especially those who are still on iron supplementation, was to continue iron prophylaxis until nine to 12 months corrected age. At four or six months corrected age, hemoglobin and serum ferritin levels were measured again in all the infants.
Ben Courchia MD (30:32.728)
The iron deficiency was defined as having a serum ferritin level that was less than 20 micrograms per liter at four months or less than 12 at six months. So I'm going to go into the results. They included 146 infants in the study. And the prevalence of iron deficiency anemia was 45 .9%. So it's quite impressive.
When they did the analysis between the kids who had iron deficiency anemia versus not, they saw some significant differences between the two groups. The mean serum ferritin values was 16 .4 for the iron deficient group compared to 50 for the non -iron deficient group. The mean reticulocyte value was 28 .4 picogram for the iron deficiency group versus 31 .6 picogram in the non -iron deficiency group. This was significant.
Now the reasons that I really want to get to and that's sort of the crux of this paper is that breastfeeding or exclusive or partial compared to formula fed alone at four or six months corrected age was identified as the only significant factor in the final analysis of this study that was protective for iron deficiency anemia. And what I mean by that is that 54 % of formula fed extremely preterm infants were iron deficient compared to
Daphna Yasova Barbeau, MD (31:44.194)
Wow.
Ben Courchia MD (31:52.408)
21 .6 % of breastfed infants. was not... I was thinking the opposite. I would have thought the opposite. And it's interesting because exactly what you said, the heuristic that we have right now that we're thinking of is probably the reason why this is happening. So I'm going to go through a bit more results and I'll talk about what the discussion really focuses on. The mean growth rate for breastfed infants was 24 .3 grams per day compared to 23 .4 grams per day in the formula fed infants. Basically, this was the same.
Daphna Yasova Barbeau, MD (31:55.468)
Wow, because we don't usually think that, right?
Ben Courchia MD (32:20.152)
While iron therapy at follow -up was also protective for iron deficiency in the univariate analysis, it was not significant in the final model of the multivariable analysis. Interestingly enough, iron therapy was discontinued in 27 % of extremely preterm infants before the follow -up at four or six months corrected age. And there was a notable difference in supplemental iron intake between feeding methods. So exclusively formula fed infants had a lower intake compared to breastfed infants. Yeah, we're getting to that. Of note,
Daphna Yasova Barbeau, MD (32:46.102)
Hmm.
Ben Courchia MD (32:49.538)
They're saying that iron deficient infants had a higher incidence of mother with gestational hypertension. And this condition, didn't remember that. Maybe I knew that at some point, but I didn't remember it when I read the paper that said this condition has been associated with basically lower serum ferritin levels at birth in these infants, thereby increasing the risk of poor iron store. They're saying that the explanation behind the association regarding gestational hypertension and worsening iron deficiency anemia,
is the relationship maybe due to elevated maternal level of hepcidin during pregnancy. And we know that hepcidin is basically this molecule that is supposed to regulate your iron stores, actually bring them down. so that elevated hepcidin levels have been previously associated with an increased prevalence of infant iron deficiency anemia, and that this elevation can impair the iron absorption during the first year of life, thus promoting iron deficiency. I know.
Daphna Yasova Barbeau, MD (33:43.02)
So interesting.
It's just a wealth of information today. Board review prep tips here.
Ben Courchia MD (33:48.824)
I know. But sometimes you read these brief communications from certain journals, and they're so packed. You're like, how come is that a brief? You should have given them more word count for these people. They're so good. So they're saying that in summary, iron deficiency continues to be a significant issue in extremely preterm infants. Despite the iron supplementation, they said that iron therapy in formula fed infants is a challenge.
Daphna Yasova Barbeau, MD (33:57.322)
Yeah, right.
Ben Courchia MD (34:13.598)
owing to the lack of understanding on the exact iron requirement of extremely preterm infants and the current variability in the preterm iron therapy recommendations by different pediatric bodies. Basically, what they're saying is that it is very possible that because everybody sort of assumes that there's some iron in the formula, iron supplementation, you may feel like is not as needed as in breast milk, where everybody's being told, you really need to supplement the iron, and that some people may stop the iron supplementation earlier in babies who are formula fed.
Daphna Yasova Barbeau, MD (34:29.462)
Mm -hmm.
