Neonatal Research Shorts : May 2025

Posted on 13 May 2025 by Keith Barrington

Dutta S, et al. Seven-day versus 14-day antibiotic course for culture-proven neonatal sepsis: a multicentre randomised non-inferiority trial in a low and middle-income country. Arch Dis Child Fetal Neonatal Ed. 2025.

This is a multicentre trial from India of neonates (0-28 d of age), term and preterm (down to 1kg b.wt) who had culture positive sepsis and were stable by 5 days of treatment. There is a detailed algorithm in the supplemental materials to define “clinical remission of sepsis”, which looks quite fair. At 7 days of treatment of sepsis, with antibiotics to which the organism was shown to be sensitive, the babies were randomized to stopping the antibiotics, or continuing for 14ays. They excluded babies with S Aureus, or fungi, or meninigitis, or other infections considered to definitely need longer antibiotic courses, such as osteomyelitis. There were about 1000 babies with culture positive sepsis, and following the deaths, transfers and non-eligibility criteria there were 261 randomized.

The primary outcome of the trial was definite or probable relapse, with definite being defined by recurrent infection with the same organism, and probable being “culture-negative sepsis”, within 21 days of the end of the antibiotics. The short duration antibiotic group could be discharged before the end of the antibiotic course of the long duration group, and most of them were, the median hospital stay after randomization was 6 days in the short treatment group. That introduces a possible bias, as surveillance, and risk factors, are obviously different after hospital discharge. Also, many of the results, including the primary outcome is calculated as the occurrence of the outcome within 21 days after stopping the antibiotics. In other words, a 7 day longer period in the long treatment group than the short duration group.

It looks like someone during the peer-review process had the same concern, and the results are all also presented as the occurrence of the outcome during various time periods after randomization. You can see those results below. The first column being the 7-day duration group, the2nd being the 14-day group.

There are no important differences, with all outcomes being in favour of the short treatment, and the trial was stopped early, after about 2/3 completion, because the DSMC stated they had demonstrated non-inferiority. The duration of hospitalisation after randomization was 4 days shorter in the short treatment group, despite the inclusion of preterm infants whose discharge may well be unrelated to the sepsis treatment.

Are these data relevant to High Income Countries? The bacteriology is somewhat different to HICs, this study had no cases of GBS, and a variety of mostly Gram-negative organisms, including Acinetobacter baumanii. Many of the organisms are multi-resistant, including the A. baumanii which is always Beta-lactam resistant, and is usually resistant to aminoglycosides and to meropenem. (Russell NJ, et al. Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS). PLoS Med. 2023;20(6):e1004179).

Take Home Message : It is reasonable to consider shorter courses of IV antibiotics in newborns with culture positive sepsis who have received 7 days of treatment with antibiotics to which the organism is sensitive, if they stabilised, and were clinically improved, within the first 5 days of treatment.

Hough JL, et al. Intermittent sigh breaths during high-frequency oscillatory ventilation in preterm infants: a randomised crossover study. Arch Dis Child Fetal Neonatal Ed. 2025;110(3):297-302.

I remember when we first started using HFO in preterm infants, we thought it might be important to have intermittent sighs, as Alison Froese had shown in an animal model that they seemed to be important for aiding lung expansion. She had shown that lungs which were atelectatic, such as we see in HMD, couldn’t really be opened up by HFO without sigh breaths. They rather fell out of use as we gained experience with HFO, but there are a number of studies looking at various methods for improving lung recruitment, including substantial increases in mean airway pressure, followed by rapid weaning. Like many others, given the lack of any evidence that first intention HFO improves pulmonary outcomes compared to first intention conventional IMV, I keep HFO to use as a rescue mode, and if I am changing to HFO because of problems with oxygenation (rather than difficulty with ventilation) I increase the mean airway pressure by 2 cmH2O initially, which often leads to a decrease in FiO2, and therefore, likely, an improvement in lung recruitment.

In this randomized cross-over trial, a very diverse group of preterm infants on HFO with an oxygen requirement (25 to 75% O2), who were already on HFO either stayed as they were, or had sigh breaths added, and then switched to the other condition. The sigh breaths were delivered with a pressure of 30 cm H2O, and an inspiratory time of 1 second, 3 times per minute. One part of the protocol I’m not sure I understand is that “MAP-set was reduced in proportion to the difference between MAP-set and PIP = 30 cmH2O aiming to keep average MAP unchanged”. I think I know what they did, its just the “…in proportion to the difference between…” part that is confusing. I think that, for an infant starting on an MAP of 15 cmH2O, during the sigh breath period, they would reduce the HFO mean pressure to account for the 3 seconds/min of a pressure of 30 cmH2O, in other words, they reduced the mean pressure to 14.2 during the sigh period. Or an infant on a MAP of 12 would be reduced to 11. They could just have said, “the set MAP was reduced slightly, to keep average MAP unchanged”. Each period lasted 2 hours. During the 2 periods, they estimated changes in lung volume using trans-thoracic impedance, and distribution of ventilation using the same methodology.

Although each period lasted 2 hours, they only present data at 0, 30 and 60 minutes, I am not sure why. Lung volumes appear to have increased during both phases of the study, but with a greater increase when sighs were added.

Take Home Message : Intermittent sigh breaths improve some regional lung inflation, and have a small effect on oxygenation. Further study should determine whether this improves pulmonary outcomes.

Muts J, et al. Macronutrient concentrations in human milk beyond the first half year of lactation: a cohort study. Arch Dis Child Fetal Neonatal Ed. 2025;110(3):248-52.

This was an analysis of milk donated to the Dutch national milk bank. Mothers who donated more than 6 months after delivery had the macronutrient composition of their donation. Protein concentrations decreased slightly up to 8 months of donation, and then re-increased. Carbohydrates remained stable, and fat concentration increased after 8 months.

Take Home Message : Up to 2 years after delivery, donated breast milk is satisfactory as a source for preterm infants.

Eisenberg MA, et al. Epinephrine vs Norepinephrine as Initial Treatment in Children With Septic Shock. JAMA Netw Open. 2025;8(4):e254720.

A retrospective single centre cohort study, from Boston Children’s, with over 200 children with septic shock, compared renal outcomes between those treated initially with epinephrine to those who received norepinephrine first. The primary, renal, outcomes were not different between groups, but survival was greater with norepinephrine, (0% mortality, compared to 4% mortality with epinephrine).

Take Home Message : we have very little reliable data on which to base choice of agents for cardiovascular support in septic shock. This study suggests that norepinephrine is a reasonable first choice, for older children.

McLean MA, et al. Neonatal Sucrose and Internalizing Behaviors at 18 Months in Children Born Very Preterm. JAMA Netw Open. 2025;8(4):e254477.

In 3 Canadian NICUs, daily pain exposures and sucrose administration were recorded for infants born at 24 to <33 weeks. Opiates and other analgesics were also recorded. 200 babies had Child Behaviour Checklists completed.

