#388 - 📑 Journal Club - The Complete Episode from December 21st 2025

Hello friends 👋

In this Journal Club episode, Ben and Daphna review five recent studies with practical implications for neonatal care. The FEED1 trial examines whether starting full milk feeds from day one is safe in 30-32 week preterm infants, finding no difference in length of stay compared to gradual feeding but fewer central line days. A brief communication from UAB explores high-volume feeding strategies (≥170 ml/kg/day) and their impact on body composition in very preterm infants.

The hosts discuss a mannequin study from Italy measuring forces applied during intubation with different laryngoscope types and bed heights, revealing that video laryngoscopy at navel height applies the lowest forces—contrary to most clinicians' perceptions.

A large Japanese cohort study highlights the association between maternal psychological distress and neurodevelopmental delays, with postpartum distress showing stronger effects than prenatal stress. Finally, analysis of Neonatal Research Network data identifies predictors of early cord clamping in extremely preterm infants, with lack of magnesium sulfate, cesarean delivery, and antepartum hemorrhage being key factors.

The episode wraps with reminders about upcoming conferences, including the Delphi Conference in Fort Lauderdale in January 2026.

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

Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): a open-label, parallel-group, multicentre, randomised, superiority trial.

Ojha S, Mitchell EJ, Johnson MJ, Gale C, McGuire W, Oddie S, Hall SS, Meakin G, Anderson J, Partlet C, Su Y, Johnson S, Walker KF, Ogollah R, Mistry H, Naghdi S, Montgomery A, Dorling J; FEED1 collaborative.Lancet Child Adolesc Health. 2025 Dec;9(12):827-836. doi: 10.1016/S2352-4642(25)00271-8. Epub 2025 Oct 17.PMID: 41115446 Free article. Clinical Trial.2. Does Early High-Volume Feeding Improve Body Composition in Preterm Infants?

Early body composition outcomes of infants born very preterm and receiving high volume, human milk feedings (≥170 ml/kg/day) before postnatal day 14.

Gunawan E, Molleti M, Salas AA.J Perinatol. 2025 Oct 31. doi: 10.1038/s41372-025-02469-w. Online ahead of print.PMID: 41174086 No abstract available.3. Does Video Laryngoscopy Reduce Forces During Neonatal Intubation?

Applied forces during neonatal intubation with direct and video laryngoscopy at different bed elevations: a randomized crossover manikin study.

Cavallin F, Pasquali G, Maglio S, Villani PE, Menciassi A, Tognarelli S, Trevisanuto D.Eur J Pediatr. 2025 Nov 5;184(12):732. doi: 10.1007/s00431-025-06524-8.PMID: 41191125 Free PMC article. Clinical Trial.4. Can Maternal Mental Health Predict Neurodevelopmental Delays in Toddlers?

Maternal Psychological Distress Before and After Childbirth and Neurodevelopmental Delay in Toddlers.

Matsumura K, Tanaka T, Kuroda M, Tsuchida A, Hatakeyama T, Kasamatsu H, Inadera H; Japan Environment and Children’s Study Group.JAMA Netw Open. 2025 Oct 1;8(10):e2540907. doi: 10.1001/jamanetworkopen.2025.40907.PMID: 41171271 Free PMC article.5. Can We Predict Which Extremely Preterm Infants Need Early Cord Clamping?

Antenatal Prediction of Early Cord Clamping among Infants Born Extremely Preterm.

Katheria A, Dorner RA, Grobman W, Rysavy MA, Koo J, Wyckoff MH, Sandoval G, DeMauro SB, Das A, Lee HC, Cotten M, Calvo L, Saha S; Eunice Kennedy Schriver National Institute of Child Health and Human Development Neonatal Research Network.J Pediatr. 2025 Oct 31:114878. doi: 10.1016/j.jpeds.2025.114878. Online ahead of print.PMID: 41177398 

Treatment of Hypotension of Prematurity: a randomised trial.

Alderliesten T, Arasteh E, van Alphen A, Groenendaal F, Dudink J, Benders MJ, van Bel F, Lemmers P. Arch Dis Child Fetal Neonatal Ed. 2025 Dec 15;111(1):F60-F66. doi: 10.1136/archdischild-2024-328253.PMID: 40413017 Clinical Trial.

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Watch this week's Journal Club on YouTube 👇

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

Ben (00:01.09) Hello everybody, welcome back to the incubator podcast. We are back today for a new episode of journal club. Daphna, good morning. How are you doing today?

Daphna (00:08.74) I'm doing well. It's nice to be home. Both of us have been traveling. It's nice to be home doing journal club.

Ben (00:15.724) Yeah, we're living life on the road these days. You were at CHNC (Children's Hospital Neonatal Consortium). How was that?

Daphna (00:18.21) Yeah, seems like. My gosh, it was incredible. You know, we love going to the CHNC. The CHNC was one of the first conferences to open their doors to us. And this is what our third iteration. And I hope people will take a listen to those episodes. Almost every single episode had some take home pearls points from either what those focus groups were doing, the keynote speakers, lectures, workshops. So I think they're pretty high yield. So I hope people will go and take a look. But as usual, the group is doing a lot of work, multi-disciplinary collaborative work across the country. Making sure that people aren't reinventing the wheel, you know, working together to move medicine forward faster. So I think it's cool. That's right.

Ben (01:08.654) Truly breaking down silos. Yeah. Very cool. Yeah, the episodes were really good if you haven't, I mean, for the people listening who haven't checked them out. I definitely had FOMO listening because it's the one first time we're doing this sort of splitting of the duties. Diana Montoya-Williams did a phenomenal job filling in.

Daphna (01:23.142) Well, we missed you.

Daphna (01:36.422) She sure did, yeah.

Ben (01:37.934) Yeah, so we'll see. We'll see what happens in the future. We'll be at Hot Topics in December. If you're going to be there as well, just come say hi. And if you haven't booked your tickets for the Delphi Conference in January, please do so soon. Tickets are going fast. There's a way to get a discount on a checkout. Follow some of these popular neonatologist influencers, Dr. Fort, Dr. Narvi. We've given them some coupon codes to share. So you can definitely use those. And we look forward to seeing you in Florida in January, in sunny Florida in the middle of January. So enjoy that. Yeah.

Daphna (02:22.662) That's right, very much so. And I guess we should remind people we do have a hotel block at the Flow Hotel just down the street from the Art Museum. Great prices there, but the room blocking, room block booking, I think is only through the end of the year. So hopefully people will go ahead and finish that as well.

Ben (02:38.828) Yeah. Yeah, definitely check, definitely take advantage of that. We will post on social media. 500 bucks for three nights in Florida in January. Beautiful hotel, like a really beautiful hotel.

Daphna (02:51.236) Yeah. I mean, that's just part of our mission, right? Committed to making things as, it's still hard. It's still hard to get out there and do conferences and be places, but we're trying to make it as accessible as possible.

Ben (03:04.365) You're not going to regret coming to this one. So we look forward to seeing you there. All right. We have a lot of articles to review and the first article we will begin with is an article that I found in The Lancet published a couple of weeks back actually in October. And the title of the paper is Full Exclusively Enteral Fluid from Day One versus Gradual Feeding in Preterm Infants. It's called the FEED1 Trial. It's an open-label, parallel group, multi-center, randomized, superiority trial. First author is Shalini Ojha. And there's a lot of other collaborators that create the FEED1 collaborative. So we will see, actually, if more papers come from this group.

Traditionally, infants who are born preterm or with low birth weight are managed very cautiously, specifically when it comes to their feeds. And they're usually started on IV fluids or TPN (total parenteral nutrition). And then milk feeds begin at a small volume that is slowly increased until they reach a full enteral regimen. And this slow start is often driven more by fear than evidence is what the authors say. Right? The perception has always been that feeding too soon or too quickly could increase the risk of necrotizing enterocolitis. Ooh, ding for you, Daphna.

Daphna (04:33.201) Ooh, it's been a while since I left everything on. Sorry for the interruption.

