One of the numerous major advances in neonatology during my career has been the introduction of therapeutic hypothermia for infants with Hypoxic Ischemic Encephalopathy (HIE). Mortality is decreased, by about 25%, and long term morbidity among survivors is also decreased, by about 33%. Those estimates of effect size come from the Cochrane review, which provides the following Forest plot (I'm sorry about the quality of the image, the version in the pdf of the review is much clearer, but it extends over 2 pages, with a page break in the middle).

Blank DA, et al. Face mask versus nasal mask device use for initial resuscitation in extremely and very preterm infants (FONDUE): an open-label, single-centre, randomised, controlled trial. Lancet Child Adolesc Health. 2025;9(10):715–23. An excellent acronym for this trial. Hopefully it will lead to a trend in acronyms based on European culinary specialities. Very preterm infants, n=151, of 23 to 32 weeks GA were randomized to receive delivery room CPAP with a face mask, or with a nasal mask in a single centre study from Monash in Melbourne. Delayed clamping was attempted, without respiratory support, or immediate clamping if the baby needed intervention.

I subscribe to Google alerts, which sends me an email whenever the phrase "neonatal research" appears on a new website or a new post. I was interested, therefore to receive an alert about an article which, according the blog "Bioengineer.org", showed a major genetic contribution to the occurrence of Necrotising Enterocolitis. The blog post includes the following quote "Bai et al.’s study represents a landmark in neonatal research by providing compelling evidence for the heritability of necrotizing enterocolitis in very preterm infants. The twin study design elegantly disentangles genetic predisposition from environmental influences and firmly establishes a genetic foundation for this complex disease".

Ybarra M, et al. Low-Grade Germinal Matrix Hemorrhage-Intraventricular Hemorrhage and Concomitant Preterm Brain Injuries: Neurodevelopmental Outcomes at 3 Years of Age. J Pediatr. 2025:114713. Previous studies of the long term outcome of infants with germinal matrix or low grade IVH have been inconsistent. Some have shown an association with poorer developmental progress, and others have shown no impact. Some of this variability may be due to uncertainty about diagnostic criteria, with slightly larger amounts of intraventricular blood being classified differently. Some is probably due to the variable association with other brain injury, not readily seen on ultrasound, such as white matter injury, or cerebellar haemorrhages.

Andromeda-Shock-2 Investigators for the Andromeda Research Network SSoAR, et al. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial. JAMA. 2025. This is a very interesting trial evaluating the usefulness of clinical assessment of the circulation in adults with septic shock in a large international multicentre trial. Patients with suspected sepsis, who required norepinephrine after 1 litre fluid bolus, and had an elevated serum lactate, were randomized. A standardized method of measuring capillary refill time was agreed upon, CRT was assessed by applying firm pressure to the ventral surface of the distal phalanx of a finger, using a glass microscope slide.

Many of my readers will remember the impressive results of the high-quality study by Paolo Manzoni, Manzoni P, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA. 2009;302(13):1421–8) which showed that routine supplementation of preterm infants with bovine lactoferrin (bLF) dramatically reduced late-onset sepsis. Many of us were quite excited with this finding, and launched our own studies, I performed a pilot in my NICU, hoping to use the data to get funding for a confirmatory trial (Barrington KJ, et al.

After my post on regression to the mean, and its importance in studies of apnoea therapy, I was thinking of other examples. Some which have been most evident to me are those which impact on areas of medicine that I have researched myself. One example, from many years ago now, looked at the haemodynamic effects of dopamine in sick preterm infants. Seri I, et al. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr. 1998;133(6):728–34. This study was performed during the 1st 2 days of life, a period when blood pressure normally gradually increases, and when renal vascular resistance falls dramatically.

I mentioned in my previous post, an issue with meta-analyses; there have been several I have read recently which are very problematic. They seem to be produced by groups that have little concern for the quality of their product. This recent meta-analysis, for example, of transfusion thresholds in the preterm, stated that they found 12 RCTs (Fu et al Ann Hematol 2023).

There has for a long time been a thought that anemic babies with many apnoeas could benefit from a blood transfusion which would decrease their apnoeic spells. This idea has never been directly tested by an RCT. That is, a trial in which infants with apnoea were randomized to receive a transfusion or control, and the response accurately determined. I actually started such a trial when I was in San Diego, but only enrolled a tiny number of babies before leaving to return to Canada; the fellow who was involved finished at about the same time as me, and the project was sadly terminated.

Non-invasive HFOV can be delivered by a variety of different equipment and interfaces. The high flows and upper airway turbulence probably have an impact on gas exchange; It appears that the effective dead space of the oro-nasopharynx is washed out (De Luca D, Dell'Orto V. Non-invasive high-frequency oscillatory ventilation in neonates: review of physiology, biology and clinical data. Arch Dis Child Fetal Neonatal Ed. 2016;101(6):F565–F70), but how much transmission of the oscillatory pressures to the lung occurs is uncertain. Transmission does occur under some circumstances, however, as several groups have shown.