I was shocked to see that one of the 3 centres does not use Sucrose! I can’t imagine why. Sucrose clearly reduces pain in very preterm infants, and the idea of performing a mean of 170 painful procedures on the poor babies in centre 1 without the use of sucrose, I find appalling. For many painful procedures, such as heel puncture, opiates are ineffective, and pain control is optimal with a combination of sucrose, soother, and skin to skin care.

There was some older data from a trial by Celeste Johnston that suggested that the infants with the highest sucrose exposure had poorer long term outcomes, but they also had more painful procedures. No other data are available to show adverse long term impacts of sucrose.

The study showed that, “after accounting for site differences in clinical factors, greater neonatal pain (number of painful procedures) was associated with greater internalizing at 18 months CA. Cumulative sucrose exposure in early life was not associated with child internalizing behaviours”. They also note “point estimates indicate no clinically meaningful difference in internalizing behaviours for children exposed to sucrose (B = 2.38)”, and “Cumulative sucrose was not associated with internalizing scores (B = 0.41; 95% CI, −0.52 to 1.41) accounting for neonatal pain”. The authors then try and stretch their data, suggesting that, because the confidence intervals around the effect of sucrose on internalizing behaviour are asymmetric, the “point estimate” of the association between sucrose and the internalizing T-score on the CBCL is consistent with a clinically relevant impact.

Take Home Message : Painful procedures among preterm infants in the neonatal period are associated with increased internalizing behaviour at 2 years of age. Sucrose does not change that association.

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Therapeutic Hypothermia at 35 weeks

Posted on 11 April 2025 by Keith Barrington

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  
DeathDisabilityNo disabilityDeathDisabilityNo disability
41175223

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.

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Therapeutic Hypothermia in the Late Preterm Infant

Posted on 9 April 2025 by Keith Barrington

Current guidelines support the use of therapeutic hypothermia for term infants with hypoxic ischaemic encephalopathy. Both the Canadian and the US guidelines include infants born at 35 weeks gestation. However, the data supporting efficacy for those late preterm infants, is extremely limited, and less mature infants were excluded from all the major trials. The discussion section of this new publication reveals that the 2 RCTs which included babies of 35 weeks GA had a total n of 7.

This lack of reliable information for a group of infants who are referred with acute encephalopathy led to the performance of an RCT by the NICHD network. 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. They enrolled 168 infants born at 33 to 35 weeks gestation, with moderate to severe encephalopathy, including a depressed level of consciousness, they did not require EEG (or aEEG). The intervention group were cooled to a standard 33.50 for 72 hours, starting within 6 hours of birth, and the controls were maintained around 370.

The primary outcome was death or disability, with disability defined as severe : Bayley III cognitive score <70, GMFCS level 3-5, blindness, or deafness despite amplification; or moderate : cognitive score 70-84 or, GMFCS level 2, treated seizure disorder, or hearing loss requiring amplification. Primary analysis was a Bayesian approach, with the prior assumption being no effect of the intervention.

As you can see there was no indication of any benefit. Death was more frequent in the hypothermia group, and outcomes among survivors were just about identical, a slightly proportion with severe disability in the hypothermia group (and interestingly, almost no survivors with moderate disability, in either group, 2 vs 0). The Bayesian analysis shows there is very low probability of benefit of cooling in this population. Also, there were many of the cooled babies who overshot their target, 32 of them had a temperature recorded under 320 during the first hour of intervention.

Interestingly, the way this is presented in the table is that there is only a 13% chance of benefit on mortality with cooling; in the discussion this is stated as an 87% probability of harm from the treatment, which gives a zero chance that the treatments are equivalent! Maybe it’s just my poor understanding of Bayesian analysis. Within Bayesian analysis there are ways of evaluating different magnitudes of treatment effect, which is something that I think we should consider for the future, rather than presenting data as if the only 2 possibilities are that the outcomes are either better or worse, it would perhaps be more helpful to calculate the probabilities of a particular, clinically important impact, and the probability that mortality is about the same, using whatever limits are considered appropriate. I guess, if the probability of benefit had been about 50%, then you could say the treatments are equivalent?

On the other hand, for this intervention, as there is very low probability that cooling is beneficial, we should not cool the late preterm infant with encephalopathy. For babies at 35 weeks, these data are much stronger than those previously available, and 35 week GA infants should probably not be offered therapeutic hypothermia, and should be excluded from the next version of any guidelines.

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Prolonging CPAP in the preterm to improve pulmonary outcomes

Posted on 8 April 2025 by Keith Barrington

I wrote about this trial after last year’s PAS meeting, mentioning that it looked like a potential significant improvement in respiratory care of the preterm The full publication confirms that is a real possibility. McEvoy CT, et al. Extended Continuous Positive Airway Pressure in Preterm Infants Increases Lung Growth at 6 Months: A Randomized Controlled Trial. Am J Respir Crit Care Med. 2025;211(4):610-8.

The trial enrolled 100 preterm infants (24 to 32 weeks GA) who had at least 24 hours of CPAP and were considered ready to have the CPAP stopped (5 cmH2O, 21% O2, without tachypnoea or retractions or frequent apnoea, and tolerating breaks from CPAP during care procedures). They had to satisfy these criteria for 12 hours to be considered “stable”. (The pilot trial published previously used a pressure of 4-5 cmH2O, with the same criteria). They randomized the babies to their usual care, which was stopping the CPAP, or to remain on CPAP for a further 2 weeks. Neither this publication, nor the pilot, nor the registration documents, states what pressure was used for this extended CPAP treatment. Which I think is critical, did they use 4 or 8 cmH2O? or something in between?

Babies averaged about 30 weeks GA, and were eligible for the trial at a mean 32.4 weeks PMA, a minority in each group had required surfactant (25% vs 37%). Occasional infants paused the extended CPAP because of local nasal trauma, and occasional controls had to have their CPAP restarted.

Short term results confirmed the increase in FRC with prolonged CPAP, as demonstrated in the pilot, when measured just after the intervention period. At 6 months the infants had lung function testing, which showed improved Alveolar volume, improved DLCO, and better Forced Expiratory Flows.

FEF is, of course, a measure of small airways function, and is frequently impacted by preterm delivery, this result is reassuring that the increase in alveolar volume is not just because the alveoli are distended, but probably lung growth overall is increased, including small airways. That would be consistent with findings from animal models; prolonged CPAP does not simply distend the lungs, it seems to promote lung growth, and, in a couple of models, decreases airway reactivity.

Parents were questioned about wheezing, and bronchodilator use. The questionnaire also asked about hospitalisations, and respiratory hospitalisations, but those data are not reported. Babies in the extended CPAP group were less likely to have wheeze, 43% vs 56%, but this is within the confidence intervals of no difference.

The major limitation of this trial, in terms of impact on clinical practice, is that these are babies with very little lung disease, only about 7% in each group had BPD, (Oxygen at 36 weeks). Although even such relatively minor lung disease of prematurity is known to lead to long term impacts on pulmonary health, whether the intervention would be equally as effective among infants with sicker lungs is unknown.

