A nationwide Swedish study found very preterm babies given daily probiotics had lower rates of NEC and death, but sepsis risk remained unchanged.
Study: Probiotics and Risk of Death, Necrotizing Enterocolitis, and Sepsis in Very Preterm Infants. Image credit: Iryna Inshyna/Shutterstock.com
Daily probiotic supplementation was associated with a lower risk of death and necrotizing enterocolitis in very preterm infants, according to a new study published in JAMA Network Open.
Why probiotics may protect vulnerable preterm infants
Probiotics are live microorganisms that provide health benefits when consumed in adequate amounts. Several animal studies have linked probiotics to a range of gastrointestinal health benefits, including regulation of intestinal permeability, stimulation of immune functions, and inhibition of pathogenic bacteria.
Necrotizing enterocolitis is a severe gastrointestinal condition that mostly affects preterm infants with immature gut structure and function. The condition is characterized by inflammation and intestinal tissue death.
The central role of gut microbiota dysbiosis in the pathogenesis of necrotizing enterocolitis suggests that probiotic supplementation may help prevent this condition in preterm infants. Emerging evidence has linked specific probiotic strains to reduced incidence of necrotizing enterocolitis and all-cause mortality in preterm infants.
In 2020, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition issued a position statement conditionally supporting the use of specific probiotic strains in preterm infants. In line with these recommendations, the Swedish Neonatal Society issued a national recommendation that year for probiotic supplementation in very preterm infants. However, the Swedish recommendation did not include extremely preterm infants born before 28 weeks of gestation due to insufficient evidence at that time.
This nationwide implementation of the recommendation provides researchers with real-world patient data from national health registers to explore associations between probiotic supplementation and clinical outcomes in preterm infants.
Using data from the Swedish Neonatal Quality Register, the current study examined whether probiotic supplementation was associated with the risks of necrotizing enterocolitis, sepsis, and death in very preterm infants.
The study included 4695 very preterm infants (mean gestational age: 30.2 weeks). Among them, 33.5% received a probiotic formulation containing three bacterial strains: Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus, and 66.5% were not supplemented with any probiotics.
Probiotic use linked to lower NEC and mortality
The national recommendation for probiotic use in preterm infants was issued in 2020 in Sweden. Following the implementation, probiotic uptake increased from 16.9% in 2020 to an average of 64.8% from 2021 to 2024. The current study also descriptively compared health outcomes between 2017 and 2019 and 2021 to 2024, i.e., the period before and after the national recommendation.
From 2021 to 2024, the rate of the composite outcome of death and necrotizing enterocolitis was lower in infants exposed to probiotics (0.8%) compared to those not receiving probiotics (2.9%). Across the full 2017–2024 cohort, the corresponding rates were 0.8% and 3.4%, respectively, with probiotic supplementation associated with a 72% lower adjusted relative risk of death and/or necrotizing enterocolitis.
When both outcomes were analyzed separately, the findings revealed that the risks of both necrotizing enterocolitis and death were lower in infants exposed to probiotics. The analysis restricted to surgical necrotizing enterocolitis showed an even larger relative risk reduction associated with probiotic supplementation, although there was only one case of surgical necrotizing enterocolitis in the probiotic group compared with 40 in the non-probiotic group.
However, no significant association with the risk of the composite outcome of death and sepsis was observed with probiotic exposure.
To examine the association between probiotic exposure and mortality, a separate analysis was conducted considering necrotizing enterocolitis as a mediator of death. This exploratory analysis suggested that a significant proportion (42.3%) of the observed mortality reduction associated with probiotic exposure was mediated through a lower incidence of necrotizing enterocolitis.
Findings support probiotics while highlighting important limitations
This population-based cohort study reveals that multistrain probiotic supplementation was associated with significantly lower risks of necrotizing enterocolitis and death in very preterm infants. These findings support the broader literature linking probiotic supplementation to a lower risk of mortality and necrotizing enterocolitis in preterm infants.
Notably, the study did not find any association between probiotic exposure and sepsis risk reduction. This finding is consistent with a randomized clinical trial conducted in Australia and New Zealand using the same bacterial strains.
In contrast, a cohort study conducted in England and Wales showed a 6% reduction in sepsis risk among infants receiving probiotics. These inconsistencies in findings may be due to variations in disease definitions, study populations, or probiotic strains used.
During the supplementation period, a survey of Swedish neonatal intensive care units reported no cases of probiotic-associated sepsis, supporting the safety of this strategy. However, the national register did not contain information on the bacteria responsible for sepsis cases. Some risks may still exist, including bacteremia from translocation in high-risk infants and contamination during handling of formulations. These risk factors highlight the need for continuous safety surveillance.
Overall, the study findings support an association between multistrain probiotic supplementation and lower risks of necrotizing enterocolitis and related mortality in very preterm infants, which may help inform shared decision-making between clinicians and families. However, these findings should not be generalized to extremely preterm infants born before 28 weeks of gestation, who typically exhibit much higher baseline risks of adverse outcomes.
The study relied primarily on data collected from the Swedish Neonatal Quality Register, with linked maternal and pregnancy data and validation of mortality data using other national registers. Misclassification of necrotizing enterocolitis cases in the neonatal register may lead to overestimation of the necrotizing enterocolitis incidence. Existing evidence indicates significant differences between register-reported necrotizing enterocolitis cases and medical record reviews.
The authors also disclosed that study author Stefan Johansson is co-founder and chief medical officer of Neobiomics AB, the company listed as the supplier of the probiotic preparation used in the study. The research was funded by the Gastroenterological Research Fund/Swedish Medical Society and the Swedish Research Council, and the authors reported that the funders had no role in the study design, analysis, interpretation, or decision to publish.