Ben (04:41.229) That's okay. But the perception that we were just, what we were just saying is that the perception that if we go too fast too soon is dangerous because we think that it could increase the risk of necrotizing enterocolitis, NEC. And even though there's not really any solid evidence to support this particular concern. In fact, evidence from randomized trials has suggested the opposite, that advancing feeds more quickly may reduce invasive infection and does so without increasing the risk of NEC or death. The incidence of severe NEC is already quite low in infants who are born at or beyond 30 weeks of gestation, which is the population that they're going to examine in this trial. So I think it's very important to always look at the patients that are looked at. And 30 weeks and greater, we're not talking about a 23-week group. Just keep that in mind.

The introduction is very interesting. They mentioned how smaller trials over the past 15 years, particularly in infants who weigh between 1 and 1.5 kilos, suggested that early, exclusively enteral feeding, meaning full milk feeds without any form of IV supplementation from the start, may actually improve growth. They can shorten hospital stay. But these studies were relatively small and came most of the time from single centers, which doesn't negate the data but makes the generalizability a little bit more uncertain.

So their hypothesis is that starting full feeds on day one could have multiple benefits, right? You could basically avoid central lines and venous access. You could reduce pain by reducing the procedural sort of exposure. You could reduce exposure to TPN. You could also maybe speed up readiness for discharge. And it's going to cost the health care system less potentially. And importantly, they also mentioned that obviously consultation with parents highlighted how strongly families value an earlier discharge and fewer interventions. I think this is so interesting and I'm very happy to start seeing this in papers where the input of parents on how important the outcome that we're about to discuss is justifying the study altogether is very important.

Ben (07:02.091) So against this backdrop, the FEED1 trial is designed to answer a simple but an impactful question in infants who are born between 30 and 32 and six weeks. Does starting full milk within the first three hours of life, does that reduce length of hospital stay compared with a usual feeding approach? So the FEED1 trial was a large open label parallel group multi-center randomized superiority trial that was conducted in the UK across 46 neonatal units.

The participants were selected based on their gestational age. They had to be 30 to 32 weeks and six days at the time of enrollment. They had to be enrolled before three hours of life. And they had to be deemed clinically stable according to the attending clinician to go through this process. They excluded infants who had congenital GI (gastrointestinal) anomalies if they had a birth weight that was less than the 10th percentile with reversed end diastolic flow before birth, or if a mother had participated in their trial previously. So infants requiring support, CPAP (continuous positive airway pressure), mechanical ventilation, or other supportive therapies were still eligible as long as the team felt true equipoise existed for these babies.

The randomization happened in a fairly standard fashion, just so you know if you had babies who were twins, they remained in the same treatment group. And so the intervention basically is full milk feeds group is a group that starts feeds within three hours of life with an initial feeding volume of about 60 to 80 ml per kilo per day. No IV fluids, no TPN unless the team deems that it is needed due to some form of intolerance. We'll talk about that in a second.

Gradual feeding group is kind of like what we do, Daphna and I. I mean, we haven't really adopted this fully, but basically, right, you start with some IV fluids, you start with maybe some starter TPN, and then you start also some small milk volumes at about 30 ml per kilo per day on day one, and you advance slowly titrating the feeds up and the TPN down. In both groups, the decision about the milk type, the feeding intervals, the definition of feeding intolerance, and supplementation with donor milk or formula, all that was left to the local standards of each institution. It was a very pragmatic approach to the trial. So they allowed them to just continue to practice as they did. They also did not request, for example, like feeding guidelines or anything like that. Whatever the team was accustomed to doing, they continued to do.

What did they define as adherence to the allocation group? For the full milk group, they were considered adherent if IV fluids or TPN were used for less than 24 hours across the study period. And for the gradual feeding group, they had to receive IV fluids or TPN for more than 24 hours. The primary outcome of the study is the length of hospital stay measured from birth to discharge home. They had a lot of other secondary outcomes, survival to discharge, late-onset sepsis, hypoglycemia, et cetera, et cetera.

I think we've talked a lot about the background and the methodology, so I'm going to get into the results. A total of 2,088 infants were enrolled. The mean gestational age was 31.7 weeks with a mean birth weight of 1.621 kilos and a mean age at randomization of 1.7 hours. I think that sometimes we shrug at larger babies like this, but remember that I don't know how comfortable we would all feel about feeding this baby full enteral feeds within three hours of life.

So let's talk about adherence and feeding tolerance. So in the full milk group, 20% received exclusively the full milk from birth with no IV fluids. So it was not such a great proportion of infants that really breezed through this particular intervention. 61.5% received either no IV fluids or maybe less than 24 hours in total. 37% had the recorded reason for non-adherence to the protocol. 12% was because of feeding intolerance, vomiting, large gastric aspirates. About 3% were having some abdominal concerns, suspected NEC and so on. 6.5% was due to hypoglycemia. 0.5% were because of parental choice. 7% due to escalation of respiratory support and 8% for other reasons.

Now, the gradual feeding group had a high adherence. 91% received more than 24 hours of IV fluids or parenteral nutrition. This is not very surprising. The duration of IV fluids, the duration of IV fluids or TPN was obviously much, much greater in the control group that had 99 hours versus 14 hours in the full milk group.

All right, with that being said, let's look at the primary outcome. Did these babies on full milk have a longer length of stay? The answer is no. There was no difference in length of stay. 32.4 days for the full milk group, 32.1 days for the gradual feeding group. In terms of key secondary outcomes, no differences either, which was quite reassuring. Survival to discharge was similar. No increase in late onset sepsis, no increase in NEC, no increase in hypoglycemia, and no change also in breastfeeding rates at six weeks corrected age.

The other interesting findings, which I will mention, are that in the full milk group, the infants reached full enteral feeds earlier. They had a shorter duration of parenteral nutrition. They required fewer central lines and peripheral IVs. They had fewer days of IV lines. And they spent fewer days in intensive care, some of them being sort of turfed down to like a lower acuity level care. There were no differences in the time to regain birth weight or adjusted weight for gestational age at discharge. And subgroup analyses showed no differences by gestational age or SGA (small for gestational age) status. Serious adverse events were also rare and not too different between the groups.

So the authors say in conclusion that in infants born between 30 and 32 weeks, full milk, enteral feeds from day one does not alter length of hospital stay. It does not increase the risk of necrotizing enterocolitis or hypoglycemia. So while it doesn't seem to provide an edge, an additional benefit, it also doesn't seem to be unsafe and it seems to be equivalent. And I feel that this is very interesting data nonetheless, because it touches on a lot of different things in my opinion that we are all struggling with. You may be a unit that is really trying to reduce central line days. You may be a unit that is really trying to save money. Resources may be limited. I think that all these could be potential reasons to look at this type of protocol. And again, you could even work your way to the 30-weeker by introducing this into the 33-weeker and then going down to 32 weeks and so on and so forth.

Daphna (14:35.481) Right.

Ben (14:37.976) So it's very interesting, and it was a very solidly designed study. I will point people to figure three, which has the subgroup analysis by gestational age, which is quite interesting. And yeah, I think that's pretty much it for this paper. I'm curious to see if you have any thoughts on the matter.

Daphna (15:01.699) Yeah, I mean, I think to your point, sometimes we're not even that aggressive with full term babies who just come in on CPAP, right? We still don't start them on full enteral feeds, even though had they gone to the nursery, they may have gone to the breast. They may have taken a full bottle. I think this is balanced with awaiting mom's own milk. And that's a different challenge. But I think to your point, we have these babies that are difficult to IV access, you know, we ramp up their feeds, we worry a little bit, right, but we got to do what you have to do. I think it makes me feel better about those cases. I was really hoping to see some improved nutritional outcomes. Obviously, I mean, it's not that small. You're right. You're right.

Ben (15:50.221) Well, it's not that small, number one. I mean, 2000 babies is not too small. But I think the biggest thing is the pragmatic approach. I think the pragmatic approach allows you to have that many babies, but you really have no control over what is defined as feeding intolerance. I mean, to be honest with you, I've worked in a lot of units and just from my very small experience, the definition of feeding intolerance varies dramatically. One single gastric residual can send a whole unit into panic while another will not even check. So I think that is also an issue. And then there's a lot of things that are left to the discretion of the clinician in terms of who's eligible for this particular protocol and so on and so forth. Maybe that will lead to more studies down the road. But nonetheless, yeah, there's some limitations as usual.