Routinely extending every baby’s CPAP by 2 weeks would have major impacts on resource utilisation, so we really need robust data. It also could have adverse impacts on oral feeding, especially breast feeding, during the time period when orality is also developing. Most of the babies in this study finished the intervention between 34 and 35 weeks, so the interference with developing breast feeding may have been small, but if babies who become eligible later (in terms of PMA) are treated with extended CPAP, the progression of breast feeding might be a major issue.

I hope that further trials, including infants requiring oxygen supplementation, and with more extensive analysis of outcomes of direct interest to parents, are planned. I also hope that the possible impact on breast feeding is investigated. If every very preterm baby, who is otherwise clinically ready to have their CPAP discontinued, will have that treatment extended for 2 weeks, we need to be very sure that the benefits justify the extra resources, and that there are no balancing negative effects.

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Neonatal Research Shorts : April 2025

Posted on 7 April 2025 by Keith Barrington

I used to do a series of shorter posts called “weekly updates” but I ran out of steam and have concentrated on longer posts in recent years. The last couple of weeks, with clinical service, I have had less time for a longer post, but a few things piqued my attention:

Alexe PI, et al. Prematurity and Congenial Diaphragmatic Hernia: Revisiting Outcomes in a Contemporary Cohort. J Pediatr. 2025:114545. I thought I would write about this article before the title got corrected, (unless, that it, they really are discussing “congenial” diaphragmatic hernia). Right now if you do a search on “congenial” in pubmed, you get this hit and a couple of auto-mis-corrected titles!

There was also an article about congenial cataracts, and several others about congenial heart disease. The pre-print of the article has the error right on its front page, it has probably been seen by hundreds of pairs of eyes, and everyone’s brain auto-re-corrected it back to congenital! I am not writing about this just to poke fun, however, it really is a very interesting piece of work from an international consortium, reporting analysis of over 13000 cases. It demonstrates very clearly the major impact of prematurity on management and outcomes of CDH. Survival of all cases progressively increases up to 40 weeks gestation.

For infants of <34 weeks gestation, large numbers never have a surgical repair, nearly half, and those that do, get their surgery much later, at 11 days mean, compared to about 1 week for the early term and term groups. ECMO was used in about a third of the cases after 34 weeks, but only 7% of the <34 week infants. ECMO survival was 30% for the <34 weeks, 40% for the late preterm, and just over 50% for the term infants. All of the measures were more marked for the very preterm, and worse again for the extremely preterm.

Within the database there are many infants who delivered after fetal intervention (FETO), which was associated with lower survival. This was clearly because they were a much higher risk group, which is why they were selected for FETO, overall survival was only 54% after FETO, compared to 71% among the remaining infants, and almost all of the FETO babies needed a patch repair. FETO was also associated with increased prematurity, and among those who did deliver preterm, survival was poor, about 40%, but was identical with or without a prior FETO.

Take Home Message : Prematurity is very bad news for infants with CDH.

Franz AR, et al. Effects of liberal versus restrictive transfusion strategies on intermittent hypoxaemia in extremely low birthweight infants: secondary analyses of the ETTNO randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2025. This is a secondary analysis of the ETTNO trial, the primary publication of which which showed no overall benefit of a higher versus a lower transfusion threshold in the very preterm infant. This analysis focused on any potential impact of transfusion threshold on apnoea spells, which are the usual pathophysiology behind intermittent hypoxia. Multichannel recording and analysis of apnoea patterns, which I have done, and published, many hundreds of times and published is much more difficult and time consuming than just recording oximeter saturation data. In addition, unless you record airflow as well as just respiratory movement and heart rate, you gain very little, and measuring airflow is tricky. Most recent studies therefore have measured, and discuss, intermittent hypoxia.

I actually started an RCT of transfusion therapy for apnoea when I was in San Diego, we enrolled only about 20 patients prior to me leaving UCSD, and the fellow also graduated, so the trial ground to a halt unfortunately. I did have a poster at an SPR about our preliminary findings, but never felt that it was worth a publication. Basically we performed multi-channel recordings, including an expired CO2 detector next to the nose of the infants, among convalescent preterm babies with apnoea and a hemoglobin <100. We randomized them to get an immediate transfusion if the attending physician thought it was reasonable to transfuse, or to not be transfused for at least 72 hours, and did physiological recordings for 72 hours. The trial was of course therefore very underpowered, but there was no impact of transfusion on the respiratory patterns of the babies.

We did that trial because, at the time, recurrent apnoeic spells were often as an indication for transfusion in anaemic preterm infants. There were also a few observational cohorts, which suggested that apnoea becane less frequent after transfusion, but those cohorts were all uncontrolled. Control groups are essential for many things, but especially with a condition such as apnoea of prematurity, which always gets better with time anyway! Without a control group, any intervention that you can imagine will be followed by decreased apnoea, especially when you factor in that babies are usually enrolled in a trial when their apnoea frequency is at its highest. I was rather sceptical about apnoea as a transfusion indication, which was the justification for the RCT.

This new publication has compared intermittent hypoxia episodes, occurring between days 8 and 49, between infants in the higher transfusion threshold group to the lower group. All the babies were less than 1kg, and there were over 250 per group.

There was no difference between the groups in numbers of IH episodes, duration of episodes, more severe episodes, or the median duration of episodes. Or indeed, as they have previously published, on survival or neurological or developmental outcomes. There was also no interaction between IH, transfusion strategy, and outcomes.

Take Home Message : Intermittent hypoxia, and/or apnoea of prematurity is not an indication for blood transfusion.

Cheung PY, et al. Dose-related systemic and cerebral hemodynamic effects of norepinephrine in newborn piglets with hypoxia-reoxygenation. Pediatr Res. 2025. Po-Yin Cheung and the group in Edmonton refer to the lab where they do their animal work, as my old lab; I set up many of the processes and bought some of the equipment that they are still using 30 years later, including the Transonic flow probes! Po-Yin, and Georg Schmolzer, and their colleagues, have gone far beyond what little I accomplished there, however. This new publication is in acutely instrumented anesthetised newborn piglets, and investigates the haemodynamic and cerebral circulatory effects of norepinephrine infusions. The model they use is one developed by Po-Yin, of hypoxia and re-oxygenation, and is designed to be a model of infants after perinatal asphyxia.

Our group in Montreal have been using norepinephrine for circulatory support for a few years now, mostly for septic shock or for infants with PPHN who need support. In both circumstances there is a small amount of animal data, and a very small amount of human neonatal data suggesting advantages over other agents. One thing that has been missing is a good idea of what the agent does to the cerebral circulation, being very difficult to accurately measure cerebral perfusion in the newborn infant.

