#396 - [Journal Club] - 📌 Cooling Late Preterms: Higher Mortality in 34-35 Weekers?

In this segment, Ben and Daphna review a retrospective study from the Hospital for Sick Children comparing outcomes of therapeutic hypothermia in late preterm (34-35 weeks) versus early term (36-37 weeks) infants. They discuss the significantly higher rates of mortality, hemodynamic instability, and hypoglycemia found in the younger cohort, known as "Group 1". The hosts explore the implications of using MRI scoring systems like the Weeke score for preterm brains and debate the ethical challenges of conducting future randomized trials as clinical practice shifts away from cooling younger babies based on emerging retrospective data.

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Whole-body hypothermia in late preterm and early term infants: a retrospective analysis from a neurocritical care unit. Martinez A, Cikman G, Al Kalaf H, Wilson D, Banh B, Abdelmageed W, Beamonte Arango I, Christensen R, Branson HM, Cizmeci MN.Pediatr Res. 2026 Jan 7. doi: 10.1038/s41390-025-04701-x. Online ahead of print.PMID: 41501407

Transcript

[00:00.558] Ben Courchia MD Hello everybody, welcome back to the Incubator Podcast. We're back today for another article in Journal Club. Daphna, good morning, how are you?

[00:09.238] Daphna Yasova Barbeau MD I'm doing well. I was thinking when I sat down this morning—we're recording in the evening—when I sat down in the real morning of our real day to review all my articles, I was like, "How do people have time to do this? Review all their articles?".

[00:25.068] Ben Courchia MD Well, just so you know, the people who write these articles ask the same question about you and me: how do we have time to do this? And just like we're recording at 7 p.m. on a Thursday night, they're probably writing their manuscript at 7 p.m. on a Thursday night.

[00:37.442] Daphna Yasova Barbeau MD Sure, for sure. But my point is, if I wasn't sitting down with you this evening to record, I probably wouldn't have gotten through all these articles today. It's why we started the podcast to begin with. So it was a good reminder to keep doing what we're doing.

[00:51.054] Ben Courchia MD Same for me, by the way. I would have been doing something very different. All right, where are you taking us today?

[00:58.738] Daphna Yasova Barbeau MD Okay. So this is a research article from the Society for Pediatric Research: "Whole-Body Hypothermia in Late Preterm and Early Term Infants: A Retrospective Analysis From a Neurocritical Care Unit". The lead author is Alejandro Martinez, senior author Mehmet Cizmeci. This is a pertinent and timely paper out of Canada. Basically, with all of our new thoughts and with the newest papers coming out about cooling late preterms, a lot of major centers are going back and looking retrospectively at their data and breaking babies up into these cohorts. So basically, they wanted to compare the outcomes of whole body cooling in infants with neonatal encephalopathy born at 34 and 0/7 to 35 and 6/7 weeks (so that was the lower gestational age group) versus 36 and 0/7 to 37 and 6/7 weeks gestation.

[00:58.738] Daphna Yasova Barbeau MD So, you know, all these babies are less than 38 weeks. I think a lot of people are using the 36-week cutoff because one, that's what the trials used, and two, given the newest articles on cooling late preterms. I'll give you a little bit more information. I told you as a retrospective observational cohort study, they had 122 late preterm and early term infants with HIE admitted to the Hospital for Sick Children between January 2015 and December 2023 who underwent whole body cooling. So in general, at that time, whole body cooling was provided to all infants greater than or equal to 35 weeks gestation with moderate to severe encephalopathy. Those were the unit guidelines. But there were babies who underwent whole body cooling below the 34-week threshold. Again, that was happening all over the country, all over the world potentially at the discretion of the attending neonatologist.

[00:58.738] Daphna Yasova Barbeau MD So I told you Group 1 included infants from 34 and 0/7 to 35 and 6/7 weeks. And Group 2 was for infants 36 and 0/7 to 37 and 6/7 weeks. I won't belabor the cooling criteria. I think they're pretty standardized at this point. Interestingly though, a lot of studies look at inborn versus outborn. Their unit is an exclusively outborn referral center. So all the infants were outborn and brought in. Initial neurologic assessments and encephalopathy staging are performed at the bedside by experienced neonatal transport clinicians using modified Sarnat and Thompson scoring systems before transfer.

[03:58.541] Ben Courchia MD What are you gonna get into then?

[04:04.097] Daphna Yasova Barbeau MD But I want people to know these things exist in the article, even if we're not gonna talk about them. All right, all the babies got their initial cranial ultrasound within the first 48 hours of admission. And then all infants underwent post-rewarming brain MRI as a part of the standard care. They were aiming to obtain post-rewarming brain MRIs within the first seven days after birth, hoping to obtain all on postnatal day four. And they used the Weeke scores for MRI evaluation. Now that is something to highlight, I think, for all of these papers. And I think they did a nice job doing that. So the Weeke score has really been developed and standardized for infants that are greater than 36 weeks gestation. In particular, they highlighted myelination in the PLIC, or the posterior limb of the internal capsule—a really common place for ischemic injury—is expected to be absent or only partially present in the late preterm and even near term infants. So they took special care, scoring that as abnormal when there was diffusion restriction in that area. They had two MRI readers who conferred on the MRI scoring.