Daphna (16:44.367) Yeah, but I think it's exciting. I think it's exciting. And it's the perfect segue to my paper, which is, it's really a brief communication in the Journal of Perinatology. But this is a senior author, Ariel Salas, first author, Emily Gunawan. Early body composition outcomes of infants born very preterm and receiving high volume human milk feedings before postnatal day 14. And parenthetically, high volume is greater than or equal to 170 mls per kilo per day before postnatal day 14.

So a little bit of the background. You know, we skip the background a lot, but I'm trying to include it more often because the team highlights that we really don't have standardized recommendations for what are the feeding volumes. Units can fluid restrict. It says from 140, I think some units go even lower, to 200 mls per kilo per day. We don't really have a consensus on the ideal maximal target volume. I know in our unit, if you're getting up to 200 mls per kilo per day, people are starting to worry about that. And the opposite, other layer of concern is that potentially this rapid early growth in preterm infants. If we feed them too much early on, could this result in excessive fat mass accumulation rather than kind of this lean growth? So that's really what they wanted to look at.

It was a retrospective cohort study coming to us from UAB (University of Alabama at Birmingham) between 2020 and 2022. And they looked at infants with a gestational age between 28 and 32 weeks. So not the smallest babies, but this group, much like the other study, a group that's still at risk, but at lower risk for things like NEC. And all of these infants included received enteral nutrition with maternal or donor milk, starting at volumes ranging between 20 and 80 mls per kilo per day within the first 36 hours after birth. And they achieved enteral feeding volumes of at least 150 mls per kilo per day or more by postnatal day 14.

And those infants who achieved enteral feeding volumes of greater than or equal to 170 mls per kilo per day by the 14th day were assigned to this high volume group. And infants who achieved less than 170 mls per kilo per day by postnatal day 14 were assigned to the usual volume group. Infants with congenital anomalies that affect growth were excluded.

So they wanted to look at the primary outcome, a percent body fat measured using air displacement plethysmography. I think I said it.

Ben (19:46.552) Plethysmography? Okay.

Daphna (19:48.196) Plethysmography, yeah, around postnatal day 14 and then the secondary outcomes were time to regain birth weight and change in weight for age Z scores from birth to 14 days. I mean, I'm gonna get into the results. This is, like I said, a short, brief communication, but they're trying to do a lot, I think, in 14 days, in my opinion, so I'll just preface it with that.

They had 212 infants included in the study. The birth weight did not differ between the groups and both groups reached full enteral feeds. So this threshold of greater than 150 mls per kilo per day at a median of seven days, which in and of itself, I think is a feat. In the high volume group, the median postnatal age at reaching the enteral feeding volumes of greater than or equal to 170 mls per kilo per day was on average 10 days. So the median duration of enteral feeding volumes greater than or equal to 170 mls per kilo per day in the first 14 days was about four days. So they're asking those four days to do, I think, a lot of work.

What did they find? There was no significant difference in percent body fat around postnatal day 14 between the two groups. Infants in the high volume group did have an earlier return to birth weight, 14 versus 15 days compared to the usual volume group. And there were smaller declines in weight Z-scores from birth to postnatal day 14 in the high volume group. And this was also statistically significant.

So the discussion of this was that the higher enteral feeding volumes during the first 14 days were not associated with higher percent body fat, but they had less weight loss, slightly earlier regaining of birth weight. So they say that their findings support the safety and potential utility of higher volume enteral feeding strategies in clinically stable preterm infants receiving predominantly human milk-based diets. So I think they didn't look at some of those other outcomes in this particular editorial, let's say, is part of their larger studies. But much like the other paper, I mean, they were starting for some of these babies, 80 mls per kilo per day within the first 36 hours, which in and of itself, I think is quite interesting. Thoughts?

Ben (22:20.939) Yeah, I think it's a very interesting, it's a short communication and I think it's still very helpful because I think that we have to target a certain amount of growth, right? We have to target a certain amount of growth velocity and sometimes we have babies that are quote unquote on full feeds per whatever protocol we've decided to adhere to and their weight gain is just shy of probably where they would normally, where they should normally be. And the question is, if you would like more weight gain, could you push the feeds? But, no, the dogma says I'm at 150. I cannot go any higher. Well, it turns out you could go a little bit higher. The question that this paper really leaves open-ended is what is the safe range beyond the usual 150, 160? But I mean, okay, like you go 160, 170 even. That's not, doesn't seem completely out of the standard of care. And a baby that's gaining 10 grams a day, maybe you want to optimize that a little bit if you're on like 145, 150 or something. I think it's an interesting approach and something that could be quite beneficial.

Daphna (23:25.548) Yeah, I'd be interested to see the longer term nutritional parameters, right?

Ben (23:29.709) To be fair, we kind of have some experience with this. We kind of do this in our unit. We do push babies up to 160, 170. And it's worked quite well for us. So yeah, so I'm kind of an advocate. I am pro.

Daphna (23:48.773) Yeah, I'd say probably most of the babies in our unit are about 160 and we're routinely pushing the poor growers to about 170. Yeah. Okay, your turn.

Ben (23:58.318) Very cool. OK, yeah, my turn. I'm going to take a detour to maybe a little bit of a fun study, because I think this is a fun study, because it feels like during the actual conduction of this, when they were conducting this study, it felt like this was an interesting question to answer. I think they had fun.

Daphna (24:11.306) All these studies are fun.

Daphna (24:22.308) You think they had fun.

Ben (24:25.485) This is in the European Journal of Pediatrics. It's called Applied Forces During Neonatal Intubation with Direct and Video Laryngoscopy at Different Bed Elevations, Randomized Crossover Mannequin Study. First author is Francesco Cavallin. And the last author is Daniele Trevisanuto, who we've had on the podcast before. Daniele is a neonatologist out of Italy, and he came on during our special series on thermoregulation. We were all very impressed with his body of work.

So in the introduction of this paper, it's interesting because I think that the elevation of the bed is always a subject of conversation at the time of an intubation. And I've seen everything. I've seen people who have the bed up to their chin. I've seen people who have the bed as low as their knees. So I think it was interesting to read that. And the authors remind me.

Daphna (25:19.726) Yeah, I feel like it was just where you trained, when you trained with the bed at what height.

Ben (25:24.204) Yeah. And the question that this paper basically brings up is when we intubate a baby, how much force are we actually applying? And how does the equipment and the elevation of the bed influence those parameters? They start by reminding us that even though intubation at birth is required in about like 1% of neonates, we're getting less and less opportunities to practice today with a shift towards effective non-invasive ventilation like CPAP and IPPV (intermittent positive pressure ventilation).

And while intubation is a life-saving procedure, it's also very invasive. It can lead to complications, airway trauma, bradycardia, hypoxia, even sometimes a sad complication like an intraventricular hemorrhage. Now, there's also increasing attention on the forces applied on the baby during intubation. Movement during laryngoscopy compresses tissue. That compression can cause ischemia. It can cause perforation and potentially developmental complication of the surrounding structure. So prior work using mannequins in the form of simulation studies had shown that video laryngoscopy applies lower forces than direct laryngoscopy, suggesting possible safety benefit.

The one key procedural aspect has been understudied, which is how does that change with the bed height relative to the operator? Now, the adult literature is a bit all over the place when it comes to that. Some recommend the table should be at the operator's xiphoid. Others suggest that it should be at the operator's navel. Others find no meaningful difference. Now, the Neonatal Resuscitation Program tells us to adjust the bed so the baby's head aligns with the operator's upper abdomen or lower chest. There's another study that was recently published that recommends positioning the bed closer to the elbow height, which is kind of what I do actually.

So this trial basically says, let's try to set the record straight by comparing the forces applied during neonatal intubation using either direct or video laryngoscopy at two bed heights, either the xiphoid level or the umbilical level. They also looked at a lot of different things and we'll talk about that. So this was a randomized controlled crossover trial that was conducted on a full term neonatal mannequin. The structure basically was a, it was a four-sequence, four-period, four-treatment crossover design. So I'll explain that in a second.