Ben Courchia MD (34:42.572)
thinking that there's enough when in truth there's not enough and that maybe it's not that the breastfeeding infants get more iron from the breast milk, but maybe there's more awareness of the fact that they will definitely continue to need iron and so that continues to remain supplemented. And so they're saying that iron deficiency is a modifiable risk factor for neurodevelopmental delay in extremely preterm infants and an immediate attention is important to improve the neurodevelopmental outcomes of these infants.
Additional research to accurately define the specific iron needs, etc. etc. is imperative.
Daphna Yasova Barbeau, MD (35:16.395)
Okay, very helpful. All right, so it might be our fault, some of these findings. So we got to keep that in mind, I think.
Ben Courchia MD (35:17.184)
Yeah. Mm -hmm.
Ben Courchia MD (35:22.813)
I think it's our fault from the, if we had to blame it, because I want to give a little bit of the blame to the outpatient pediatricians as well.
Daphna Yasova Barbeau, MD (35:32.511)
Just to assuage our guilt a little.
Ben Courchia MD (35:33.816)
No, yeah, what happens after they discharge kind of falls on the community petitions, but I think we could do a better job at giving better anticipatory guidance at the time of discharge for sure, telling them that this is something they'll need probably for the coming 12 months at the very least. Yeah.
Daphna Yasova Barbeau, MD (35:42.272)
That's right.
Daphna Yasova Barbeau, MD (35:51.106)
Okay, I had a paper, I'll try to go through this one quickly from the archives. Pediatric intensive care admissions of preterm children born less than 32 weeks gestation, a national retrospective cohort study using data linkage. Lead author, Tim Van Hasselt. This is coming from the UK on behalf of the United Kingdom Neonatal Collaborative and the Pediatric Critical Care Society study group. So basically,
They took a linkage of these two major databases, the National Neonatal Research Database and the Pediatric Intensive Care Audit Network, the PCAN net and the NNRD. And they were on to look at the kind of cross -reference of these patients. So to look at the risk of and risk factors associated with admission to the PICU after neonatal discharge for babies born at 22 to actually 22 to 31 weeks gestation.
They didn't even include babies that are in that kind of 31 to 36 week gestation, which I thought was interesting. So they identified all babies born less than 32 weeks gestation from January 2013 to December 2018 and admitted to neonatal care in England and Wales. I mean, I love being able to say that sentence for so many of these papers. Like when you can look at all of the babies born in your country, I think that's a nice feature to have.
Ben Courchia MD (37:15.874)
nice
Daphna Yasova Barbeau, MD (37:19.778)
And all babies born in this gestation should have received neonatal care and though they were anticipated to have NNRD data. They excluded babies born in less than 22 weeks and whose neonatal emissions were recorded as occurring after day one. I'm not sure what happened to all of those babies, but it's okay. Each child was followed up until two years of age to investigate if they were admitted to the PICUs in England and Wales during that time.
So they basically looked at kids who were discharged home from neonatal units and then looked at their PICU admissions in two ways, either PICU admission from home, at least 24 hours following when neonatal discharge home, and specifically looking at unplanned PICU admissions. So they wanted to exclude PICU admissions for like a planned surgery after discharge. They used a logistic regression model predicting unplanned PICU admissions and they used
a whole host of neonatal comorbidities to look at these risk factors. So in total, they had 46 ,698 children born less than 32 weeks between 2013 and 2018 and admitted to the neonatal units. After exclusions, there were 46 ,684 children. In total, 3 ,929 babies died in neonatal care.
and 2 ,065 were discharged to receive ongoing care in other settings. And then the rest of the babies were discharged home from neonatal care. So that cohort, 40 ,690 children. And 5 .7 % of these neonatal admissions who were discharged home had at least one admission to PICU after discharge, comprising 3 ,270 PICU admissions in total.
So all PICU admissions, the subgroup of these children admitted to the PICU had a greater proportion of males, lower birth weight. So the mean birth weight of babies admitted were 1 ,131 grams versus 1 ,246 grams. They had lower gestational aids at birth, median 28 weeks versus 29 weeks.
Daphna Yasova Barbeau, MD (39:42.114)
And they had a greater proportion with neonatal morbidity such as brain injury, 11 .4 versus 6 % compared to the overall cohort of babies discharged home. Not surprisingly, the observed percentage of children who were admitted to PICU after discharge varied by gestational age. So 13 .6 % of all children born less than 24 weeks added admission to the PICU versus 3 .7 % of children born at 31 weeks.