The model used in this study leads to a severe metabolic acidosis, lactate of 20 and Base Deficit of 20, and 2 hours later, prior to the study medications begin administered, the acidosis was a little improved. Animals then got either saline, or epinephrine infusion at 0.1 mcg/kg/min or one of 3 doses of NorEpinephrine (0.05, 0.1 or 0.2 mcg/kg/min). Without going to all the details of the findings, NE at 0.1 mcg/kg/min had the biggest positive impact on cardiac function and cardiac output, With cardiac output increasing by 100%, due to a small increase in heart rate, of about 20%, and a major increase in stroke volume. At the same time systemic blood pressure increased by about 20%.

In addition carotid blood flow increased by nearly 20% leading to an increase in cerebral oxygen delivery and brain oxygenation.

Clearly, one cannot directly extrapolate these results to the human newborn, and particularly not specific dose responses, but they do give some reassurance that norepinephrine does not vasoconstrict the neonatal cerebral circulation.

Take Home Message: (with lots of caveats) norepinephrine infusions may lead to improved cerebral oxygenation.

Fox L, et al. A Pilot Randomized Control Trial of Holding During Hypothermia and Effects on Maternal and Infant Salivary Cortisol Levels. Adv Neonatal Care. 2025;25(2):173-80. Many centres, including ours, have instituted “cool cuddles” (câlins-frisquets in Quebecois), whereby infants with HIE being cooled are allowed to be cuddled by their mothers (or fathers!). We have demonstrated, for our own purposes, that this doesn’t adversely impact temperature control. We still have a few restrictions, for infants with multiple central lines it gets quite difficult to ensure safety. Although it seems like the right thing to do, from first principles, this new randomized trial sought signs of infant stability and stress, and maternal stress from their salivary cortisol levels. Mothers in the cuddling group had lowered cortisol, as did their infants, who also showed lower, stable heart rate and respiratory rate, without desaturation, or temperature problems.

Take Home Message : Cuddling during therapeutic hypothermia reduces maternal stress.

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Early hydrocortisone in shock?

Posted on 21 February 2025 by Keith Barrington

A few years ago, we published our experience with the use of hydrocortisone in newborn infants in septic shock (Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? Am J Perinatol. 2018;35(2):146-51), like many such studies the numbers were small, but the 39 babies who received hydrocortisone in addition to their inotropic support had rapid haemodynamic improvement, within 6 hours of starting hydrocortisone, mean BP had increased by over 30%, urine output was better, and inotropic support was being weaned. They were, however, somewhat less likely to survive the episode (59% survival vs 78% without hydrocortisone) and to survive until discharge, neither of which comparisons were “statistically significant”, and the babies who got hydrocortisone were sicker, less mature and more likely to have NEC, than the septic babies who did not get hydrocortisone.

Those data suggested that there was a major rapid haemodynamic response to hydrocortisone in newborn infants with septic shock, but they clearly could not answer the important question about whether they improved survival.

A new, single-centre prospectively-registered RCT has examined this issue. (Dudeja S, et al. Early hydrocortisone verses placebo in neonatal shock- a double blind Randomized controlled trial. J Perinatol. 2025). Newborn infants with shock, of any aetiology, were enrolled in 2017 and 2018 (not clear why the delay in publishing) and randomised to receive early hydrocortisone, or placebo. It is also not clear why they bothered with the placebo, as the bedside nurse was not masked to study group assignment. The main problem with the trial is the definition of shock, which was either A or B criteria “(A) either systolic or diastolic blood pressure (BP) less than 5th centile; (B) Any two of the following five criteria- capillary refill time >4sec, core-periphery temperature difference >3 °C, urine output <0.5mL/kg/hr in previous 6 h, base excess worse than −5.0mmol/L and lactate >5mmol/L”.

The use of BP alone to define shock is problematic, at any moment 5% of healthy babies are below the 5th percentile, and therefore over 5% of all babies are in shock at any time according to this definition. In addition, the definition allows cuff, non-invasive, BP to be used, which are very unreliable, and they used standards for BP which are limited (Zubrow AB, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol. 1995;15(6):470-9). Many infants had a large PDA, which will lead to low diastolic pressures satisfying this definition, but without necessarily having other features of shock. Nevertheless, these were babies that the clinicians felt warranted vasopressor/inotrope intervention. To be eligible for the trial the infants had to be “fluid-resistant”, that is not responding to 1 to 2 10 mL/kg fluid boluses, they also excluded infants with NEC, I am unsure why.

Infants were started on vaso-active drugs at the same time as the study drug, and had functional cardiac echography. The primary outcome was survival to 14 days of age, rescue hydrocortisone was allowed if the infant became unresponsive to their vaso-active drugs.

Survival was very poor in both groups, 17% with placebo, and 28% with early hydrocortisone. and 80% of the controls eventually received open label hydrocortisone (compared to 70% of the early HC group).

There are a couple of reasons for this post, the first being that I think this is the first report of an RCT of steroid use in the treatment of circulatory collapse in the newborn, which points out how poor the evidence is to support anything that we do. And also because the survival is reported just as being “not significant”. I mentioned Bayesian analysis in a previous post, and I think that a small trial such as this, which was very unlikely to have a “statistically significant” result, because of low power, is nevertheless informative, and is a good candidate for Bayesian analysis. Using an on-line Bayesian calculator, it seems that likelihood that the early hydrocortisone group is better is about 88% (I am certainly no expert in these calculations, and I may be in error!)

Another way of presenting these results is with the relative risk and its confidence intervals, which is 0.87, 95% CI 0.69 – 1.10. Which means that the results are consistent, with that level of confidence, with no difference in mortality, a small increase in mortality, and a major decrease of 31% in mortality.

The implication of this is that there is certainly enough suggestion of a substantial benefit that further trials are warranted.

I am not against publishing such small trials, I think they can give valuable pointers for the future, but we should be very careful how the results are presented. The abstract of this article just states “we did not observe a significant reduction in 14-day mortality”, which is actually misleading. It would be more accurate to state “we observed a major reduction in mortality with early HC use, but it was not statistically significant, and may have been due to chance effects in a small underpowered trial”. Maybe we should ban the use of the word “significant” from the medical literature. It is often used, as in this abstract, to mean “statistically significant”, but is often interpreted as “real”, “meaningful”, or “important”.

What are we currently doing for this problem? A questionnaire study among Canadian neonatologists was published last year, (Kharrat A, et al. Corticosteroid use in neonatal hypotension: A survey of Canadian neonatologists. Pediatr Neonatol. 2024;65(5):451-6 they were asked if they used HC for hypotension, and if so when. The results showed the variability that you would expect in a situation where there is almost no reliable data.

I can’t remember is I participated in this questionnaire, but, if I had, I would be one of the “other” group! I don’t give fluid boluses for hypotension, unless I have good reason to suppose that the infant is hypovolemic. Early hypotension in the preterm is now much less common, because of delayed cord clamping, and is almost never due to hypovolemia. I will sometimes giving a fluid bolus in shock, if I think that the baby needs more preload, and I tend to start HC very early when I feel that vasopressor/inotrope therapy is needed. In suspected septic shock, for example, I will usually start HC at the same time as the norepinephrine. I have no idea if that is the right thing to do, but 100% of the respondents to the survey reported using HC for hypotensive babies, at least some of the time.