It took place in Italy at the University Hospital of Padua over the course of about a week in July of 2024. The participants were either neonatal consultants or attendings, as we like to call them in the US, and trainees in pediatrics. The intubation equipment, they had access to two devices, the direct laryngoscope with a Miller blade size one or a video laryngoscope with a Miller Spectrum S1 blade. Each participant intubated the NeoNatalie mannequin using both devices at two bed heights, the xiphoid and navel. They were given a 3.5 millimeter endotracheal tube that was used in every single attempt.

And they underwent a little bit of a video and demonstration of the techniques so that they could have like a little bit of a refresher. But in the paper, they talk about this sort of ABDC sort of sequence. So basically, at the end of the day, it's the permutation of these different interventions. So you have to do video laryngoscopy at a certain bed height, like let's say your xiphoid, then you're going to do direct laryngoscopy at the xiphoid, then you're going to do direct laryngoscopy at the navel, and then you're going to do the same for the video, which makes you have to do this four times. And then they gave like a three hour washout that separated each period to reduce any carryover from one to the next. They considered an intubation a failure if the tube was not positioned in the trachea or if the attempt took more than 60 seconds.

Now they had some very cool gadgets to measure force. So it was measured using the FlexiForce A301 sensors, and they placed those at several locations. One was the epiglottic sensor that was placed distal to the blade surface, and then they had two palatal sensors placed proximally where the blade contacts with the upper gum and the hard palate. These sensors recorded peak force, average peak force, and force variability. So you see you read this and you're like, I'm very eager to find out what they discovered.

The primary outcome was force applied to the epiglottis and the palate. And the secondary outcome included success on the first attempt, total intubation time, et cetera, et cetera. Because expected differences in force were unknown, they used a convenience sample of 32 participants and looked at the results. So the participants were composed of 23 females, nine males. Median age was 32 years. And it was 47% NICU attendings or NICU consultants and 53% trainees. The median ICU experience was five years.

The clinical experience with laryngoscopy did vary. So for direct laryngoscopy, 16 participants said they had 10 or more intubations, nine participants said they had one to 10, and six said they had never used it. And then for the video laryngoscopy, six participants said they had done 10 intubations or more, 19 said they had done one to 10, and six said none. Most commonly, clinicians reported adjusting the bed height to somewhere between xiphoid and navel in clinical practice.

Let's look at the results. What are some of the forces applied? So when it comes to the epiglottis, the highest forces were applied using the direct laryngoscope when the bed was positioned at the xiphoid level. Forces were also higher with the direct laryngoscope at the navel height when we compared to video at the same bed position. When using the video laryngoscope, forces were higher at the xiphoid height than the navel height, and the lowest forces overall came from video laryngoscopy with the bed at the navel level. When we look at the hard palate, the higher forces occurred when using direct laryngoscope at either bed heights, and the lower forces were recorded with video laryngoscopy again at the navel. When we're looking at upper gum, they found no differences across the different configurations.

Success at the first attempt were for direct laryngoscopy at the xiphoid position was 84%, direct laryngoscopy at the navel 91%, and then for video, it was about the same at either position, 97%. Across all the comparisons, the differences were not statistically significant relative one to the other.

Daphna (32:16.856) Hmm.

Ben (32:26.358) In terms of median intubation time, it ranged from 17 to 19.5 seconds, with the fastest being achieved with video laryngoscopy, 17.5 seconds, at the navel compared to slowest in direct laryngoscope at the xiphoid position. These were different, but not statistically significant. Then they did something interesting, which they asked people's perception of what they felt like they went through. In terms of preferred table height, most preferred the xiphoid position. Surprisingly, 53% said they preferred the table a bit higher up.

In terms of difficulty, the median difficulty was ranked on the Likert scale 2 out of 5 at the xiphoid versus 3 out of 5 at the navel. The reported troubles at the xiphoid height were postural discomfort, visualization difficulty, ETT (endotracheal tube) positioning difficulty, and laryngoscope management issues. At the navel height, we also had postural discomfort, visualization difficulty, and ETT positioning difficulty.

The preferred laryngoscope at the xiphoid height, 53% preferred video, and at the navel height, 75% preferred video. So majority of people preferred the video at either bed position. And when they asked them about perceived forces, 72% thought they used less force at the xiphoid height. But actual measurements showed lower forces at the navel height with video laryngoscopy. So perception was not a good representation.

So I'm going to leave you with this. You can review the paper. It's very well written, and it's fun to dissect the data. The authors conclude that in this mannequin model intubating with a video laryngoscope and the resuscitation table being leveled at the operator's navel was associated with the lowest forces applied to the epiglottis and to the hard palate. The participants achieved a high success rate at the first attempt and comparable procedure times with all combinations of direct slash video laryngoscope and low to high bed elevation. Subjective perceptions of applied forces differed from the actual measurements. Applying lower forces during neonatal intubation may be desirable, but the clinical implications remain to be evaluated in further clinical studies. I thought this was very interesting. I really enjoyed that.

Daphna (34:45.592) I thought this was a very interesting paper that is going to have me reassessing my technique.

Ben (34:49.805) Yeah. And I find that the perception is very interesting because when we have two people at the bedside, very often you have your partner that tells you, hey, like you're overextending a bit too much. And obviously you don't want to do that. So you don't realize sometimes how the baby ends up being positioned as you're trying to visualize the cords. And sometimes having somebody else next to you to say like, no, like we need to reposition is very helpful. So really enjoyed. Congratulations to the team in Italy for this paper. This was one of the rare scientific papers you read and it's like, this is actually quite fun to read.

Daphna (35:31.352) Very cool. Well, I mean, even again, when we're talking about how can we use, it's not so high tech, but it's high tech. You know, these mannequins that show you where you're putting the pressure is like kind of neat, very neat, you know?

Ben (35:44.975) Yeah, but I mean, I think that to be honest with you, I don't think that they had, I think the mannequin was just a standard mannequin. And I believe, if I'm not mistaken, that they basically purchased these different sensors, which I looked them up. They're not that expensive. If you are interested in doing a study, go look them up. I mean, it's not very hard. I believe that the most expensive I've seen is like between 50 bucks and 100 bucks a sensor.

Daphna (36:01.124) Super cool.

Daphna (36:15.521) Yeah, easy.

Ben (36:18.348) I mean, if you're a fellow, take 200 bucks or take 100 bucks and go get one and play around with it. See what you find.

Daphna (36:25.761) Yeah, and I thought they were pretty creative about all of the things they wanted to look at, like you said, especially perception. I mean, our perception was the opposite for everything.

Ben (36:30.466) Opposite. We all think we're exceptional intubators.

Daphna (36:41.955) So I had to think about that. 

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Ben Courchia (00:01.195) We are back today for another Evidence-Based Neonatology segment where we review an article that was deemed by the community to be of high impact. And I am joined today by a group of experts composed of three physicians. Our first guest is Dr. Deepika Sankaran. Deepika, welcome to the podcast.

Deepika (00:21.026) Hi Ben, thank you.

Ben Courchia (00:22.945) We are joined by a colleague from the pediatric intensive care unit, Dr. Heather Sifkes. Heather, welcome to the show.

Heather (00:33.762) Good morning. Thanks for having us.

Ben Courchia (00:35.941) And last but not least, we are joined by a veteran of the incubator team and the Delphi Conference, Dr. Satyan Lakshminrusimha. Satyan, welcome back to the show. It's always a pleasure to have you on.

Satyan (00:47.017) Great to be back Ben, looking forward to this.

Ben Courchia (00:49.289) Yeah, you guys have written a very nice commentary for the Evidence-Based Neonatology team on a paper called The Treatment of Hypotension in Prematurity, a Randomized Trial. The first author is Thomas Alderliesten. It is published in the Archives of Disease in Childhood, Fetal and Neonatal Edition. This paper was, I don't really have the date, it was released at some point in 2025. I don't remember the exact date. It's out. Everybody can have access to it. Why does it matter at this point? The exact date, it's out. That's all we need to know. And we've had the chance to review this paper on the podcast before. Obviously, it created a lot of discussion. But for the purpose of just review, Deepika, I'm hoping maybe for the audience, you can give us a little bit of an overview of what this trial is about, what were the authors trying to do, and then we will talk a little bit about the results later on.

