In response to a couple of thoughtful comments to my previous post, I thought I would try to address the specific issue of the infant of 35 weeks. (Faix RG, et al. Whole-Body Hypothermia for Neonatal Encephalopathy in Preterm Infants 33 to 35 Weeks’ Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2025;179(4):396-406).
There is clearly some room for discussion, not only are obstetric estimates of gestational age uncertain, but what is the real difference between an infant at 35 weeks and 6 days, compared to 36 weeks exactly? Should we really determine therapy based on whether the baby was born before or after midnight?
The discussion section of this new article reports on personal communication with the investigators behind the 2 previous trials that included some babies at 35 weeks gestation. Apparently, in total there were 7 babies, 2 controls (1 died and 1 survived without handicap), and 5 cooled (2 deaths, 2 survivors with disability, and 1 without). From the supplemental data supplied with the new article, there were 48 infants of 35 wk GA in this trial, 20 controls and 28 infants treated with hypothermia.
Adding all the results together gives the following :
| Control | Hypothermia | ||||
| Death | Disability | No disability | Death | Disability | No disability |
| 4 | 1 | 17 | 5 | 2 | 23 |
I performed an ad hoc Bayesian analysis myself, using an on-line calculator, which gave probabilities of close to 50% for each of the 2 options being preferable, for the combined outcome of “death or disability”, but you don’t really need to do that, there clearly is next to no difference in the outcomes.
This is, of course, an extremely limited analysis. I do not know if the definitions of disability (moderate or severe) were the same in those 2 prior trials as in the new trial, the 2 prior trials being Eicher et al and ICE. I don’t know how definite the obstetricians were in their calculation of GA, I don’t know how many babies in the various trials were lost to follow up, or if there were babies who died between discharge and follow up in the previous trials. All that said, the very limited data available do not show a major benefit of cooling at 35 weeks.
We could ask, why would therapeutic hypothermia suddenly become effective at 36 weeks 0 days? That is inherently unlikely, and I think we really need to have an Individual Patient Data meta-analysis, analysing the outcomes of the hypothermia trials by week of gestational age, the most likely outcome of such an analysis, I posit, would be a progressively greater benefit as GA advances, with perhaps harm prior to 35 weeks, no real difference between around 35 and 36 weeks, and improved survival and improved outcomes among survivors born at term. Here are the Forest plots of the results for death, and for major disability among survivors, from the latest version of the Cochrane review, which dates from 2013. CoolCap, n.neuro, TOBY, Shankaran and the NICHD trial all included babies from 36 weeks, the others were limited to at least 37 weeks GA.
That Cochrane review does not include data from more recent trials, which are largely in Lower and Middle Income countries. Those trials have been reviewed several times recently, including in a very new publication which appeared in a Supplement to “Neonatology” dealing with neonatal priorities in LMICs. You may already be aware of the HELIX trial, which really threw a spanner into the cooling machine works, it was a very important multicentre trial, from India, Bangladesh and Sri Lanka, which showed an increase in mortality with cooling. As an accompanying editorial clarifies, many of the infants were SGA, were outborn and were not transported by ambulance, many had MRI injury suggesting more chronic asphyxia. Nevertheless, overall, it looks from a complete SR/meta-analysis like there is no major benefit of Therapeutic Hypothermia in LMICs, but several single centre trials have often shown a benefit. I haven’t studied this data enough to be sure about the right approach, but many neonatologists working in LMICs do still offer hypothermia, if the conditions are right.
The reason for that little detour was just to demonstrate that hypothermia isn’t always beneficial, other studies have shown increases in mortality, as also suggested by the new late preterm trial. My conclusion is that for late preterms, there is no evidence of benefit; as gestational age increases it looks more and more likely that cooling decreases mortality and decreases disability. The exact point at which the probable harm among the preterm changes to the probable benefit at term is uncertain. It probably isn’t exactly at 36 weeks 0 days. It may well depend on other factors than purely GA, such as whether the infant is SGA, the duration of the asphyxial insult, and avoidance of excessive hypothermia, as well as perhaps the severity of the encephalopathy and the occurrence of seizures. Without knowing the impacts of those factors, it is impossible currently to select 35 week GA babies with HIE who are more likely to benefit.
