For Doctors in a Hurry
- Researchers investigated whether probiotic supplementation reduces mortality and morbidity in extremely preterm or extremely low birthweight infants.
- This nationwide registry study analyzed 1268 infants born before 28 weeks or under 1000 grams across all Norwegian neonatal units.
- Probiotics were associated with lower all-cause mortality (adjusted odds ratio 0.65, 95% confidence interval 0.43 to 0.97) among treated infants.
- The authors concluded that early probiotic use reduces mortality and high-utilization protocols may decrease surgical necrotising enterocolitis risk.
- Clinicians should weigh these survival benefits against a 0.58 percent risk of probiotic-associated sepsis observed in the cohort.
Mitigating Mortality and Dysbiosis in the Extremely Preterm Infant
Necrotizing enterocolitis affects approximately 7% of very low birthweight infants (95% CI: 6.0 to 8.0%) and remains a primary driver of neonatal mortality [1]. Pathogenesis is often preceded by intestinal dysbiosis, a microbial imbalance where an overabundance of Proteobacteria and a reduction in Firmicutes occur prior to clinical onset [2]. Meta-analyses of randomized trials indicate that probiotics reduce the risk of severe necrotizing enterocolitis (RR 0.57, 95% CI 0.47 to 0.70) and all-cause mortality (RR 0.77, 95% CI 0.65 to 0.92) in preterm populations [3, 4]. Despite these benefits, clinical guidelines remain cautious for extremely preterm infants born before 28 weeks of gestation due to a historical lack of sufficiently powered subgroup data [5, 6]. Concerns persist regarding iatrogenic systemic infection, meaning infections caused directly by the administered live cultures, as approximately 55% of reported probiotic-associated infections occur in premature infants [6, 7]. A recent population-based study of 1,596 infants now provides large-scale evidence regarding the efficacy and safety of this intervention in the extremely preterm population, offering clinicians clearer guidance on routine supplementation [8].
A Nationwide Registry of the Smallest Neonates
The researchers conducted a nationwide, population-based registry study encompassing every neonatal intensive care unit in Norway. This comprehensive approach captured data on all extremely preterm infants, defined as those born at less than 28 weeks of gestation, and extremely low birthweight infants, defined as those weighing less than 1,000 grams. Between 2014 and 2021, a total of 1,596 live-born infants met these criteria and were admitted to a neonatal intensive care unit. By utilizing a national registry, the findings provide a high level of external validity, reflecting real-world clinical practice across an entire healthcare system rather than the highly controlled environment of a single-center trial.
To isolate the impact of early probiotic administration, the authors applied specific exclusion criteria to the initial cohort. They excluded infants who died within the first week of life, those who required surgery for necrotizing enterocolitis during that same first week, and those who did not receive any enteral feeds. Additionally, infants who began probiotic supplementation after the first week of life were excluded from the primary analysis to ensure the focus remained strictly on early intervention. These exclusions resulted in a final study population of 1,268 infants for the main analysis. Within this group, 676 infants (53.5%) initiated probiotic treatment within the first seven days of life, providing a substantial sample size to compare outcomes against neonates who did not receive early supplementation.
Survival Benefits and the Impact of Unit-Wide Adoption
The primary outcome was defined as all-cause mortality occurring after the first week of life. To account for the inherent confounding biases of an observational registry, the authors employed rigorous statistical methods, including logistic regression, propensity score matching, and clustering analyses. A central component of their evaluation was inverse probability of treatment weighting, a statistical technique that balances patient groups to mimic a randomized trial by weighting individuals based on their likelihood of receiving the intervention. Using this approach, the study found that probiotics were associated with lower all-cause mortality, yielding an adjusted odds ratio of 0.65 (95% CI 0.43 to 0.97). For practicing neonatologists, this translates to a 35 percent reduction in the odds of death for extremely preterm and extremely low birthweight infants who receive early supplementation.
While the mortality benefit was clear, the impact on surgical necrotizing enterocolitis was more nuanced. In the main analysis, probiotics were not associated with a reduction in surgical necrotizing enterocolitis (adjusted odds ratio 0.83, 95% CI 0.49 to 1.43). However, the researchers further investigated the data using an emulated intention-to-treat scenario, a model designed to simulate the strict protocol of a randomized controlled trial using real-world observational data. When comparing neonatal intensive care units with high probiotic use (greater than 80 percent) to those with low use (less than 30 percent), the results shifted significantly. In this unit-level comparison, high probiotic use was associated with a reduction in surgical necrotizing enterocolitis, demonstrating an adjusted odds ratio of 0.40 (95% CI 0.19 to 0.86). These data suggest that the protective effects against severe intestinal inflammation may be most robust when probiotic administration is adopted as a near-universal standard of care within a hospital unit.
Safety Profile and Clinical Considerations
To determine the broader clinical impact and safety of early probiotic administration, the researchers evaluated several secondary outcomes, including late-onset sepsis after the first week, physical growth, and probiotic-associated sepsis. Despite the clear mortality benefit, the data showed that no association was found between probiotics and late-onset sepsis or growth. These findings suggest that while the intervention supports overall survival, it does not significantly alter the incidence of general hospital-acquired infections or the trajectory of physical development in this highly vulnerable population.
Safety monitoring focused heavily on the risk of systemic infection from the administered live bacterial cultures. Among the cohort, 5 out of 858 infants (0.58%) exposed to probiotics developed probiotic-associated sepsis. While this confirms a measurable risk of bloodstream infection directly linked to the supplement, the clinical outcomes for these specific cases were highly favorable, as all 5 infants who developed probiotic-associated sepsis survived. For clinicians managing extremely low birthweight infants, these results provide a highly quantifiable risk-benefit ratio. The data indicate that the substantial reduction in all-cause mortality likely outweighs the less than 1 percent risk of a treatable, supplement-induced infection, offering strong reassurance for the integration of early probiotics into routine neonatal intensive care protocols.
References
1. Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: a systematic review and Meta-analysis. BMC Pediatrics. 2020. doi:10.1186/s12887-020-02231-5
2. Pammi M, Cope J, Tarr PI, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome. 2017. doi:10.1186/s40168-017-0248-8
3. Dermyshi E, Wang Y, Yan C, et al. The “Golden Age” of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants. Neonatology. 2017. doi:10.1159/000454668
4. Deshpande G, Athalye‐Jape G, Rao S, Patole S. Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomised controlled trials. BMJ Open. 2017. doi:10.1136/bmjopen-2017-017638
5. Kruth SS, Willers C, Persad E, Sjöström ES, Lagerström SR, Rakow A. Probiotic supplementation and risk of necrotizing enterocolitis and mortality among extremely preterm infants-the Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial: study protocol for a multicenter, double-blinded, placebo-controlled, and registry-based randomized controlled trial.. Trials. 2024. doi:10.1186/s13063-024-08088-8
6. Neonatology OBOTISO, Aceti A, Gori D, et al. Probiotics for prevention of necrotizing enterocolitis in preterm infants: systematic review and meta-analysis. The Italian Journal of Pediatrics/Italian journal of pediatrics. 2015. doi:10.1186/s13052-015-0199-2
7. D’Agostin M, Squillaci D, Lazzerini M, Barbi E, Wijers L, Lozzo PD. Invasive Infections Associated with the Use of Probiotics in Children: A Systematic Review. Children. 2021. doi:10.3390/children8100924
8. Hapnes NC, Stensvold HJ, Dalen I, et al. Probiotics for extremely preterm infants: a Norwegian population-based study.. Archives of disease in childhood. Fetal and neonatal edition. 2026. doi:10.1136/archdischild-2025-330176