Deepika (01:43.265) Sure. So like you said, the Treatment of Hypotension in Prematurity or TOHOP trial is a single center randomized trial that was conducted in the NICU at Wilhelmina Children's Hospital in the Netherlands between 2011 and 2018. And like I said, it was discussed previously in the journal club on June 8th by Ben.

This trial challenges the current standard of using the mean arterial blood pressure in millimeters of mercury being less than the gestational age in weeks as a cutoff for treating systemic hypotension in preterm infants. They included preterm infants born between 24 weeks and 29 and six weeks gestational age. And they excluded infants who had congenital anomalies, sepsis, who were greater than 72 hours, and had no arterial line and obvious evidence of poor end-organ perfusion.

And they randomized them to either receive standard treatment where they were treated if the blood pressure was less than gestational age in weeks, or into a permissive hypotension strategy where they were treated if their mean arterial blood pressure was more than five below their gestational age in weeks, or if they had any signs of poor perfusion, such as decrease in cerebral NIRS (Near-Infrared Spectroscopy) or cerebral regional oxygen saturation less than 50% for more than 30 minutes, decreased urine output of less than 0.6 ml per kilogram per hour, capillary refill, which is delayed more than three seconds on two consecutive measurements, or increased lactate more than six mmol per liter.

And if they met any one of these criteria, then they would be treated. That's the permissive hypotension strategy. And the treatment consisted of saline bolus as the first line, followed by dopamine, followed by addition of dobutamine, and finally epinephrine plus or minus hydrocortisone. So the primary outcome they looked at was neurodevelopmental outcome at 24 months. And interestingly, the indication for initiation of treatment, even in the permissive hypotension group for the majority of the infants was blood pressure less than gestational age minus five and not necessarily markers of poor perfusion.

And they found that the primary outcome of neurodevelopmental outcome was not different between the two strategies of managing systemic hypotension. Interestingly also, the infants in the permissive hypotension group had less frequent initiation and less duration of inotrope treatment despite having similar blood pressures in both groups. However, the cerebral NIRS was lower in more infants in the permissive hypotension group compared to the standard treatment group. However, it was not statistically different. And also the study was underpowered, achieving only 57% of the projected enrollment with the potential for Type 2 error.

Ben Courchia (04:56.225) Very, very interesting. I think that, again, I think that's what makes this paper so relevant is that it's trying yet again to hack at this practice of assessing blood pressure based on gestational age, which really sounds wrong and there has to be a better way. And so this idea of maybe being a little bit more permissive, as the authors say, using additional markers to assess perfusion is obviously very interesting.

It's very difficult to study this particular subject. And so as you will notice, the number of babies in each group are quite low. Heather, I'm wondering if you can tell us a little bit how did the authors approach both the design of the study in terms of powering the study, consenting parents, and so on and so forth. Because that's something that we've seen in prior studies to be obviously a big issue.

Heather (05:48.866) Yeah, I think it is important to comment on the low enrollment, which Deepika mentioned was only 58% of their targeted enrollment. And anytime your study is underpowered, you have a risk of falsely rejecting your null hypothesis. And in this case, that there was no difference in the neurodevelopmental outcomes. So their power calculation was based off of a seven point difference in their primary outcome, the neurodevelopmental outcome score, in which they ultimately saw a much lower difference in that score. So had they enrolled more, would they have seen this difference of seven points? Maybe not, but also if you look at their confidence intervals, they technically include that seven also. So they could have seen that difference.

And you ask about the consenting process and enrolling sick newborns. And even though I'm a pediatric intensivist, my primary research is in the NICU. And it is hard to enroll these very sick babies, stressed parents in the consenting process early on in their life. What I'm wondering is if questions like this should really be best studied using cluster randomized trials where your treatment and your intervention are both considered appropriate within our groups of probably appropriate ways to treat a baby, but we just don't really know which one might be a little bit better. And I think that might be a better way to study something like this.

Ben Courchia (07:18.109) Very interesting. Thank you. Thank you for that. And so, Satyan, I'm going to turn to you and maybe you can share with us a little bit what your impression of the outcomes of this trial are in terms of what are we supposed to do with this? Obviously, on the one hand, the study was designed and initially was aimed to be powered for an outcome that is measured at about two years of age, looking at Bayley scores.

And we don't see a big difference and it seems like statistically there's no real difference. But again, the trial is underpowered. And so then we start dissecting the paper and we find a lot of other outcomes in the secondary sections that to us might be quite concerning. For example, you guys have highlighted the fact that the rates of NEC (necrotizing enterocolitis) are quite different between the two groups, 12.5% in the standard treatment versus 15% in the permissive hypotension group. Again, statistically, because of the low numbers not reaching significance. And so the same for grade three or any grade IVH (intraventricular hemorrhage), 7.5% in the standard treatment, 13% in the permissive hypotension group. Again, small numbers, but we're now wondering, well, what am I supposed to do with this? So I'm just curious, how do you take all this information and what do we make of this potentially even more intelligent way of looking at hypotension? And is this something that is ready for prime time in your opinion, or do we still need to do it the old way and just keep correlating with gestational age?

Satyan (08:59.637) Ben, those are really interesting questions. As you know very well, for the longest time I have been in the death to dopamine in PPHN (persistent pulmonary hypertension of the newborn) camp. I'm not a huge fan of using dopamine in babies with pulmonary hypertension. I've also been against using blood pressure medications when mean arterial blood pressure falls below gestational age in weeks. But this paper and the recently published HIP trial follow-up have begun to worry me that maybe my approach is not the right thing. And so let me talk about that for a second.

Two striking things I found in this paper are one, there was nothing bad that happened with standard use of dopamine at mean arterial blood pressure less than gestational age. None of the outcomes were negative in that particular group. Same thing with the HIP trial as well. And the second striking finding for me was even if you waited for mean arterial blood pressure to go five below the gestational age in weeks, none of the signs of hypoperfusion were really manifested in that group. In fact, although it's called the permissive hypotension group, the main indication for enrollment was the fact that these babies hit a mean arterial pressure of five less than gestational age. So if you're talking about a 26-weeker, you're talking about a mean pressure of 21 millimeters of mercury. Despite that, none of the babies showed any signs of hypoperfusion except for two infants who showed low regional oxygen saturation numbers.

So in my opinion, this clearly shows that lactate is too late. That's a classic thing that started in adult medicine. So increase in lactate, drop in urine output are really late signs in hypotension or hypoperfusion. Similarly, capillary refill is very subjective. So in my opinion, the only real live thing that you're seeing here as a sign of hypoperfusion is low cerebral oxygen saturation. So I think that's the real finding here. I sincerely wished that they combined it with one of the TnECHO (targeted neonatal echocardiography) measures of low blood flow, such as reduced superior vena cava flow or something like that, which had been used by Martin Kluckow and others in previous studies. I wish they had combined that along with this feature.

So the second finding is if you combine the findings of the HIP trial, just to remind everybody, the Hypotension in Preterm Infants, the HIP trial was done by Eugene Dempsey and his colleagues. And it was a fairly similar trial where they compared dopamine versus placebo when mean arterial pressure went below gestational age in weeks. And the bottom line is that there were no difference in short-term outcomes, but the HIP trial showed survival without impairment in 48% of infants in the dopamine group and 25% of infants in the placebo group with an odds ratio of 2.79 with a p-value of 0.078. Even that trial, as Heather had mentioned earlier, did not complete enrollment and so has some concerns about Type 2 error there as well.

So those are my concerns. And so where do we go from here? One approach is precision medicine. If you have access to NIRS, if you have access to all the blood gas measurements, if you have access to POCUS (Point-of-Care Ultrasound) and TnECHO, then I think we should really look at blood flow to the brain and also cerebral oxygen saturations and compare the two and come up with an accurate diagnosis of hypoperfusion and treat that if it is seen. But if you're in a small unit where you don't have access to these approaches, maybe, just maybe following the traditional approach of treating hypotension with a fluid bolus followed by dopamine while assessing all the other features is not, is reasonably okay for the time being. I would really like to see further studies that look into evaluating hypoperfusion in a much more objective way, especially superior vena cava flow, and combining NIRS with TnECHO. I would really like to see that in the future.