I am trying to imagine what I would do tomorrow if I was asked to see a baby of 35 weeks and 5 days, who was, otherwise, a perfect candidate for cooling, with a good weight, a normal fetal heart rate trace until there was a clear sentinel event like a cord prolapse, who developed moderately severe encephalopathy and seizures at 3 hours of age. I think it is too easy to just say that it would have been OK to cool if he had been born 2 days later. On the other hand, without some sort of protocolised limits then we could cool everyone! I think, right now, I would say there is no clear evidence of benefit, and maintaining strict normothermia is the best, evidence-based approach. But I couldn’t be too angry at a colleague who had decided to cool such a baby.
Neonatal Research 
What you propose is an ethical issue: Tolerance to the uncertainty range.
As a Neo doing this now for over 45 years in FT practice and being directly involved in at least 35,000 NICU babies over those very enjoyable years, the problem I have with the issue of there being a specific EGA where it either is likely to help or doesn’t help or even harm is that it horribly fails the « sniff test ». Where is the physiologic underpinning for that difference in response in later preterm infants ? Perhaps there is a difference but that doesn’t seem to be the subject of discussion. What is it about we what we know of the difference of neurogenesis, synaptogenesis, brain metabolic response to asphyxia’s operant conditions, or other organ system responses to hypothermia that would help to explain such a difference ? Absent this underpinning, I would look more to variability of ascertainment of actual developmental effects impacted by gestational age differences than actual differences in either the pathology initiating the potential for injury or the response to a potentially therapeutic intervention such as hypothermia. Using that « sniff test » for common sense, one could wonder why there would be a difference even down to 33-34 weeks gestation. Perhaps there is a genuine difference in response at a cellular, biochemical level but in such an intensely studied area–what is it ? We’ve made progress in the fundamental metabolic and structural differences related to EGA in other organ systems including the gut, liver, lungs, heart and have recognized those real differences by developing or modifying therapeutic options for rectifying many of their pathologies. Those therapies have been based on and validated by their addressing specific metabolic/structural aspects of development shown to vary significantly with developmental age. Perhaps I just don’t know what the brain equivalent to surfactant deficiency or microbiome status actually constitutes but as I stated, not knowing that, the dichotomy of responses to a therapy like hypothermia within a few weeks of gestational development seems like more a problem of tools of assessment normalized for EGA versus a fundamental difference in biologic effects.
In the RCT by Faix et al. results of therapeutic hypothermia (TH) following perinatal asphyxia have been analyzed in infants with a gestational age (GA) of 33-35 weeks. The authors conclude that TH is not effective, and potentially harmful. Unfortunately, stratification for GA has not been performed in this study. On careful reading the results for the infants with a GA of 35 weeks were based on 48 infants (TH n=28, control n=20) and neither details on cause of perinatal asphyxia (e.g. fetomaternal transfusion causing a more chronic asphyxia, or complete placental abruption causing acute asphyxia), nor other clinical variables such as intrauterine growth restriction have been provided. These variables could be unbalanced between the two study arms, and affect the outcome of TH.
From a neurodevelopmental point of view there are no major differences (if any) between the brain of an infant born at 35 5/7 weeks and that of an infant of 36 1/7 weeks following perinatal asphyxia. Both are at risk of injury of the basal ganglia and thalami and subsequent dyskinetic cerebral palsy following a sentinel event, and benefit from TH. This is different from infants born at 33-34 weeks who often show cerebral white matter injury following perinatal asphyxia.
Surprisingly, the question whether TH is effective has not been asked in infants born at a GA of 36 weeks, who are near-term (not ‘full term’) and represent only 10% of the population of infants receiving TH. They are most likely underrepresented in the larger RCTs, and detailed results of TH at 36 weeks (as opposed to 37-42 weeks) are largely unknown.
Following the study by Faix et al. not only effects of TH in infants of 35- and 36-weeks’ GA should be reported in larger cohorts, but also clinical details such as cause of the perinatal asphyxia. Thereby, clinicians will be able to avoid useless interventions and potential harm. From future prediction models we may be able to identify the patients (born at both 35 or 36 weeks) with a high chance or no chance of a beneficial effect of TH.
At present, in my view the best option is to continue offering TH at 35 weeks after informed parental consent, meanwhile gathering and exploring real life data from as many units as possible.
From a physiological/developmental window point of view, I would offer TH at 35 wks.