For PICU admissions, the primary diagnosis on admission was most commonly respiratory disease at 62%, followed by infection 10 % and cardiovascular disease 8%. Overall, 22 % of children admitted to the PICU from home had at least one further PICU admission before the age of two. And this has increased to 32 % for children born less than 32 weeks. Respiratory conditions were consistently the most common cause of admission.
And the observed mortality within the PICU, so babies who left the NICU but died in the PICU at all gestations was about 2 .4%, which was actually less than I thought. So the unplanned PICU admission group, the majority of first admissions to PICU following neonatal discharge were unplanned. This was 82 .4%. The percentage of children discharged home who had, again, subsequent
Ben Courchia MD (40:49.399)
Mm -hmm.
Daphna Yasova Barbeau, MD (41:05.922)
PICU admissions varied by gestational age. 10 .2 % of children discharged born less than 24 weeks had a PICU admission compared to 3 .3 % of those born at 31 weeks. So again, these are kind of the unplanned PICU admissions. As gestational age birth increased, neonatal discharge occurred at early post -menstrual age as did the first unplanned PICU admission. Among unplanned admissions, 23 % of children had further PICU admissions.
This was highest in those born in less than 24 weeks. So 33 % of babies born in less than 24 weeks had more than one PICU admission. Following a series of adjustments, unplanned PICU admissions was associated with lower gestational age of birth, male sex, BPD, severe neck, and brain injury. Of the neonatal morbidities, brain injury actually had the greatest increase in adjusted odds ratio of 1 .42, followed by severe neck 1 .39 and BPD 1 .37.
And increases in predicted risk of unplanned PICU admission appeared to relate to the total number of neonatal morbidities. So if you were a child who was born less than 24 weeks with BPD, neck and brain injury, you had about a 20, 17 % chance of being admitted to the PICU. So the conclusions, the majority of babies born less than 32 weeks in discharged home do not require PICU admission the first two years of life. However,
Unexpected admissions are most common in the most preterm children, especially those with brain injuries, severe neck and BPD. And the main driver, as usual, of picky admissions is respiratory illness.
Ben Courchia MD (42:47.945)
Did they get a problem with us?
Daphna Yasova Barbeau, MD (42:50.306)
This was, okay, right now is the British Association of Perinatal Medicine meeting. So if you're attending the meeting, you can give us some feedback, but they were presenting this data along with other data. So what this data showed, 5 % of babies who leave the NICU are admitted to the PICU, but 20 % of PICU admissions are made up of previous NICU.
babies. So there was just this sense about NICU admissions if you're examining it from the neonatal perspective or the PEDS ICU perspective.
Ben Courchia MD (43:30.264)
I think it's, from a statistical standpoint, it kind of makes sense, obviously, depending on the degree of severity of the NICU stay. But I also really like to figure it through the Sankey diagram, basically showing a little bit. Because I think it gives you a good idea of the proportions of the people who need an initial admission versus the ones who never really need a second one and how it really thins out pretty quickly, basically. But I'm going to post that on social media this week just so that people can see it. It's an interesting parameter.
Daphna Yasova Barbeau, MD (43:34.144)
Yeah.
Daphna Yasova Barbeau, MD (43:39.452)
Mm -hmm.
Daphna Yasova Barbeau, MD (43:51.242)
Yeah, that's right.
Ben Courchia MD (43:57.602)
could help us potentially understand a bit how to counsel these families and remembering that it's not because your kid goes home on room air that respiratory complications are out of the way. think a lot of parents sometimes leave the NICU thinking, we sorted that problem out before we left, but.
Daphna Yasova Barbeau, MD (44:00.62)
Mm -hmm.
Daphna Yasova Barbeau, MD (44:05.003)
Mm -hmm.
Daphna Yasova Barbeau, MD (44:08.578)
That's a great point.
Daphna Yasova Barbeau, MD (44:12.736)
Yeah, or they're really hopeful that like, man, we're just out of it. We don't have to worry about anything anymore. think they're hopeful.
Ben Courchia MD (44:19.141)
Yeah. All right. We're going to part ways very quickly, but I just wanted to, since the Delphi conference is coming up next week, I wanted to bring up like a very innovative paper that I just stumbled upon. It's a paper that was in press in the Journal of Pediatrics. And the title of the paper is Mitigating Alarm Fatigue and Improving the Bedside Experience by Reducing Non -Actionable Alarms. This is a paper, first author is Jeffrey Kang. This is a
Daphna Yasova Barbeau, MD (44:40.066)
Mm -hmm.