Ben Courchia (13:00.065) Very interesting, Satyan. Heather, I'm going to turn to you and ask you the same question. What are your takeaways based on the statistical limitations that we've discussed inherent to the difficulties in studying that particular subject? What is your perspective specifically? It's interesting because of the fact that you're coming from the PICU world.

Heather (13:26.69) Well, I think the question is a very good one to ask. And I think we definitely do that in the PICU world too of, well, do we really need to treat only the number or is the baby appearing or the patient appearing to tolerate these slightly lower blood pressures? So I think it's a great question to ask and to study. You know, we talk a lot about the statistical analysis and whether something's statistically significant, but then also I like to focus on, well, is there something that's clinically significant? And one of the things that stood out to me in the results is maybe perhaps a bigger concern was the potential clinically significant difference in the death rate. And that 13% of deaths in the permissive hypotension group and 7.5% in the standard treatment group. And even though some of those deaths in the permissive hypotension group were due to late onset sepsis, and we don't know if something earlier in their course could have been related to their treatment, could have ultimately still put them at risk for that late onset sepsis.

It reads as though it could have been due to a secondary episode of hypotension, but there were also, as you already commented and we pointed out in our commentary, there were more patients in the permissive hypotension group with NEC as well. So I think ultimately, I'm just not sure if this study shows if permissive hypotension and the way that it was evaluated here is telling us if it's safe yet, even though their overall outcomes and their analysis show that it was statistically not different. I'm just seeing some signals that have me concerned that we still don't know if it's safe.

Ben Courchia (15:08.299) Deepika, any thoughts on that?

Deepika (15:08.932) I would agree with Heather in that this study shows that permissive hypotension strategy is feasible and allows individualized care while there is a possible risk of cerebral hypoperfusion and hypoxia that questions the safety. And I think it is worth taking into account the chronological age at onset of hypotension when we consider such studies in the future, maybe classifying babies with hypotension at less than six hours, six to 24 hours and beyond 24 hours as the etiology may vary. And also taking into account the iatrogenic risks of blood pressure management strategies that may, for example, dopamine or other medications may induce acute fluctuations in blood flow and blood pressure that may be harmful in these preterm infants. So just weighing the risks and benefits of permissive hypotension and the treatment strategies would be helpful.

Ben Courchia (16:06.827) Satyan, I wanted to turn to you. I know you had something to share, but basically I wanted to get your thoughts on the collective intellectual process that we have throughout this issue where we don't know what the right answer is, it seems. And so we approached the subject by saying, let's see what maybe we are having some degree of certainty and saying, well, we shouldn't be doing that. And dopamine was the first to take the axe. And people were saying, maybe dopamine is not the right way to go. As you mentioned earlier, these papers coming out with the limitations that are inherent to their studies seem to be questioning even this particular assumption. And so personally, I'm left with, we don't really know much. We don't know what's right, we don't know what's wrong, and we haven't made that much progress. I'm just curious about whether you share that perspective or you think that maybe we do have some better understanding with the help of these particular trials.

Satyan (17:03.071) Ben, one thing that's clear from these studies is that we all should follow your suit and learn TnECHO. That's what is the final outcome here for us. Because it's very clear that the tools that we are using to assess hypoperfusion are not accurate. And they're really late and they're not accurate and they're not the right tools that we should be following. So figuring out what the cardiac contractility looks like, what the flow looks like are really two crucial items that we need to figure out before choosing the inotrope if you need one.

The one striking finding from the TOHOP trial is that if you follow the permissive hypotension path, the use of inotropes is less frequent, which is probably a good thing, and the duration of therapy is also shorter. So those two are clear benefits of using the permissive hypotension arm. And as Deepika was mentioning, starting an inotrope is not benign. The moment you start dopamine, you see a huge increase in blood pressure, and that can give rise to, potentially cause IVH, so there are negative effects of that. So my takeaway from this is that starting an inotrope is not a benign thing. We should be really careful in assessing signs of hypoperfusion, accurate signs of hypoperfusion before we do that. And once we assess and figure out that these signs are present, then gradually initiating a fluid bolus and a vasoactive medication is the right approach. And prolonged permissive hypotension is probably not the right approach either. So these two studies, the HIP trial and the TOHOP trial, give me, I think we need to be really careful when managing hypotension and optimal use of dopamine is probably not a bad thing as long as we know what we are doing and we're able to assess hypoperfusion much more accurately.

Ben Courchia (18:48.395) This is all very exciting, by the way, because my wife is an adult cardiologist and the subject of hypotension, at least in the adult world, feels like it's been worked out. Like they understand it pretty well. But the fact that in neonatology, we're still at the very early understanding steps of figuring out what defines hypoperfusion, what does not, means that for whoever is interested in exploring that subject, there's a lot of things to go at. And so for that alone, I think that from a career perspective, it's exciting for whoever is interested in pursuing that. So that's the silver lining, I guess.

Satyan (19:18.653) I'm married to a cardiologist as well, so my wife is also an adult cardiologist. The big difference between adults and preemies is that adults have a really nice prolonged cerebral autoregulation where they can maintain their perfusion at a wide range of mean arterial blood pressure. Whereas preemies, they hardly have any autoregulation and that's what makes this field even more interesting than adults.

Ben Courchia (19:40.245) Do you also have to sleep on the couch if you mention you're treating a blood pressure based on gestational age?

Satyan (19:46.429) I will not mention that on a live broadcast.

Ben Courchia (19:50.337) Deepika, Heather, Satyan, thank you so much for joining the podcast. This was a fun conversation and thank you for this very well-written Evidence-Based Neonatology commentary, which will be available both in Acta Paediatrica and on the Evidence-Based Neonatology website for people to review. Congratulations and talk to you very soon.

Satyan (20:08.949) Ben, can't wait for you to finish your fellowship and do a real trial and give us the right answer.

Ben Courchia (20:14.561) Thank you Deepika, thank you Heather.

Heather (20:16.76) Thank you.

Deepika (20:17.309) Thank you.

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Daphna (36:41.955) Okay, I'm going to take us in a less fun route. This is in JAMA Network Open, it's actually under psychiatry. It's entitled, Maternal Psychological Distress Before and After Childbirth and Neurodevelopmental Delays in Toddlers. A really neat study, lead author Kenta Matsumura and senior author, Hidekuni Inadera. These are a group of researchers through the Japan Environment and Children's Study Group. Obviously, they have a lot of access to a lot of information. So it's a birth cohort study. The JECS (Japan Environment and Children's Study) is an ongoing nationwide longitudinal cohort.

They recruited participants through 15 regional centers across Japan from January 2011 to March 2014. They had 82,000 mother-child pairs enrolled in the JECS and they are data mining. They have been data mining for about the last year. So I thought this was an interesting question. Ben also thought it was an interesting question and I think relatively pertinent to our group of parents.

It comes on the heels of the CHNC meeting where we spent a lot of time actually talking about maternal or parental mental health. I'm so thrilled that the tides are turning and the community is recognizing how critical parental mental health is to kind of our long-term neurodevelopmental outcomes. And I think the study underscores that.

They wanted to look at is the timing of maternal psychological distress differentially associated with the risk of neurodevelopmental delay in toddlers. Specifically, they wanted to look at what if the mothers experienced psychological distress during pregnancy as compared to up to one year postpartum. And additionally, they wanted to look at the interplay of these time points. Could moms, some moms who experienced psychological distress during pregnancy have ongoing psychological distress? So they may have psychological distress at both time points. Could a neurodevelopmental disorder in that first year impact psychological distress one year? So they really had a number of time points where they wanted to assess these moms and look at neurodevelopmental delays.