There is clearly a need for further trials; the question of timing of HC use in babies with shock is clearly very important, and could have an important impact on mortality.

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Is it a duck? Is it a mole? Platipus and Trial Design Innovations.

Posted on 19 February 2025 by Keith Barrington

When the platypus was first captured, killed, skinned and the pelt sent to a zoologist in London, George Shaw in 1799, he thought he was being scammed. He tried to find the stitches that had been used to cobble together the specimen. Being unable to do so, he then concluded that it was probably real, and was unique. It was what we would now consider an evolutionary innovation, it had features of previous organisms, such as laying eggs, and several new features, being venomous and producing milk to feed their young, once they have hatched. Here is a photo I took in March 2023 at the Woonoowooran national park.

Brett Manley and the group from Melbourne are doing something analogous with their PLATIPUS (Manley BJ, et al. Adapt to survive and thrive: the time is now for adaptive platform trials for preterm birth. Lancet Child Adolesc Health. 2025;9(2):131-7) adaptive platform. Taking features of standard RCTs, and evolving a new way to do trials in perinatal medicine.

Adaptive designs first went mainstream during the COVID epidemic, with the dramatically effective RECOVERY platform. The trials were able to be launched, and to rapidly provide clinically vital results within a very short period of time, while the pandemic was still at its height. RECOVERY was able to rapidly prove the value of standard dose steroid treatment for improving outcomes, and then showed that higher dose dexamethasone was a bad idea, and should not be used. They have also shown that some antivirals are ineffective, that routine azithromycin made no difference, and have to this point enrolled nearly 50,000 patients, having now expanded to find treatments for complicated influenza and non-viral community acquired pneumonia.

Another platform design has, just this last week, produced some important results in ALS, also known as Lou Gehrig’s disease in the USA, and Motor Neurone Disease in the UK. There are 4 simultaneous comparisons published, with 3 different interventions compared to a common control group. None of the interventions showed a clear benefit, but there were some suggestions of some improvements, which allows, within the platform design, to proceed rapidly to adjusted protocols, perhaps in subgroups. An editorial article accompanying the publications discusses the limitations, and the major advantages of such trials. In ALS, the Healey platform was funded by, and named after, a very wealthy man who has the condition himself.

The first comparisons being investigated by PLATIPUS are, for the maternal domain, different antibiotic regimens for preterm PROM, with 3 different regimens being investigated. I must say I thought this was relatively settled, among the antibiotics in the trial, and that it was already fairly clear that azithromycin plus amoxycillin was the way to go, but it seems there is still some doubt about their relative efficacy, and the platform will allow the future investigation of other regimes with minimal adjustment. For the neonatal domain of the platform, they are investigating 3 different dosage regimes of caffeine, the standard dose that we used in the CAP trial, (20 mg/kg of caffeine citrate load, then 10 mg/kg/d, which they call the low-dose group) to a medium dose group which is 50% higher, and a high dose group which is double the standard dose.

The figure below is a schematic of how it might proceed.

The other part of the innovative nature of this trial is the outcome measure that is being used, which is an ordinal composite adjudicated at 42 weeks PMA. The outcome is scored from 1 to 15, with 15 being the worst outcome, death. Levels 1 to 15 are described as follows:

1= Well, liveborn infant; 2= Neonatal unit admission for <48 hours; 3= Neonatal unit admission for >/= 48 hours; 4= Non-invasive respiratory support or oxygen therapy for ≥ 4 hours & < 5 days; 5= Non-invasive respiratory support or oxygen therapy >/= 5 days; 6= Mechanical ventilation via endotracheal tube for ≥ 4 hours & <7 days; 7= Mechanical ventilation via endotracheal tube for >/=7 days; 8= Moderate respiratory morbidity; 9=Necrotising enterocolitis AND/OR Sepsis; 10= Severe Respiratory Morbidity; 11= Major Surgery; 12= Brain Injury; 13= TWO of severe respiratory morbidity OR major surgery OR brain injury; 14= Severe respiratory morbidity & major surgery & brain injury; 15 = Death

There is obviously a lot to pick apart and discuss here, but my first response is Bravo!! At last a composite outcome in a neonatal trial that recognizes that all competing outcomes do not have the same value! The definitions of each of these outcomes are on the clinicaltrials.gov website. For example “severe respiratory morbidity” is respiratory support at 40 weeks PMA, or discharge home on oxygen or respiratory support. Which seems to me to be a definition which is both consistent with parental concerns and reasonably predictive of longer term respiratory outcomes.

As for Brain Injury, I have a few more concerns, the definition given is : Major intraventricular haemorrhage, unilateral or bilateral, defined as i. Papile Grade 3 or 4 AND/OR ii. Moderate-severe periventricular haemorrhagic infarction b. Cystic periventricular leukomalacia, unilateral or bilateral c. Moderate or severe white matter injury on MRI at near-term or term equivalent age d. Any cerebellar haemorrhage e. Other major ischaemic injury such as arterial stroke or hypoxic ischaemic injury f. Post haemorrhagic hydrocephalus requiring drainage.

The problems with this part of the outcome are 1. using the Papile classification 2. including “any” cerebellar haemorrhage. 3. White matter injury on the MRI.

For this particular part of the composite outcome, I am not sure how much this matters, but if the high-dose caffeine group, for example, had more cerebellar haemorrhages, but less severe respiratory morbidity, then that group would be considered to be worse off, even if the haemorrhages were all tiny and had no long term impact. However, I am not sure if you could really tease all that out as part of an ordinal composite like this one, if there is a difference in brain injury, as defined in the protocol, between groups, that would probably be a reason for choosing between interventions, even if some of the haemorrhages had little long term impact.

For an adaptive platform trial trial like this the outcomes have to be determined rapidly after the intervention; 2 year neurological/developmental outcomes, or other long term outcomes of interest to parents cannot be the primary. Hopefully, all the infants randomized in the platform will have longer term outcomes evaluated and reported in addition to the primary short term outcome. I’m sure you are all aware that caffeine therapy in the CAP trial did have some minor short term benefits (infants came out of oxygen a little faster, so were less likely to be diagnosed with BPD, and less likely to have treatment for a PDA), but substantial, very long lasting benefits on follow-up.

Analysis of the trial results is also a major issue, the RECOVERY trials have used a fairly standard frequentist approach, with the first results showing advantages of standard dose dexamethasone being presented as the proportion of deaths in each group, the relative risk (0.83) and confidence intervals (0.75 to 0.93) and the p-value P<0.001. Platipus is planned with a Bayesian approach, which is less familiar to many clinicians, but has potential advantages. The Bayesian approach clarifies that no RCT really proves that one approach is better than another, which is suggested by our dichotomous “significant or not significant” current typical presentation of results, but gives an estimate of how likely it is that one intervention is better than another.