[04:04.097] Daphna Yasova Barbeau MD So I told you there were 122 babies. In Group 1, there were 17 babies in the 34-week group and 46 babies in the 35-week group. So we know that looking for these late preterms gives us a lot of small numbers. In Group 1, 14 out of the 63 babies died: two in the 34-week group and 12 in the 35-week group. In Group 2, there were 59 babies: 25 in the 36-week group, 34 in the 37-week group. A total of seven babies in Group 2 died: five in the 36-week group and two in the 37-week group. So that was seven in Group 2 compared to 14 in Group 1 (the 34 and 35 weekers). They did have some babies lost to follow-up, but they were able to administer Bayley tests in five 34-weekers, 18 35-weekers, 12 36-weekers, and 23 37-weekers as their long-term neurodevelopmental outcome measure. Those babies who were assessed were assessed at 18 months using either the Bayley-III or the Bayley-4.

[07:01.281] Daphna Yasova Barbeau MD Okay. What are we going to get into? I'll tell you. We're going to get into the results. I told you a little bit about the group at presentation. In Group 1 infants, a moderate Sarnat was observed in 70%. The remaining 30% presented with severe Sarnat staging. So that was in the younger group. In Group 2, the older group, 83% presented with moderate Sarnat staging and 17% with severe staging. Overall, Group 1, the younger group, had lower umbilical cord artery pH—a median of 6.9 versus 7.0 in the older group. They had a higher Thompson score prior to therapeutic hypothermia. And compared to Group 2, more infants in Group 1 developed hemodynamic instability requiring inotrope or vasopressor administration: 67% in the 34 and 35 weekers versus 32% in the 36 and 37 weekers. They more often had hypoglycemia requiring dextrose boluses followed by increased glucose infusion rate: 54% in the 34 and 35 weekers versus 36% in the 36 and 37 weekers. 13% of infants in Group 1 required a glucagon infusion compared with 5% in Group 2. Other major clinical parameters and comorbidities did not reach statistical significance between the two groups. And in the subgroup analysis, more infants born at 35 weeks gestation developed hypoglycemia requiring dextrose boluses followed by increased glucose infusion rates compared even with those babies born at 36 weeks.

[09:18.209] Daphna Yasova Barbeau MD The EEG findings: severely suppressed background patterns—things like burst suppression, continuous low voltage, and flat tracing—were more common in Group 1, 40% versus 33% in the older infants. This did not reach statistical significance. And then in regards to seizures, there were 38% in Group 1, 27% in Group 2. This also did not reach statistical significance. And even subgroup analysis didn't really reveal any major differences between the group of 35-weekers compared to 36-weekers.

[09:18.209] Daphna Yasova Barbeau MD All post-rewarming brain MRIs were obtained within the first eight days. 95% of these scans were performed between days three and five. The median corrected gestational age at brain MRI was 35.7 weeks for Group 1 (the little group) and 37.7 weeks in the older group. Overall, all infants in Group 2 underwent a post-rewarming brain MRI. There were six patients in the first group who did not. There was good inter-rater reliability for the MRI scores. And in general, germinal matrix hemorrhage or IVH was observed on cranial ultrasound scans in 7% of infants in both groups. Overall, the white matter injury sub-score and the total injury scores were higher in Group 1, the younger group, compared to Group 2. This was statistically significant. Cerebellar sub-scores were also higher in Group 1. This was statistically significant, although the median scores were the same.

[11:29.089] Daphna Yasova Barbeau MD The outcomes. So overall mortality was seen in 22% (14 out of 63) in Group 1 versus 12% (seven out of 59) in Group 2, an odds ratio of 2.12. Mortality was more common in infants who presented with severe encephalopathy compared to those with moderate encephalopathy: 38% in Group 1 versus 11% in Group 2. This was statistically significant. And being in Group 1, the younger group, was associated with higher odds of mortality after adjustment for encephalopathy severity. Among survivors, the Bayley assessments were completed in 47% of surviving infants in Group 1 and 67% of surviving infants in Group 2.

[11:29.089] Daphna Yasova Barbeau MD And then they had composite outcomes for the long-term outcome. So the composite outcome of mortality or moderate to severe neurodevelopmental impairment, and mortality or at least one severe developmental delay. So they had two composite outcomes, which showed a trend toward being more common in Group 1, but this did not reach statistical significance. Group 1 did have higher odds of adverse outcomes. The composite outcome of mortality or moderate to severe neurodevelopmental impairment reached statistical significance after adjusting for encephalopathy scores.

[12:40.911] Ben Courchia MD And Group 1 is the little group, yeah. And Group 2 is the more traditional group that would get called sort of full term or near term.