So the measurements, they use a self-administered questionnaire on 10 occasions. So they used it during early and mid to late pregnancy. They used it at zero and one month postpartum. They used it at six months, a year, 18 months, two years, 30 months, two and a half years, and three years postpartum to collect information on demographic and socioeconomic status, medical and obstetric history, physical and mental health of the mother and the child, their lifestyle, and other aspects. They collected a lot of data. Most of these in the antepartum and immediately postpartum period, they were visiting these healthcare centers, so they were administered by the staff. And then subsequently after about six months postpartum, the questionnaires were distributed and collected by postal mail.

So they asked parents to rate their psychological distress using the Kessler questionnaire. It's a six item self-administered questionnaire and it's been validated in this population with an optimal cutoff score between four and five defined as a score that maximizes the sum of sensitivity and specificity. The group used psychological distress as a K6 score of five or greater. That was the exposure.

So the outcomes looked at Ages and Stages Questionnaires, which was assessed every six months from one and a half years to three years. So the primary outcome of the study was neurodevelopmental delay defined as a score below the cutoff in any of the five developmental areas at any of the four measurement time points. And then the secondary outcomes were 20 individual delays, looking at developmental area and time point, the interplay of both.

Okay. So they have this cool graph, directed acyclic graph, which uses this time point. So it represents these baseline confounders. They had tons, tens and tens of baseline confounders. Then they looked at these kind of time-varying covariates. Was it the psychological distress at time point one during pregnancy? How did that impact psychological distress at time point two, which is in that one year postpartum? How did that psychological distress during pregnancy impact neurodevelopmental delay at time point one, so in that first year? How did those impact neurodevelopmental delay at time point two, so after that time period? Really, really interesting. A lot of data pouring out of this paper.

So I told you they looked at a lot of baseline confounders. I mean, I'm not even going to go through all of them, but I mean, they're really here. I mean, mother's age during pregnancy, parity, highest education, alcohol and smoking history, passive smoking, employment status, history of depression, anxiety, schizophrenia. What was the folic acid intake, the energy adjusted omega-3 fatty acid intake, negative feelings upon learning of pregnancy. Who were they living with? What was the feeding method, nursery attendance, pet ownership, all sorts of things that might impact it. So they created basically kind of four models based on these time points. And I'm not going to get into all of that information. I'm just going to basically get you to the results.

So in total, this group of 82,418 mother-child pairs were analyzed. The mother's mean age was 31.1 years. The mean pre-pregnancy BMI was 21.2, which is probably much lower than the mean pre-pregnancy BMI in America. A total of 48.7% of the infants were female. A total of 23,365 mothers, so that's 28% reported psychological distress during the mid to late pregnancy only. So they didn't feel like they had that, they didn't score positive in the one year. 18,000 or 22% at one year postpartum only. So they flagged at one year, but they didn't flag during the pregnancy. And 10,000 or 12%, almost 13% had psychological distress at both time points. And the whole group neurodevelopmental delay was observed in 23,000 children, nearly 30%.

And compared with the analyzed mothers, so any babies who were excluded, interestingly tended to smoke, tended to be younger, be less educated, to be a passive smoker and have lower income. So I wonder how that would have impacted some of these results. But then they wanted to look specifically at the ASQs. So looking at the overall adjusted odds ratio for neurodevelopmental delay. So the adjusted odds ratio for developmental delay in moms who flagged during pregnancy only was 1.08. The adjusted odds ratio for moms who flagged at one year only was 1.38. And the adjusted odds ratio of neurodevelopmental delay for moms who were found to have psychological distress at both time points was 1.02.

They also looked at adjusted odds ratio across these four time points for delays in each of the five areas of the ASQ. And overall at all time points and in all domains, the adjusted odds ratio for psychological distress at one year postpartum only were higher than those for psychological distress during mid to late pregnancy only. And the adjusted odds ratio for psychological distress at both time points were higher as well.

So I thought this was interesting, especially as we recognize how much psychological, or we feel like psychological distress during pregnancy impacts long-term outcomes. But I think this is, what this is really showing is that the results showed a stronger estimated risk for psychological distress at one year postpartum during, then compared to mid to late pregnancy. And this tendency was true for each risk across all five developmental areas at all four time points. So there was more distress at one year and distress at one year even compared to stress during pregnancy was associated with more developmental delays.

So I thought this was interesting. I think it's a reminder, of course, that there's this interplay between what's happening during pregnancy and what's happening in that first year. But for our parents, what's happening in that first year is a NICU admission. So certainly that stress is going to be increased. And we know that maternal and paternal stress and anxiety persist definitely past a year if we're seeing it in those first few months. And so a reminder that tackling parental mental health may really help with those long-term neurodevelopmental outcomes.

Ben (47:09.346) Yeah, yeah, it's quite fascinating because we do know, I mean, obviously this cohort is quite representative of a general population. The number of mothers who delivered preterm was about like 4%, 4%, 5%, I believe. And in terms of babies that were small, it was also a relatively small percentage. So what dawned on me is that obviously, there's no, to me, it felt very obvious that, of course, a parent that is under psychological stress, that's not going to be positive for a child and it's definitely going to have an impact. But it also made me think of, can you imagine if we could quantify the stress, if it could give you a number, kind of like the volume dial on your stereo? Like, can you imagine how much that must be turned up when a mother just gave birth and has a very critically ill baby in the NICU. I can only assume the level of stress that we're dealing with. And like you said, how does that not have a negative neurodevelopmental impact? So, yeah.

Daphna (48:23.649) Yeah, and to your point, this was just regular stress of being a parent for the most part, right? It's not the NICU population. It's just the regular stress and put on top of that some medical complexity and all. Add on top of this was in Japan where, you know, the social support is totally different than it is for, you know, paid parental leave and NICU parents.

Ben (48:44.802) Yeah. Yeah. Yeah. We have NICU parents who have a sick baby in the NICU, who have other kids to take care of, who have job situations that need to be addressed. It's crazy. Unbelievable. All right. I have time for one more. All right. I'm going to go quick then. In the Journal of Pediatrics, first author is Anoop Katheria. And it's called Antenatal Prediction of Early Cord Clamping Among Infants Born Extremely Preterm.

So I highly suggest people go and check out the episode that we did not too long ago with Henry Lee to review the latest updates of the Neonatal Resuscitation Program's ninth edition release. I think that it's very interesting to see what has changed and what is the expectation. And one of the big things, obviously, is that delayed cord clamping is here to stay. And now the recommendation is for delayed cord clamping to take place for at least 60 seconds. And already I was on call last night, like the implementation of 60 seconds is something that at least our OB colleagues are painfully accepting.

Daphna (49:53.645) They're, yeah, they're doing it, but they're not thrilled about it.

Ben (49:57.951) Yeah, there are lots of jokes being made at our expense about like, yeah. But I think everybody understands. While it was very cordial, I think everybody understands the benefit and it's kind of nice. So, in terms of delayed cord clamping or DCC, really, we understand it has become the standard of care. Now, this practice involves delaying the clamping of the umbilical cord. And the benefits are very well established from multiple randomized control trial meta-analyses with national guidelines now strongly advocating for its use. Population-based studies have consistently shown improved outcomes after implementation. However, despite these clear benefits, the adoption of delayed cord clamping remains limited. And I think we've all experienced that. In a survey of 2,000 maternity hospitals in the US, only 50% of hospitals reported that healthy term newborns routinely receive delayed cord clamping.

Even more concerning is the situation for extremely preterm infants, those born at less than 28 weeks of gestation who are at the highest risk for severe complications such as intraventricular hemorrhage or death. These vulnerable infants are actually less likely to receive delayed cord clamping than their term counterparts. So the authors note that investigating perinatal risk factors that could potentially affect delayed cord clamping adoption is crucial to ensure it's applied optimally and equally across patient populations who would benefit most from increased placental transfusion. Understanding these risks of early cord clamping or ECC before delivery could allow for better preparation and maybe provision of additional measures to ensure that delayed cord clamping could be performed.

The objective of this study were to determine which antenatal risk factors could affect the provision of delayed cord clamping using a data set from the Neonatal Research Network Generic Database, which has been collecting information on cord management at birth since 2016, and to use these factors to predict which infant is at the highest risk of actually not getting delayed cord clamping. So this is a retrospective cohort analysis of this prospectively collected data by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.