The Platipus platform will allow on-going adjustments, other comparisons, addition of other groups, and other interventions. It could become the default model for future trials in perinatal medicine, and should enable us to get results much faster, but just as reliably.

Platipus, just like the Platypus, will give us major scientific insights for the future. It should allow us to advance the care of newborns more rapidly than in the past.

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A lower limit for restrictive transfusion strategies? Not directly neonatology…

Posted on 9 February 2025 by Keith Barrington

Several trials of liberal versus more restrictive transfusion practices have been published, and overall, it seems that being very restrictive in transfusions has no negative impacts on clinical outcomes, and depending on the trial, some positive benefits of avoiding transfusion.

One of the important studies of the Canadian Critical Care Trials Group was the TRICC trial, which enrolled critically ill adults with a hemoglobin less than 9 g/dl, who were randomized to a target hemoglobin of 7-9 vs 10-12 g/dl. In that trial the adults with the lower target did better, with a lower in-hospital mortality of 22%, vs 28% with more liberal transfusion. In the results of that trial there was a suggestion of a different outcome in the subgroup with myocardial ischemia, so the group did another analysis in adults with cardiovascular disease, which showed no big differences in outcome, but still suggested a possible benefit of higher hemoglobin in those with unstable angina or an acute MI. Other studies have still, as far as I can see, not clearly answered the question in this subgroup of adults, and the most recent systematic review that I found basically stated “we don’t know”. As a result further trials are planned.

It could be that in patients with coronary artery disease, the ability to vasodilate and maintain myocardial oxygen delivery in the face of anaemia is limited, hence it is physiologically feasible that this subgroup would have different outcomes to those without serious coronary artery disease.

The same might be true for another subgroup, under-represented in the original TRICC and other trials, those with acute neurological injury. In this new trial in JAMA, adults with either traumatic brain injury, or a sub-arachnoid haemorrhage, or an intra-cerebral haemorrhage, who had a haemoglobin <9 g/dl, were randomized to a target of maintaining haemoglobin >9 compared to >7.

The rationale being that these groups of adults have a limited ability to increase brain perfusion in response to anaemia, and may benefit from higher haemoglobin, and that the previous studies have included very few such patients, and have also not measured longer term functional outcomes. The primary outcome of this trial was the extended Glasgow Outcome Scale after 6 months. We used a paediatric version of this scale in our recent publication (Boutillier B, et al. Survival and Long-Term Outcomes of Children Who Survived after End-of-Life Decisions in a Neonatal Intensive Care Unit. J Pediatr. 2023;259:113422. as it is a scale of functional capacities, in our study it was used in a descriptive fashion. In the new trial it was dichotomised into bad outcomes (1 to 5, 1 being death) and acceptable outcomes (6 to 8). The following table describes those scores

I will restrain myself from one of my usual rants about it being inappropriate to dichotomize continuous outcomes just for the simplicity of research design, or of equating death with being unable to use public transport! Designing and analyzing the trial using the GOS-E as an ordinal outcome would have been entirely possible.

800 patients, mostly in Europe and South America, were randomized, and outcomes were better in the higher hemoglobin group. The median GOS-E in both groups was 4, in other words large numbers of the patients had quite poor outcomes. As you can see from the graphical abstract above, the proportion with scores <6 was lower, 63%, with the higher HgB threshold compared to the higher threshold, 73%. When analyzed using an outcome of GOS-E<5, the higher HgB group still had an advantage, 50% vs 60%.

Why am I discussing this adult trial? I guess it is the first evidence, that I know of, that a higher hemoglobin threshold in critically ill patients improves outcomes. And that, in this group of patients we may have found the lower limit of acceptable HgB.

One thing we do not know in preterm babies is the extent to which they are able to vasodilate the cerebral circulation in the face of anaemia to maintain cerebral oxygen delivery. I guess this is why the people who designed the protocols that have been tested in neonatal transfusion trials have all used different thresholds during the first days after birth compared to later life. Or maybe it was just completely arbitrary!

The neonatal trials which have been published, which I have discussed previously used the following transfusion thresholds (converted to Hemoglobin in g/100mL).

The definition of “sick” varied between the trials. In none of the trials was there any sign of harm from the lower transfusion threshold.

I think we are therefore probably well above the threshold of harm, but the new trial does show that under certain circumstances a higher threshold may be better, and that, at least in adults with acute brain injury, a higher threshold may improve outcomes.

Might this be true in preterm infants? I’m not sure if there has been any subgroup analysis of infants in the RCTs who had a brain injury, obviously the pathophysiology of such injuries is dramatically different in preterm infants than the adults in the new JAMA RCT, and the physiology of the control of cerebral perfusion is different also. But those results do suggest that we should consider the possibility that there is a lower limit to transfusion thresholds, which may differ among different groups of babies.

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Bilirubin is Bad for the Brain! Who knew?

Posted on 4 February 2025 by Keith Barrington

We have known for a very long time that bilirubin can cause an encephalopathy leading to acute and chronic clinical impacts, the most severe chronic impacts being kernicterus, a disabling movement disorder and nerve deafness. What seems to be the case is that bilirubin bound to albumin doesn’t cross the blood-brain barrier, and that the BBB, which appears to develop early, and be functional by 20 weeks, is easily disrupted in the newborn. Bilirubin staining of the basal ganglia has been shown on autopsy specimens at much lower concentrations than are associated with kernicterus in term babies. This finding led to the performance of the large multicentre NICHD network phototherapy trial, which is very limited by the lack of a funky acronym. Can I suggest that we start calling it the “LITEPOP” trial: Longterm ImpacTs of Early Phototherapy for Outcomes of Preterms?

There have been multiple studies looking at “free” or “unbound” bilirubin and its impacts, which are hindered to some extent in difficulties measuring it. The subject of this post is a new re-analysis of data from that NICHD early phototherapy LITEPOP trial, which finished enrolling in 2005, and finished follow up 2 years later, with the primary publication (Morris BH, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008;359(18):1885-96) appearing in 2008. If you remember, or if you have never heard about this, the primary outcome was “death or NDI” (groan…). There were nearly 2000 babies of 501 to 1000 g bwt randomized at 12 to 36 hours of age if they had never had phototherapy. The intervention was to have phototherapy started immediately and continued until it fell below 85 micromol/L (5 in the US units). The control group had phototherapy to keep the bilirubin either below 137 (500-750 g bwt) or below 170 (751-1000 g).

The results are a very apposite demonstration of the problems with such a composite outcome. Mortality was just about equal in the two groups, 209 vs 201 died before discharge, and a further 17 vs 21 died after discharge, or 24 vs 23% total mortality.

The NDI data were presented as among the entire groups (survivors tested plus deaths), i.e. 235/902 vs 275/902, which is statistically significant, 26% vs 30%, (RR 0.86 (95% CI 0.74–0.99)) but because of the 1% higher mortality in the early phototherapy group, the combined outcome of “NDI or death” was not considered significant.

