Many publications and some guidelines about the use of probiotics for NEC prevention in the preterm make the claim that the evidence is more reliable for the moderately preterm than for the extreme preterm.
Many of the RCTs have not reported outcomes divided by GA or birth weight categories, even though they included many such infants. The 2023 Cochrane review of probiotics for NEC prevention (Sharif S, et al. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2023;7(7):CD005496) included over 10,000 infants among all the trials, but was only able to analyze 1800 ELBW or extremely preterm infants (<28 weeks). Of those infants, over 600 were from the trial by Costeloe, this was a high quality trial in the UK of Bifidobacterium breve, which was unfortunately ineffective, in infants of any gestation or weight group.
Other RCTs which have been restricted to, or have reported subgroups of, extremely low birth weight infants are all quite small, except for the Australian Proprems trial, which used a preparation that included a B infantis, and had about 460 babies <28 wks. That study had a low incidence of NEC in the controls in the <28 wk GA subgroup, of 5.8%, which was reduced to 4.2% in the probiotic group, a relative risk of 0.73, but with wide confidence margins (0.33-1.6) in that subgroup. Overall the reduction in NEC in that trial was unlikely to be due to chance, RR 0.46 (0.23-0.93) and there was no significant interaction between treatment effect and birth weight.
Most of the trials, on the other hand have included very immature and extremely low birth weight infants, they have just not reported subgroup results, meaning that Systematic reviews have little power to determine efficacy specifically in that subgroup.
A recent Norwegian observational study, reports a national cohort of extremely preterm infants (<28 weeks or <1000g) covering the period, 2014-2021 (Hapnes NC, et al. Probiotics for extremely preterm infants: a Norwegian population-based study. Arch Dis Child Fetal Neonatal Ed. 2026). This period started when the Norwegians issued a recommendation to give probiotics to this group, but uptake was far from universal. It also covers a period when the commonly used preparation Infloran was available, then withdrawn from use, leading to a drop in utilisation for a year, then another preparation was used, Labinic droplets, and more recently, another preparation, Proprems which is the one used in Sweden that I discussed in my previous post, was starting to be used. All 3 preparations include a B infantis.
The outcomes of interest were mortality, late-onset sepsis, and surgical NEC; like some other databases, the concerns about the subjectivity of the diagnosis of medical NEC are such that they concentrate on surgical NEC, and all of the cases were reviewed to ensure they met diagnostic criteria. The vast majority of these babies received maternal or donor breast milk, fortified as a routine with bovine based fortifier, until 32 to 34 weeks PMA. Of note, the babies receiving probiotics had a lower birthweight average, by 100 g, and were less mature, with worse CRIB scores, meaning they had a higher baseline risk, so the adjusted analyses are important. The associations with all cause mortality and surgical NEC are shown below.
There is lower mortality, lower surgical NEC, less “death or surgical NEC”, and, importantly, very similar late-onset sepsis (LOS), even though they did have 5 cases of probiotic sepsis among the over 600 babies who received them.
Overall, from multiple systematic reviews, despite the risk of sepsis from the probiotic organisms, LOS is similar, or lower, with probiotic use than without. This recent SR, with a cute graphic Maulida R, et al. Probiotics for preventing neonatal sepsis in preterm neonates: a systematic review and meta-analysis for clinical practice. Epidemiol Health. 2025;47:e2025051, is open access, and concludes that multistrain probiotic mixtures reduce LOS.
Like many SRs, the single strains are grouped by genus, even though there are major differences between the different species within a genus, but it seems to hold true that a mixture of strains are probably the most effective for reducing LOS, and mixture containing a B infantis seems to hold the best chance of both LOS and NEC reduction.
An overall review of the impacts of probiotics on sepsis, by Nick Embleton, Chris van den Akker and Belal Alsheikh (Embleton ND, et al. Probiotic supplementation – does it prevent or cause neonatal sepsis? Semin Fetal Neonatal Med. 2025;30(4):101668) comes to the clear conclusion that probiotic supplementation does not increase sepsis, it most likely reduces sepsis overall, despite the occasional case of probiotic sepsis, which makes the decision of the FDA seriously questionable.
Indeed that decision has had serious negative impacts on our babies, this analysis (Tolia VN, et al. Probiotics and necrotizing enterocolitis in preterm infants after the food and drug administration warning actions. J Perinatol. 2026) used data from the Pediatrix data warehouse. It analyses NEC incidence by NICU rather than by baby, and divided NICUs according to whether they were giving more or less than 80% of their 23 to 29 week preterm babies probiotics, before the FDA warning.
Probiotic use dropped from 86% to 7% in the high use centres, and from 13% to 0.1% in the low use centres. Both medical and surgical NEC increased when probiotics were stopped, LOS did not change.
There are several observational studies, therefore, restricted to extremely preterm infants (either <28 or <29 weeks GA) which show the same impacts of probiotic therapy on NEC as are seen among more mature preterm infants.
It seems to me that there is no good evidence to exclude the most immature babies from the benefits of routine probiotic supplementation. Putting everything together, a multistrain preparation containing a B infantis probably has the greatest benefit for preventing NEC, and likely has a modest impact on overall LOS also.
