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.

We have just published our experience with sepsis caused by organisms in the probiotic mixture that we were using (Abda A, et al. Bifidobacterium And Lactobacillus Bacteremia among Infants Receiving Probiotics in the Neonatal Intensive Care Unit. J Pediatr. 2025:114521). Among over 2000 infants who received probiotic prophylaxis in our NICU there were 12 cases of bacteraemia with one of the bugs in the mixture. Over that period we had 2 other babies who did not fit criteria for the study, who had bacteraemia with either a lactobacillus or a bifidobacterium that was either a different strain to our mixture or in a baby who had never received the mix.

The babies who had bacteraemia frequently had major GI problems, especially perforation, which creates, obviously, an entry portal for the probiotic organisms to invade the circulation, the affected infants were all less than 28 weeks gestation. The degree of illness was mild among those without other serious complications, (clearly an extreme preterm infant with GI perforation is often very sick). No mortality was attributed to the sepsis.

There is also a new analysis from the CNN, (Alshaikh BN, et al. Effectiveness and Risks of Probiotics in Preterm Infants. Pediatrics. 2025;155(3):e2024069102), confirming the benefit of probiotics in current usage in Canada. This very large observational study showed lower mortality with probiotic usage, and a limited reduction in NEC. For the purposes of this discussion, they showed a small reduction in late-onset sepsis. Despite an incidence of LOS caused by probiotic organisms of about 0.4% (not very different to our local rate of 0.6%) the overall adjusted Odds Ratio of LOS was 0.9.

A brand new SR of probiotic sepsis (Feldman K, et al. Incidence of probiotic sepsis and morbidity risk in premature infants: a meta-analysis. Pediatr Res. 2025) calculates the frequency as being much lower than that, at 8/20,000 (but depends on how many cases were reported in the published RCTs). It calculates the risk benefit as overwhelmingly in favour of probiotics, which is still the case even if the true incidence of probiotic sepsis is 10 times higher than their estimate.

Prebiotics

There is a huge amount of ongoing research into prebiotics, most particularly the Human Milk Oligosaccharides (I just did a PubMed search on “HMOs and newborn” and there are already 120 articles in 2025). One of the challenges with probiotic usage in the preterm is the difficulty in achieving an intestinal microbiome which is similar to healthy, vaginally delivered, exclusively breast-fed term infants. Despite colonization with probiotic organisms, they only represent a small proportion of the gut bacteria. One potential way of improving this (which has been shown to be effective in other situations, such as after antibiotics) is to co-supply probiotics and HMOs. This is, of course, what breast feeding does! (Lubiech K, et al. Breast Milk as a Source of Prebiotic Human Milk Oligosaccharides and Bacteria from the Lactobacillaceae Family. Folia Biol (Praha). 2025;71(1):44-53). Recent articles have shown an impact on gut colonization after antibiotics of prebiotic supplementation, and, in this mouse model of NEC, HMOs seemed to decrease the loss of enteric neural cells. Whether this was a direct effect, or mediated by changes in the microbiome isn’t clear to me, as they don’t seem to have done any microbiome analysis. (Sodhi CP, et al. Necrotizing enterocolitis: specific human milk oligosaccharides prevent enteric glia loss and hypomotility. Pediatr Res. 2025).

There is clearly much work yet to be done, but it seems likely to me that supplementing enteral feeding with human milk, preferably unpasteurized maternal milk, with a probiotic mixture and HMOs to support growth of the organisms, especially, probably, with the use of DSLNT, will allow much more appropriate intestinal colonization, and our best chance of reducing NEC.

Breast Milk

Another analysis from the CNN reinforces much of what we know about NEC, and introduces something that we haven’t discussed much, which is the period of time that an infant is npo after birth. (Bando N, et al. Association of Enteral Feed Type with Neurodevelopmental and Neonatal Outcomes among Infants Born Preterm. J Pediatr. 2025:114536). This is an analysis of infants <29 weeks GA who received either maternal or donated human milk, or a mixture, but no formula, within the first 28 days of life, and did not have more than 7 days npo during this period. There is a lot of information about follow-up in this article, which supports an association between maternal milk (Mother’s own Milk MoM) and improved long term outcomes, such as cognitive scores, compared to donor milk, or a mixture, or being npo.