If we recalculate the outcome of “NDI” just among the survivors who were tested, 235/672 vs 275/684, 35% vs 40%, and the proportion with low PDI scores 127/672 vs 152/684, 19% vs 22%, or with severe hearing loss, 9 infants vs 28, or with athetosis, 2 infants vs 10, then the differences all suggest benefit of early phototherapy.

Babies in this study had a blood sample stored at 5 days of age, which was later measured at one of 2 laboratories. Although they used the same method, (the peroxidase method) and the same analyser, there were enough differences between the 2 labs that the results were converted to z-scores for each lab, and are reported in the newest publication as percentiles of the z-score.

The first publication reporting these data, however, was in 2010, Oh W, et al. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr. 2010;99(5):673-8. The reporting of the free or Unbound Bilirubin (UB) in that first publication was weird. The graphs appear to show UB concentrations in the microg/dl range,

Adjusted probability plots and adjusted odds ratio (95% CI) for unbound bilirubin versus proportion of death or NDI, death or CP, death or hearing loss, and death before follow-up in clinically stable and unstable infant

But a correction published 3 years later reveals that they actually show the UB divided by 0.3 “we have standardized the unbound bilirubin by dividing the actual values by the standard deviations which is 0.3. The standardized values (in units) were used in the presentation of data in this figures which appear to be 0–3.0 units. The actual unbound bilirubin values are 0–0.9 mcg/dL”. I don’t understand how this “standardized” the data, it was clearly just a screw up that none of the 89 authors noticed. (I exaggerate).

You may also remember a secondary analysis published 4 years after the original manuscript Tyson JE, et al. Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? J Perinatol. 2012;32(9):677-84. In that publication they performed a subgroup analysis dividing the smaller babies into those ventilated and those who were not. Whether this was a preplanned subgroup or not is unclear; the publication states rather vaguely that they had plans “to relate the risks and benefits of AgPT to baseline risk factors including measures of severity of illness”. In that secondary analysis of a subgroup, using Bayesian analysis, they claimed to show that it was highly likely that phototherapy increased mortality among ventilated infants of 500-750 g. That analysis also shows that there was a probable decrease in mortality among non-ventilated 500-750 g babies (13% vs 25%), a probable decrease among larger babies who were ventilated (16% vs 19%), and a possible increase among larger non-ventilated babies (8% vs 6%). My interpretation of which is that the differences are very likely just random variations between groups. However, the authors of that secondary analysis were much more emphatic that phototherapy was decreasing the anti-oxidant benefits of bilirubin, and was generating oxidant injury and was increasing mortality in the smallest babies, if they were ventilated.

So why have they come back to these data now? (Arnold CC, et al. Unbound bilirubin and risk of severe neurodevelopmental impairment in extremely low birthweight newborns. Pediatr Res. 2025) The authors state that there are new concerns about lipid emulsions leading to increases in Free Fatty Acids and displacing bilirubin from albumin, leading to an increase in UB. But such concerns are not new at all, they date back to the 90’s or further. Perhaps more relevant is that a new method for measuring UB has become available, which might make it more clinically useful, and there are new statistical methods available, including the TMLE (Targeted Maximum Likelihood Estimation), which apparently uses machine learning to give conservative explanations of correlations between variables.

For this analysis they concentrated on “severe NDI” or sNDI, which was “based on the NDI outcomes with the strongest associations with the phototherapy regimen in the NICHD aggressive vs conservative phototherapy” LITEPOP RCT which was : a score on the Bayley II Mental or Psychomotor Developmental Index of 50 or less or a level of 5 for gross motor function (GMF), or needing bilateral hearing aids.

They divided UB into 20 slices, based on percentile of UB, as you can see from the figure below, there seems to be a threshold effect, with sNDI increased substantially for the top 15% of UB concentrations on day 5 of life.

There was very poor correlation between the total bilirubin and UB concentrations, as you can see below. But almost all of the UB concentrations associated with worse outcomes were above the threshold for phototherapy in the early treatment group, only 1 or 2 of the dots are in the upper left quadrant. You can also see, what I was not aware of previously, that far more than half of the dots are above 5 mg/dl, which implies that the phototherapy was not very effective at keeping the total bilirubin below the treatment threshold.

Most of the babies with “sNDI” did not have classic clinical signs of kernicterus, choreo-athetoid cerebral palsy, oculomotor problems, and high-tone nerve deafness. This could be because bilirubin encephalopathy is not so specific in the affected regions in very preterm infants, especially in the presence of acidosis, sepsis etc.

What should we do about this? If UB or “free” bilirubin measurement becomes more widely available, then the lack of correlation with total bilirubin strongly suggests that UB should become the variable of choice for monitoring hyperbilirubinemia in full term infants with jaundice. We could perhaps decrease the proportion of babies who get intervention while improving the prevention of kernicterus, which continues to affect somewhere around 1 in 100,000 babies, and while rare is devastating. The potential benefits among preterm infants are numerically greater, if a new trial (the UNBEATEN trial, UNbound Bilirubin EArly TreatmENt trial, I claim copyright) could show that screening for, and treating, to maintain UB < the 85%ile, improved neurological and developmental outcomes.

At the same time the trial could investigate whether the possible impact of phototherapy on mortality among the subgroup of ventilated extremely preterm infants in the NICHD trial was a real phenomenon or not.

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Breast is Best; is Fresher Better?

Posted on 30 January 2025 by Keith Barrington

A recurrent problem in the NICU is “bandwagon-jumping”. An intervention with some preliminary positive data, and a possible physiologic rationale is widely adopted and made part of QI bundles with little or no reliable evidence that it is either effective or safe.

One such is the hype surrounding fresh mother’s milk. There are a small number of studies showing the following impacts. (references at the end)

  1. A reduction in laboratory indices of antioxidant activity with freezing and with refrigeration, has been shown, with the longer duration of refrigeration having a greater impact, compared to never refrigerated milk.
  2. An impact of pasteurization, but not freezing and thawing, on Leptin concentrations, but not Adiponectin or total protein
  3. Freezing and thawing reduce glutathione content
  4. No impact on total fat or carbohydrate of freeze/thawing, possible increase in Free Fatty Acids.
  5. Freezing inactivates the majority of CMV, decreasing viral load, but does not eliminate entirely
  6. Vitamin C concentrations are reduced by refrigeration and by freezing

The effects on cellular components of refrigeration and/or freeze thawing are unclear, which is unfortunate as I suppose this is the reason that people want to give “fresh” breast milk. My literature search for this post was unable to find much data on the impacts of freezing and thawing on the endogenous cellular components of breast milk. It has been reported that the viable proportion of white cells in milk after freeze/thawing is 78% or 19%. But exactly how to determine which type of white cell is still active, is unclear to me, the most recent report I found is a brief letter with little methodological detail, which determined viability with “propidium iodide” and measured some cell markers.

