This could have been part 3 of my recent duet of posts on the potential toxicity of TPN. Those 2 posts referred to the late preterm and the full term newborn. In this study (Razzaghy J, et al. Early and exclusive enteral nutrition in infants born very preterm. Arch Dis Child Fetal Neonatal Ed. 2023) .infants of 28 to <33 weeks GA, who were <36 hours of age were enrolled.

It is not clear in the manuscript if eligible babies could have been already receiving enteral feeding when enrolled, it seems to be assumed that they had not yet started feeds. Babies >1500g had iv fluids with just dextrose, and those <1500g had a dextrose amino acid solution started at birth, prior to enrolment in this trial.

The intervention group, once randomized, were started on enteral feeds of human milk (maternal breast milk MBM, or donor DBM) at 60-80 mL/kg/d, within the first 36 hours after birth. The controls started on 20-30 mL/kg/d within 96 hours after birth. Both groups then increased enteral feeding volumes by 20-30 mL/kg/d, having the IV fluids gradually decreased to achieve the desired total fluid volume.

Again, it is not clear in the publication, but it seems like the intervention group continued to receive the same intravenous fluids as before, i.e. the babies <1500g getting dextrose/amino acid solution continued to get it, as their iv fluids were weaned. What happened to the IV fluids in the controls is nowhere described. Did they all get started on TPN? Did they aim for a standard IV protein intake? Or, what? Surely as a trial of trying to avoid TPN in very preterm babies, the use of TPN in the controls should have been described.

Both groups aimed for at least 150 mL/kg/d of enteral feed volume. All had human milk alone for the first 14 days after birth, and then transitioned to artificial formula if there was insufficient MBM. Fortification was not standardised, and the publication states that the 1st 14 days was an “exclusive human milk” diet, but whether this means that fortification was with DBM-based fortifier or not isn’t clear. Timing of fortification is very variable in the literature, and as this was an unmasked trial it might have been different between groups. If it was decided as part of the study design to not standardize fortification, at least it should have been reported when and how it was commenced, in each group. As it is, we have no idea if the nutritional intakes between groups were different or not.

The primary outcome was the number of days within the 1st 28 days of life that the infant received at least 150 mL/kg/d of enteral feeds. Which seems a strange outcome; the feeding regimes put the intervention group a minimum of 2 to 4 days ahead of the controls by the design of the feeding protocols. So if there was no difference in this outcome that would have been very weird. It is like designing a controlled trial of caffeine vs no caffeine, with the primary outcome being whether they got caffeine or not!

An intervention group baby could be started on 80 mL/kg/d on day one, and increased by 30 mL/kg every day, reaching the outcome volume by day 4. Control babies, at the best, would have taken at least one extra day to get there, and, if started on day 3 at 20 mL/kg/d, then increased by 20 mL/kg/d, could easily have taken until day 10 to satisfy the outcome criterion.

As importantly, who cares? Surely what matters is if there were any clinically important differences between groups, such as sepsis, or NEC, or some index of growth. Much more interesting, therefore are the growth outcomes that were measured, and which included body composition, at between days 15 and 28.

The authors note that a trial with occurrence of NEC as a primary outcome would have required thousands of babies, but, with the previous data about Late Onset Sepsis being much more frequent among term and late preterm infants receiving TPN, a prioritized composite, of death, followed by NEC, followed by Sepsis (as an example) could have had a realistic sample size. A primary growth outcome would also have been feasible.

There were 102 babies enrolled, and full results for 97, the primary outcome showed a difference of 2 days, which is entirely explicable by the differences in the feeding protocols.

There are several other unexplained things in the results: results are presented for the days to “full enteral feeding”, which was 6 days vs 7 days, and other results for “exclusive human milk feeding”, which was 4 days vs 6 days. What those terms mean, and what the difference is between them is not explained. Weren’t all the babies receiving exclusively human milk for the 1st 14 days? Neither term is defined in the methods, there isn’t a published protocol, and the trial registration documentation is very sparse. I might guess that “full enteral feeding” is when the IV was stopped, but then “exclusive human milk feeding” is entirely unclear.

The mean birth weight of the babies was very close to 1500 grams, but by chance the controls weighed about 200g less than the intervention group (1385g vs 1571g). About half of each group should therefore have been getting amino acid solutions when randomized, but this would have been a greater percentage in the controls. What was done with the parenteral nutrition is never described, were AA solutions continued during the weaning of IV fluids? Did any have IV lipids? What were the total calories and protein given in each group over the first few days?

The intervention group also happened to have less growth restriction at birth, z-score -0.08 compared to controls -0.38. In both groups, weight z-scores at 36 weeks were lower than at birth (-0.9 vs -1.2), and head circumference z-scores were below the mean also (-0.8 vs -0.8), there was a difference in the 36 week length z-scores (-0.9 vs -1.5), all of which are intervention vs control, respectively. The fat free mass z-score was also different between groups at 14 days of age, 1.48 vs -2.0. It is important to note, that all the differences disappeared when they corrected for the birth weight z-scores. The only difference that remained “significant” after adjusting for birth weight z-scores was the small difference in length z-scores at 36 weeks PMA.

It seems likely that, total macronutrient intakes in the 1st few days were similar or lower in the intervention group, who presumably had a little less protein intake, at least; Growth was not substantially different between groups.

Control babies were hospitalised for 7 days longer (40 d vs 47 d), it isn’t clear why, but, by chance, the controls were 1 week less mature at birth, 30 weeks vs 31 weeks. That might entirely explain the difference in hospital stay, so they went home at about the same PMA.

I think the Archives peer review failed badly with this article; it is an RCT of a nutritional intervention that presents no data on nutritional intakes. There are very important details of the procedures that are not described. There are outcome terms which are not defined. The abstract, which is all most people read, does not mention that all the differences disappear when adjusted for an important baseline imbalance. And the results were only adjusted for the difference in baseline birth weight z-scores, there remains a difference in GA; my guess is that the residual, non-significant, difference in hospital costs (and perhaps in pre-discharge length z-score) would completely disappear if they accounted for the extra days of hospitalisation entailed by the lower GA in the controls.

As this post’s cynical title suggests, I don’t think this actually qualifies as a trial of early, exclusive, enteral nutrition; enteral nutrition routinely starting before 6 hours, for example, could be reasonably called “early” (compared to before 36 hours) and completely avoiding amino acid solutions could be called “exclusive”. But, as a first step to designing a protocol, to actually test an approach of trying to completely avoid Parenteral Nutrition in many very preterm babies, it does provide some safety data. I think it shows that we could indeed safely design a trial, in babies of 28 to 32 weeks GA, with the goal of investigating whether completely avoiding amino acid solutions, when possible, has benefits in terms of clinical outcomes or growth.

In an actual trial of EEEN, intervention babies would all receive full enteral feeds from birth, that is 60 mL/kg/day from arrival in the NICU, if unable to tolerate that, then a dextrose solution would be started from birth, and enteral feeds started within the first few hours of life, increasing at 30 mL/kg/d, which, for most babies, would cover their total fluid requirements, at 90, 120, then 150 mL/kg/d, thereby avoiding completely iv access for those who did not require antibiotics, and completely avoiding TPN, or an iv amino acid solution, for many babies. Criteria for parenteral nutritional assistance would have to be clear in such a trial, for example, if an intervention group baby had persistent regurgitation, and by day 3 was receiving less than a certain threshold, then a supplemental parenteral nutrition could be added.

Controls would have standard care, with guidelines in place for when to start TPN, and how to commence and advance feeds.