[12:43.285] Daphna Yasova Barbeau MD The little group. Correct. And then the composite outcome of mortality or at least one severe developmental delay showed a trend higher in the little group, but this did not reach statistical significance. For the composite outcome of mortality or moderate to severe neurodevelopmental impairment, this is seen in 41% in the little group and 21% in the older group. The cognitive, language, and motor test scores as well as their subdomains actually showed no significant differences between the groups for all comparisons.

[14:27.161] Daphna Yasova Barbeau MD And then they wanted to look at the subgroup analysis, looking at the groups more specifically at each gestational age: 34, 35, 36, 37. So a trend towards decreased mortality was observed among infants born at 35 weeks, 36 weeks, and 37 weeks. So it was 26% at 35 weeks, 20% at 36 weeks, and 6% at 37 weeks. The difference in mortality rate was not statistically significant between infants born at 35 weeks gestation and those at 36 weeks gestation. And this remained unchanged after adjustment for encephalopathy score.

[14:42.541] Ben Courchia MD But I think you've given us a lot already to think about. I'm very curious to ask you a few questions after you're done.

[15:00.655] Daphna Yasova Barbeau MD Yeah, I want to see if there was something else here that I wanted to highlight for you. The composite outcome of mortality or moderate to severe neurodevelopmental impairment—again, 45% in the little group versus 21% in the older group. And mortality or at least one severe developmental delay: 55% versus 29%, both statistically significant. These differences in composite outcomes between the 35-week subgroup compared to the combined 36 to 37-week subgroup remained after correcting for encephalopathy severity. They didn't say this explicitly, but you can see that they didn't compare to the subgroup of 34-weekers. But if you'll remember, they only had 17 total 34-weekers and two of them passed away. So they only really had 15 34-weekers to use and only five of them were able to complete the Bayley assessment. So, it is likely that they were just not able to make those comparisons for the 34-week group, but I think we can potentially use the 35-weekers as a proxy for the 34-weekers, who again, in some of the other studies, that was the group that did almost the worst.

[16:14.115] Ben Courchia MD But the 34-weeker group in this particular study is quite small.

[16:17.545] Daphna Yasova Barbeau MD Very small, yeah. I mean, again, five with full data and follow up. But in general, kind of in conclusion, there was greater physiologic vulnerability—so more common hemodynamic instability, hypoglycemia, and higher white matter injury scores on post-rewarming brain MRI for those babies born at earlier gestational ages. So what did you think? You said you had some questions.

[16:47.791] Ben Courchia MD Yeah, I think that the discussion of this paper is extremely relevant in light of the recent paper that was published in JAMA Pediatrics on cooling for babies below 35 weeks. And you're right. And when you submitted this paper on our group chat, I was like, "Oh, are they going to show that maybe the data is not so clear?". But it goes along. And though in this particular case, I think this is an instance where the lack of significance doesn't really bother me so much just because the signal goes in the same direction as the data that we also have. I'm just curious as to why you picked this paper and what do you make of this data? Because for people who don't know, you are our HIE neurodevelopment expert. Any question that we have goes to you. And so I'm wondering... I'm just curious what you think about this.

[17:54.443] Daphna Yasova Barbeau MD Well, I think the concern in the community is: could we swing the pendulum too far, right? Do we have enough data to swing all the way back? Because units across the country are rewriting their protocols on, I think, good data, but still small numbers of babies. I think we're going to see more of these papers from centers that have done a lot of cooling and were pushing the envelope with younger babies. Maybe we'll start seeing the 12-hour cooling papers come out from units that were already doing it. And then looking at those outcomes, is it the same as a randomized control trial? No, it's not the same, but...

[18:41.295] Ben Courchia MD That's interesting you say that, because I was wondering if you were... I was thinking you might say something like that. And I think to me it's very concerning, because this data is gonna come out, and if God forbid it goes in a diverging direction, we're not ethically gonna be able to run another trial, I feel it.

[19:01.025] Daphna Yasova Barbeau MD To do the trials. It's going to be... nearly impossible to do the trials.

[19:07.959] Ben Courchia MD Yeah, right? Because if somebody comes out with some retrospective data and says, "Hey, we have this group of hospitals, and we have 600 kids, and it turns out maybe not, you know?". And then a Cochrane Review comes around, and it's like, "Well, between these two trials, we don't know." How are you going to run this trial? How are you going to say, "All right, we have this data that shows maybe increased mortality, and we're going to randomize?". It's like, ooh, that's going to be a challenge. So we'll see what happens. But it's always interesting to follow that data, right? Because I think if you use just one paper and you say, "This discussion's over," then the discussion is never over.

[19:43.041] Daphna Yasova Barbeau MD But I think barring whatever's happening outside this recording studio right now, I think in the unit, it's giving us all pause. And it makes sense, right? We know those 34-weekers, even the 35-weekers... I mean, there's a reason we're supposed to cook so long, is what I tell the parents.

[20:12.957] Daphna Yasova Barbeau MD They are more at risk for some of that physiologic instability. And not for nothing, but potentially even if they make it through the cooling, less likely to respond to the intervention. So our risk-benefit ratios are different. All right, buddy.

[20:35.011] Ben Courchia MD All right, Daphna. Thank you very much. I'll see you next time.