It looks however, like there is probably little effect on the bacterial components of breast milk. This study, Marin ML, et al. Cold storage of human milk: effect on its bacterial composition. J Pediatr Gastroenterol Nutr. 2009;49(3):343-8, for example, showed the same species and the same number of organisms in fresh and freeze/thawed milk.

And here another word of caution, what is meant by “fresh” isn’t always the same, sometimes it means never refrigerated, sometimes never frozen, sometimes not pasteurized. A recent statement from France, for example differentiates between “Raw” milk, meaning never refrigerated, and “Refrigerated” milk, with “Fresh” meaning either raw or refrigerated but never frozen. That working group developed guidelines to improve provision of raw milk, despite not presenting any clear reliable evidence of a clinical benefit.

Overall then, it seems that there is little adverse impact of freezing and thawing on macronutrients or cellular components of breast milk. There are some individual impacts, especially on vitamin C.

I guess the current enthusiasm for trying to give fresh milk must, therefore, be based on good clinical data of a benefit? (That is an ironic question, I already know the answer!) There is one cohort study (Huang J, et al. Short-term effects of fresh mother’s own milk in very preterm infants. Matern Child Nutr. 2023;19(1):e13430) comparing outcomes between babies who received “Fresh” mothers own milk, which was what the French group would call Raw milk (i.e. never refrigerated) and used within 3 hours, with the comparisons receiving pasteurized MoM. There were 170 babies <32 weeks GA in total, averaging 1150 g and 29 weeks. NEC and LOS were more frequent in the non-randomized control group, 16% and 19%, vs 10% and 7% in the controls, and there were some very small differences in feeding tolerance. The mother had to provide milk every 3 hours during the entire NICU stay.

Another Chinese cohort study (Sun H, et al. Testing the feasibility and safety of feeding preterm infants fresh mother’s own milk in the NICU: A pilot study. Sci Rep. 2019;9(1):941) compared a group of babies <30 weeks GA who received one feed a day of “Fresh” milk (unclear whether it was allowed to be refrigerated during the 4 hours that was permitted between expression and administration) to a group who received only frozen thawed milk. Infants received either MoM or donor milk (DHM), and it seems that some of the control babies could have received only DHM. There were close to 100 babies per group, averaging about 28.5 weeks gestation and some of the fresh milk babies dropped out and were not analyzed. The birth weights in the 2 groups are not mentioned, but they both, unusually, had a birthweight z score averaging about +0.3 (preterm infants usually average below 0). There was a very high rate of late onset sepsis (38%) and stage 2-3 NEC (14%) in the controls that was lower in the fresh milk group (22% and 6%).

One other study that I have seen quoted is a French database analysis which showed less BPD in NICUs that gave Fresh milk, but in that study the comparison NICUs gave pasteurized mother’s milk, as it was the recommended standard at that time in France. It also is not clear if the Fresh milk could have been frozen prior to administration or not. There was less BPD in the fresh NICUs, but no difference in NEC or in LOS, which was extremely frequent in both groups.

Although it seems attractive to some clinicians, there really is no reliable evidence that giving fresh breast milk, however it is defined, has different clinical outcomes, compared to frozen and thawed breast milk. Differences in composition are relatively minor, and impacts on cellular viability or numbers are really unclear.

The logistic implications, on the other hand, are substantial. Enabling the provision of an early fresh milk feed, daily fresh milk feeds, or exclusively fresh milk feeds, will require some resources, and organisation of those resources, to ensure that it could be done reliably and without errors in administration. A randomized controlled trial would be worthwhile to determine the true clinical impact, if any, of avoiding freeze/thawing of MoM, to see if dedicating those resources is worth it. One is planned and hopefully underway (Sun H, et al. A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother’s own milk for preterm infants in the NICU. Trials. 2020;21(1):170), until the results are available, the potential benefits of Fresh, compared to Frozen and thawed, maternal breast milk must be considered Not Proven.

References (in chronologic order, most recent first)

Surmeli Onay O, et al. Evaluation of the Effect of Breast Milk Storage Conditions on the Viability of Cells in Breast Milk: A Pilot Study. Indian J Pediatr. 2024;91(10):1084.
Stinson LF, et al. Effects of Different Thawing and Warming Processes on Human Milk Composition. J Nutr. 2024;154(2):314-24.
Putri DK, et al. The Effects of Different Storage Conditions on Leukocytes in Human Breast Milk. Sultan Qaboos Univ Med J. 2024;24(1):91-8.
Binder C, et al. Human Milk Processing and Its Effect on Protein and Leptin Concentrations. Nutrients. 2023;15(2).
Edwards CA, et al. A systematic review of breast milk microbiota composition and the evidence for transfer to and colonisation of the infant gut. Beneficial microbes. 2022;13(5):365-82.
Volder C, et al. Transmission of cytomegalovirus in fresh and freeze-thawed mother’s own milk to very preterm infants: a cohort study. J Perinatol. 2021;41(8):1873-8.
Schwab C, et al. Characterization of the Cultivable Microbiota in Fresh and Stored Mature Human Breast Milk. Front Microbiol. 2019;10:2666.
Paduraru L, et al. Total antioxidant status in fresh and stored human milk from mothers of term and preterm neonates. Pediatr Neonatol. 2018;59(6):600-5.
Ahrabi AF, et al. Effects of Extended Freezer Storage on the Integrity of Human Milk. J Pediatr. 2016;177:140-3.
Handa D, et al. Do thawing and warming affect the integrity of human milk? J Perinatol. 2014;34(11):863-6.
Slutzah M, et al. Refrigerator storage of expressed human milk in the neonatal intensive care unit. J Pediatr. 2010;156(1):26-8.
Silvestre D, et al. Effect of pasteurization on the bactericidal capacity of human milk. J Hum Lact. 2008;24(4):371-6.
Hanna N, et al. Effect of storage on breast milk antioxidant activity. Arch Dis Child Fetal Neonatal Ed. 2004;89(6):F518-20.
Lawrence RA. Storage of human milk and the influence of procedures on immunological components of human milk. Acta Paediatr. 1999;88:14-8.
Jocson MAL, et al. The Effects of Nutrient Fortification and Varying Storage Conditions on Host Defense Properties of Human Milk. Pediatrics. 1997;100(2):240-3.
Williamson MT, Murti PK. Effects of Storage, Time, Temperature, and Composition of Containers on Biologic Components of Human Milk. J Hum Lact. 1996;12(1):31-5.
Friend BA, et al. The Effect of Processing and Storage on Key Enzymes, B Vitamins, and Lipids of Mature Human Milk I. Evaluation of Fresh Samples and Effects of Freezing and Frozen Storage. Pediatr Res. 1983;17(1):61-4.
Reynolds GJ, et al. A simplified system of human milk banking. Early Hum Dev. 1982;7(3):281-92.
Pittard WB, Bill K. Human Milk Banking: Effect of Refrigeration on Cellular Components. Clin Pediatr (Phila). 1981;20(1):31-3.

I ran out of energy in trying to add all the hyperlinks to the references, but I guess if you care you can easily find them, all available through PubMed.

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