A new very large (for neonatology) RCT has just been published. Ojha S, et al. Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): a open-label, parallel-group, multicentre, randomised, superiority trial. Lancet Child Adolesc Health. 2025. Mothers were approached prior to preterm delivery, and babies were enrolled if they delivered between 30 and >33 weeks gestation, and were deemed clinically stable, prior to 3 hours of age. Prior to delivery the mothers either gave full written signed consent, or they verbally agreed to the study, in which case they had a full written consent later.

I just learned of the very recent death of Dr Robert Hawkes Bartlett, May 8, 1939 – October 20, 2025. He was a surgeon who had been developing extracorporeal oxygenation systems for cardiothoracic surgery who realised that extracorporeal circulation could be used for prolonged support, and was willing to try it out for a baby who was dying. He told the story in his Presidential address to the American Society of Artificial Internal Organs in 1985…

Afifi J, et al. Atropine Versus Placebo for Neonatal Nonemergent Intubation: A Randomized Clinical Trial. J Pediatr. 2025;286:114719 I had thought this was a settled issue, Neil Finer showed many years ago that atropine alone decreased bradycardias during intubation. But as the authors of this new study point out, there is very little (or no) data about atropine as part of an intubation cocktail in the newborn. I have a bit of a beef with the introduction which suggests that the Kelly and Finer trial mentioned above was limited, as it did not "follow recommended premedication protocols".

There are a huge number of publications correlating medium term outcomes (by which I mean outcomes around 1 to 2 years of age) with findings in the neonatal period. Most have concerned various approaches to brain imaging, although other studies have evaluated EEG, NIRS, early structured physical examinations, counting how many complications the baby had, the type of feeding they received.... I am sure my readers could construct a longer list. There are several recent publications that have triggered this post, in the extremely preterm infant. In the preterm infant, brain injury on imaging is very common, yet most preterm babies actually function very well.

One of the pivotal RCTs in neonatology was the CAP study (Schmidt B, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357(19):1893–902). We performed that study because there was no data on the long term impacts of caffeine, and there was a worry that blocking adenosine receptors in babies having multiple hypoxic episodes might be a bad idea. Adenosine is an inhibitory neurotransmitter that is produced during hypoxia, and decreases the brain metabolic rate to protect against hypoxic damage. So giving caffeine to babies having a lot of apnoeas could potentially have been a bad idea.

One of the worst kinds of unethical research practice is to fail to publish results after a prospective study. Parents consent to research for altruistic motives, in the belief that their baby's participation will help the care of other, future, babies. Failing to carry through and publish, or at the very least, make results publicly available on the registration website, is an abuse of that consent.

There have been multiple publications concerning this issue recently, many from the tiny baby collaborative. The first 2 publications are about the overall approach to providing intensive care at extremely low GA: Bernardini LB, et al. It's the little things. A framework and guidance for programs to care for infants 22-23 weeks' gestational age. J Perinatol. 2025. This is a discussion of the many issues that should be addressed in centres trying to improve outcomes for these babies, including a recognition that they face specific challenges, require particular attention to detail, have unique physiologic limitations, and deserve an integrated caring approach with a committed team which includes obstetricians, nurses, all the allied health professionals, and parents.

A new single centre RCT of permissive hypotension (PH) compared to "standard treatment" (ST) of very preterm infants 24 to <30 weeks GA, with a mean BP lower than their GA has just appeared (Alderliesten T, et al. Treatment of Hypotension of Prematurity: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2025). In the intervention, PH, group, infants only received treatment if they developed signs of poor perfusion. In the ST group they immediately received a fluid bolus and a dopamine infusion, followed by adding dobutamine, then epinephrine, hydrocortisone was given if the baby needed more than just dopamine.

A recent confluence of 3 reviews, one on breastfeeding specifically in the NICU (Hilditch C, et al. Effect of Neonatal Unit Interventions Designed to Increase Breastfeeding in Preterm Infants: An Overview of Systematic Reviews. Neonatology. 2024;121(4):411-20) another on the evidence supporting the efficacy of lactation consultants (D'Hollander CJ, et al. Breastfeeding Support Provided by Lactation Consultants: A Systematic Review and Meta-Analysis.

I thought, as today is NEC awareness day, I would give an overview of recent research about NEC prevention strategies. Probiotics. I am sure my readers are aware of the major problems in the USA which have followed the occurrence of an episode of sepsis caused by a probiotic organism; with several preparations being no longer available. This has happened even though the data generally shows a reduction in late-onset sepsis overall with probiotic supplementation, or in some analyses, no difference in overall LOS frequency. I'm not aware of any study, or any systematic review, which has shown an increase in sepsis with probiotic prophylaxis.

In some pre-clinical models, erythropoietin acts as a neuroprotective agent, which led to the performance of clinical trials to determine whether there was a positive impact on outcomes of the preterm. The latest study has just been published, and it is another high quality trial from the NICHD NRN, and Robin Ohls. The article starts with a questionable assertion, "Erythropoiesis-stimulating agents (ESAs) such as erythropoietin...have shown evidence for neuroprotection in preterm infants". I think if that was true, they would not have done this trial! In fact the references they give for that statement show a very variable impact on outcomes, the figure below is from a SR/MA which included only erythropoietin studies, eliminating a darbepoietin (a long acting EPO analogue) group in the second study by Robin Ohls et al (2014).

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.

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?