The study included inborn infants born between 22 and 28 weeks of gestation who were delivered between January 2016 and December 2023 from 15 network centers. The researchers excluded infants with severe congenital anomalies or syndromes as well as infants receiving umbilical cord milking. So if a baby had received milking of the cord, they were sort of taken out of the cohort. They were not really able, I know that the NRP now talks about vigorousness of the baby, but they were not really able to have that captured in the database. And delayed cord clamping, because it's going back as far back as 2016, was defined as waiting at least 30 seconds. So we're not talking about a very high standard here, like the basic 30 seconds. Which, by the way, is no longer enough for the NRP. I just want to make that clear for the ninth edition.

In terms of multi-fetal pregnancies, counts were done on the individual infant level, meaning some pregnancies included instances where one got delayed cord clamping and the other early cord clamping. Some people do that. The first twin gets early cord clamping and the second one gets delayed. The statistical analysis employed two complementary approaches. I think first, they've performed a stepwise logistic regression analysis to identify variables most associated with early cord clamping. And second, they used a Classification and Regression Tree analysis or CART analysis. And for those of you who, like me, needed a refresher, CART analysis, which stands for Classification and Regression Tree analysis, you have to think of it as a sophisticated way to create a decision making flowchart based on data.

Imagine you're trying to figure out basically which factor most influences whether the baby receives early cord clamping. CART works kind of like 20 questions basically. It looks at all the possible factors and asks which single factor best splits our babies into two groups, those likely to get early cord clamping and those likely to get delayed cord clamping. Once it identifies that important factor, say whether the mom received magnesium sulfate, it then looks at each of those two groups separately and asks the same question again within that subgroup and so on and so forth. So a very common method.

Multiple maternal and prenatal factors were analyzed, including the center in which the infant was delivered, including maternal race, ethnicity, insurance, prenatal care adequacy, antenatal steroids, magnesium sulfate administration, various maternal conditions, delivery mode, time from admission to delivery, gestational age, and so on. So let's get into some of the results. The analysis included 12,622 infants that were eligible, 8,465 received early cord clamping, and 4,157 received delayed cord clamping. They had to exclude 783 infants due to congenital anomalies and 912 due to umbilical cord milking.

Now the proportion of extremely preterm infants who received delayed cord clamping at the Neonatal Research Network sites showed significant variation. I don't know if you're going to be able to guess how much variation. Between 0 and 74% per year, depending on the center.

Daphna (55:36.258) That's all the variation.

Ben (55:57.423) So that's all the variation. You cannot make the range more wide than that. There were minimal increases each year. So they saw that there was an uptake in the procedure, specifically 0.94% per year from 2016 to 2023, which was statistically significant. So that's good.

Looking at maternal characteristics, infants born to mothers who were Hispanic had a higher incidence of not getting delayed cord clamping with 18.9% in the early cord clamping versus only 13.7% in the delayed cord clamping group. Similarly, mothers with public insurance showed that 55% approximately received early cord clamping compared to 50% receiving delayed cord clamping. Limited prenatal care was associated with 12% rates of early cord clamping versus 9% delayed cord clamping. Lack of antenatal steroids showed that 36% early cord clamping versus 24% delayed cord clamping. No antenatal magnesium was strongly associated with early cord clamping, 19.1% versus 7.5% for delayed cord clamping.

Antepartum hemorrhage as well showed 25% of early cord clamping versus 16% for delayed. And cesarean delivery showed 69.7% early cord clamping versus only 61% delayed. So conversely, infants born to mothers who were non-Hispanic white had a lower rate of early cord clamping, 34.8% versus 41%. Gestational diabetes showed that babies received, 5% received early cord clamping compared to 6% in the delayed cord clamping. Chronic hypertension or pregnancy-induced hypertension also shows some similar results, 14% of early cord clamping, 17% for delayed cord clamping. Preterm premature rupture of membranes, 47% of early cord clamping, 50% delayed. And maternal antibiotics prior to delivery, 76% early cord clamping, 81% delayed.

Additionally, infants receiving early cord clamping delivered at an earlier gestational age, 25.5 weeks compared to 26 weeks, and had a higher incidence of small for gestational age at birth, and had shorter time to delivery from maternal admission with a median of 50 hours versus 66 hours.

Now let's look at the logistic regression analysis. It revealed that cesarean delivery had the highest odds of leading to early cord clamping with a 95% confidence interval ranging from 1.8 to 2.2. The CART model showed that not receiving magnesium was the most important factor for early cord clamping, followed by cesarean delivery, earlier gestational age, and antepartum hemorrhage. Importantly, the median time to delivery was significantly shorter in the mothers who did not receive magnesium sulfate. It feels like the two are connected, obviously, and that mothers who show up in precipitous labor do not get the luxury of getting magnesium treatment. And that potentially is what they're hinting at in this particular analysis.

Daphna (58:47.83) Right? Yes.

Ben (58:59.971) So the authors conclude that the study highlights the need for targeted interventions to promote the consistent application of delayed cord clamping in extremely preterm infants. And by identifying key predictors of early cord clamping, providers can develop strategies to address the barriers to delaying cord clamping and improve outcomes for this vulnerable population. Future research should focus on developing and implementing standardized guidelines and educational strategies that emphasize the importance of delayed cord clamping, and so on and so forth.

So I thought this was quite interesting. It's interesting how the data actually shakes out, right? And how these different risk factors, how the center plays a huge role, obviously, lack of magnesium, cesarean delivery, lower gestational age, and antepartum hemorrhage in that rank order is somehow the outcome. I would have suspected antepartum hemorrhage to be at the top, but surprisingly not.

Daphna (59:56.588) Yeah.

Daphna (01:00:01.027) Well, I think a lot of those things are linked to one another, but I mean, it gives this picture of, you know, a high risk emergent delivery. However, it's a good reminder that not everybody who has these emergent deliveries is not a candidate for delayed cord clamping, right? Like sometimes those babies look great, but probably the team is less likely to do delayed cord clamping in that scenario.

Ben (01:00:22.71) That's exactly right.

Ben (01:00:31.087) That's exactly right. I think that for me, the way I think about it is that we're often given like a heads up, right? We're often given like, hey, we have this parent coming in, in preterm labor and it looks like she's actively laboring and so on and so forth. And I think that we tend to say, okay, like we'll set up, but maybe when you get that little notification is the time to say, all right, since it looks like this is a patient that will deliver quite rapidly after arriving, can we have a little delayed cord clamping sort of huddle? So I think that's, if you suspect a mother that's not gonna get the magnesium, who's probably gonna go to, or somebody who comes in with a blood pressure of 250, if that's even possible, and you say, my God, they're gonna go for C-section. Think about that. Think about, can we find the time of one minute to just let that baby sort of get a bit of placental transfusion?

Daphna (01:01:04.46) Huddle. Yeah.

Daphna (01:01:27.466) Yeah, it feels like, you know, OB wants to get rid of that baby as soon as possible and we want our hands on that baby as soon as possible. However, an intermediary that could help that baby, like delayed cord clamping, I mean, maybe that's the baby who needs it more than any other baby, right?

Ben (01:01:44.035) Delayed cord clamping is probably one of the best interventions you can do in that first minute. Of all the things you could do. Yeah.

Daphna (01:01:47.658) Right? Right. That's right. So it's, I'm thinking more about it, that perhaps it's the baby who needs it most that is least likely to get it.

Ben (01:01:58.423) Absolutely. All right. That was great. Thank you, Daphna. We will continue to, we have some very exciting updates for the podcast for next year. I think that, thank you to everybody who participated in our giveaway in May and who gave us feedback. There's a lot of, there's some changes coming thanks to that feedback in order to make podcasts more manageable, more browsable. And so we'll be very excited to share with you these updates next month. And we, again, we remind you that the Delphi Conference is coming up January 26th, 2026 in Fort Lauderdale, Florida. If you are interested in innovation, if you want to meet people who are innovative and who you may want to collaborate with, come, it's a great experience. You can find out more at delphiconference.org. Daphna, thank you very much. I'll see you next time. Bye.