Ben Courchia MD (44:46.124)
paper that's coming out of Stanford. And it's not an ACUE paper, it's a PICU paper. So I'm going to give the PICU people the credit here. But basically, they wanted to know, could we make conditional bedside alarm triggers that can reduce the frequency of non -actionable alarms without compromising patient safety and enhance nursing and family satisfaction? Just that objective alone was, was like, yes, I'm on board. Tell me what you want to do. Let's do it. And they basically did a QI initiative where they basically changed the way their alarms function. So for example,
They basically had a hierarchical alarm system and they had more deliberate delays. So for example, should an alarm go off if a patient is high setting or do you want the alarm to go off after maybe 10 minutes of the patient high setting so that it doesn't right away, you know, start alarming for a problem that's not emergent basically, because it's something that you would want to improve. But should a nurse leave what she's doing to come address this alarm and find out, my patient's setting a hundred percent.
There's a bit of these delays that will basically start alarming the staff and the people around if something has been happening for quite a while. And then there'll be hierarchical sort of changes in alarms where depending on your age, maybe the alarm is different. And depending on what your the expectation, the different setups, basically. So they have I mean, the tables are quite complex. You can go take a look and they show you exactly what they did in changing these different alarms. They basically trained the staff and they had like a two year follow up. And the primary outcome of that study was
alarms per monitored patient day, which I thought was an amazing primary outcome. And then they surveyed both nurses and families pre and post intervention. So 1 ,500 patients contributed to 2 ,000 monitored patient days, The median number of alarms per monitored patient decreased by 75 % in the PICU.
and 82 % in what they call the ACCU, which is the acute care cardiac unit. And they said that this effect was sustained at the two -year follow -up. There's no increase of rapid response call. There's no increase of emergency transfer, and no increase in code events in either unit. The nursing surveys reported an improved capacity to respond to alarms, fewer perceived non -actionable alarms.
Ben Courchia MD (47:10.592)
And the family surveys did not demonstrate improved sleep quality, which I think is a little bit sad, but so be it. The conclusion of the paper are that these changes to bedside monitors can decrease total alarm frequency in both acute care cardiac unit and pediatric intensive care unit, improving the care provider experience without compromising safety.
If you're an investigator looking for a project in neonatal intensive care, please pick this up. will gladly review that paper when you publish it. It's something that I would love to see an effect.
Daphna Yasova Barbeau, MD (47:44.61)
Okay. What? I, I misspoke. have to correct myself from what I said earlier. I told you it was 20%. It was 50%. 50 % of PICU admissions were previously NICU admissions. It doesn't, it doesn't change the commentary, but it's, but I just wanted to make sure that I said that. I only had one other, brief thing to highlight. this, was a,
Ben Courchia MD (47:57.912)
50%, I see. Still, yeah, it still crosses the threshold. Yeah.
Ben Courchia MD (48:08.503)
Yeah.
Daphna Yasova Barbeau, MD (48:15.234)
What's it called? Not an editorial, a viewpoint, a viewpoint. I want to make sure I call it the right thing. You know, I'm learning as I write a perspectives piece that there are different criteria for each of these things. So don't want to call it the wrong thing. This is a viewpoint. This is by Dr. Rivara. This is in JAMA Pediatrics and it's entitled, What I Have Learned In The Last 24 Years.
Ben Courchia MD (48:19.866)
You do that every journal club by the way. A viewpoint.
Daphna Yasova Barbeau, MD (48:43.874)
being editor -in -chief. So Dr. Rivara is from Seattle Children's. He's a pediatrician and an epidemiologist. And he's been editor -in -chief, again, for two different journals over the course of the last 24 years. The Archives of Pediatrics and Adolescent Medicine, which became GM of Pediatrics in 2013. And now, most recently, where he is, I think, is currently.
JAMA Network Open. Anyways, so he had some thoughts about his tenure. So I was just going to review them in brief. I thought this is something that people would be interested to read. I think it leaves us with more questions than answers in my humble opinion. But he says, research question, without doubt, the most important criterion in assessing a manuscript is whether or not the research question investigated is important in terms of improving health, health care, or public policy that affects health.