For the purposes of this blog post, there is also a clear association between being npo and NEC, with each extra day of being npo increasing the Odds Ratio for NEC, or conversely, as shown here, an OR of about 0.77 for each day of receiving enteral human milk feeds rather than being npo. For this outcome in this analysis, donor milk was very similar to MoM.

There is often a period of being npo when an at-risk baby is admitted to the NICU, as we get lines inserted, stabilise the respiratory status, and so on. There is also, often, little breast milk production, sometimes for very good reasons of maternal illness, but sometimes because the post-partum nurses are not as focused on breast milk production as we are. It is very important to make this period as short as possible, and, as long as the baby is not in shock, we should start to give breast milk within the first couple of hours of birth. Developing systems to ensure that all MoM produced finds its way immediately to the NICU, so that we can administer to the infants, is essential. This new analysis suggests that donor milk might be just as good as mother’s milk in terms of reducing the risks of being npo; but overall, I think it is clear that MoM is preferable.

Oro-pharyngeal Colostrum

I have already blogged about my scepticism of the benefits of this procedure for preventing NEC. A new meta-analysis, which is supposed to be highly supportive, includes many trials of questionable relevance. (Anne RP, et al. Effect of oropharyngeal colostrum therapy on neonatal sepsis in preterm neonates: A systematic review and meta-analysis. J Pediatr Gastroenterol Nutr. 2024;78(3):471-87). One of the trials, which contributes 48% of the weight of the meta-analysis of the impact on NEC (Mannan 2023), had a 65% incidence of stage 2 NEC, among infants who were almost all >28 weeks GA! And includes yet another moderately large Chinese trial which was retrospectively registered, and published in contravention of the guidelines of the journal where it appeared (OuYang 2021).

The effects of the intervention on LOS were also heavily influenced by a single trial, weight 38%, which only included infants >28 weeks, and had an incidence of LOS of 75% (reduced to about 60% by the intervention. Lenonardo 2022). The inclusion of data from centres with outcomes so wildly different to our current practice in Canada, make their relevance highly questionable to my NICU.

One advantage of trying to administer colostrum very rapidly to our very preterm babies, is that it requires that the logistics of ensuring that the precious liquid arrives at the incubator-side of the baby very quickly are all in place. This should help us to reduce the time that a baby is npo to a minimum. Painting the inside of the mouth with colostrum is probably harmless, but please put the rest of the breast milk into the GI tract!

Reducing antibiotic use

An infant born by cesarean section without labour and with intact membranes does not require antibiotics. The chances of sepsis are zero. Many other preterm babies can either avoid, or have very short duration (36 hours), antibiotic therapy. The longer a baby is treated with antibiotics the greater the risk of later development of NEC, as confirmed, again, by this secondary analysis of the PENUT trial (Strobel KM, et al. Effect of early antibiotic exposure on necrotizing enterocolitis and growth in extremely preterm infants. Pediatr Res. 2025).

BreastMilk Fortification

And finally, there is still no evidence that the timing, or the type, of fortifier, added to breast milk has an impact on NEC occurrence. Once you have stopped giving artificial formula to at-risk babies, there is no evidence that one fortifier compared to another, whatever the source of the original components, changes clinical outcomes.

Other interventions

It remains unclear how blood transfusions and severe anaemia are related to NEC. Recent RCTs which have either examined transfusion thresholds, or have reduced transfusions by giving erythropoietin or analogues, have not shown a difference in NEC. It is possible that more severe anaemia than allowed by the protocols of those trials could be associated with NEC.

Gastric acid suppression can be entirely avoided in at risk patients, there is no clear indication for their use in these babies.

How we treat the PDA has little impact on NEC, although the Cochrane review shows that ibuprofen leads to less NEC than indomethacin.

On this NEC awareness day, we must remain committed to the need for more research, and for more high quality studies, to eliminate this scourge from our NICUs.