And I quote, not all unanswered questions are worth answering. All science must first pass the Sowet test. Study design. Will the study design allow the research question to be answered in a clear way? And is it rigorous enough to stand up to all the internal and external threats encountered in research? And then he goes on to describe a few of the types of research methodology, but the task of the editor and reviewers is to try to determine if it was the right design to answer the proposed research question.
Rigor of implementation. think this is an important one. A study is only as good as how well the protocol has been implemented and did people actually follow the protocol that they intended to use. Highlighting the use of statisticians. This is another point. Strive for conciseness and brevity. He reminds us that the Gettysburg Address was only 268 words long.
and that we can potentially make even more impact by having shorter papers. He highlights publishing and contra, go ahead.
Ben Courchia MD (50:44.831)
I was going to say, obviously, we're preparing a lot of presentations. And so I was reminded of this Apple incorporated rule about presentations. They say that in order to remain concise, you should use font of 30 on your slides, because that way, it's not going to fit more than what you need. So I thought that echoes a little bit at that point.
Daphna Yasova Barbeau, MD (50:48.234)
That's right.
Daphna Yasova Barbeau, MD (50:52.278)
Mmm. Mmm.
Daphna Yasova Barbeau, MD (50:59.252)
If it doesn't fit, then you don't get...
Daphna Yasova Barbeau, MD (51:05.314)
that's why the words are so big on our slides. Thank you, Apple. He made a commentary on publishing on controversial topics, which I was actually pleased about. And he says, editors should never shy away from publishing articles on hot button topics, things like fire, injuries, abortion, and the effects of racism. But they must ensure that the science is rigorous, the conclusions justified, and that there's no political bias detectable.
Ben Courchia MD (51:08.458)
Mm -hmm.
Daphna Yasova Barbeau, MD (51:34.018)
Challenges of peer review. He says, every manuscript can be improved and peer reviewers are a key part of the editorial process. But finding good peer reviewers has become difficult over time. Promotions committees look at the number of articles faculty publish, not the number of peer reviews they have done. I took issue with this point because I think he potentially could have said more about how maybe we can compensate people who do reviews.
Ben Courchia MD (51:59.756)
Mmm, mmm.
Daphna Yasova Barbeau, MD (52:01.352)
for their time, since we pay for journal subscriptions, not the open ones, but people pay to put their articles in open publications that maybe it's time for us to pay the reviewers who review the papers. And then the final two points, relationships of authors and editors. Authors can develop relationships with journals and their editors by doing high quality peer reviews, agreeing to write commentaries, and considering these relationships when deciding which journals to submit their work.
and the team, no editor works alone. Editors of high quality journals are key members of the community of science, but they work with a lot of people to put out this research. So anyways, I didn't get as much concrete information as I would have liked if I thought maybe the community needs to hear from editors personally, but there it is. Do with it what you'd like.
Ben Courchia MD (52:55.522)
Yeah, I think it's an interesting one. And I think you mentioned not shying away from publishing sort of controversial stuff. I think it's in JAMA PEDS this week, this month, where they basically had like a little thing about state to state variations in rates and cause of child and adolescent mortality in the US and basically state by state looking at primary and secondary causes. And it's basically either for every state, it's either firearm or motor vehicle. And it's basically whichever state has one or the other. It's if one if firearm is first and more vehicle is second.
Daphna Yasova Barbeau, MD (53:10.348)
Mm -hmm.
Daphna Yasova Barbeau, MD (53:14.145)
Mm
Daphna Yasova Barbeau, MD (53:18.37)
Mm -hmm. Mm -hmm.
Ben Courchia MD (53:24.47)
And if the other way around it is the other way around. I think only Hawaii has suffocation or something as one of the causes, but everybody else, it's firearms, firearms, firearms. So it's kind of crazy and goes to the testament of not being afraid of publishing some controversial data. So yeah. All right. This was a good Journal Club. I enjoyed it thoroughly. And we will be back next week.
Daphna Yasova Barbeau, MD (53:40.194)
Mm -hmm.
Ben Courchia MD (53:51.266)
for a special interview and setting up for Delphi. if, again, if you have not registered, please do so. Seats are going by quickly. And again, we have virtual registration open, so go check out delphiconference.org. Thank you all for listening, and have a good rest of your day. Bye.
Daphna Yasova Barbeau, MD (53:54.54)
Mm -hmm.
Daphna Yasova Barbeau, MD (54:08.438)
Bye, buddy.