Probiotic Implementation and Necrotizing Enterocolitis Risk in Preterm Infants.

Importance: Despite their widespread use, uncertainty remains about the effectiveness and safety of probiotics for preventing necrotizing enterocolitis (NEC) in preterm infants. Recent regulatory warnings, including from the US Food and Drug Administration, have further emphasized the need for robust clinical data on both the benefits and risks of probiotics for this population. Objective: To evaluate the association between implementation of a multistrain probiotic formulation and NEC incidence in preterm infants in a high-risk neonatal intensive care unit (NICU) setting. Design, Setting, and Participants: This multicenter retrospective cohort study was conducted at 2 NICUs in the Netherlands. Preterm infants (<30 weeks of gestational age [GA], birth weight [BW] <1000 g, or both) born between January 1, 2018, and July 1, 2024, were compared before and after the implementation of routine probiotic supplementation. The probiotic protocol was introduced in October 2020 or March 2021, depending on the center. Exposure: Routine implementation of a multistrain probiotic formulation (Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4) as part of enteral feeding. Main Outcomes and Measures: The primary outcome was NEC incidence, classified as medical, surgical, or fatal. Secondary outcomes included all-cause mortality and mortality not associated with NEC. Primary and secondary outcomes were analyzed using generalized linear regression models, comparing preimplementation and postimplementation periods and adjusting for GA, sex, BW z score, 5-minute Apgar score, prenatal steroid use, and preterm premature rupture of membranes. Interrupted time-series analysis was performed as a sensitivity analysis to assess robustness against underlying temporal trends. Probiotic-related sepsis was monitored to assess safety. Results: This study included 1413 infants (742 males [52.5%]), stratified into a preimplementation group (n = 598) and a postimplementation group (n = 815). Baseline characteristics were comparable between groups (median GA, 27.7 weeks [IQR, 26.0-29.0 weeks] and 27.9 weeks [IQR, 26.4-29.0 weeks]; median BW, 950 g [IQR, 770-1170 g] and 975 g [IQR, 790-1190 g]). Following probiotic implementation, NEC incidence decreased from 11.9% (n = 71) to 5.3% (n = 43) (adjusted risk ratio [ARR], 0.49 [95% CI, 0.34-0.70]; P < .001). No statistically significant evidence of underlying time trends was detected. All-cause mortality remained stable for the preimplementation and postimplementation groups (70 [11.7%] vs 94 [11.5%]; ARR, 1.06 [95% CI, 0.82-1.39]; P = .64); non-NEC-associated mortality increased from 7.2% (n = 43) to 9.6% (n = 78) (ARR, 1.42 [95% CI, 1.01-1.98]; P = .04). One case of probiotic-associated sepsis was identified. Conclusions and Relevance: In this cohort study of preterm infants, implementation of a well-characterized multistrain probiotic was associated with a reduction in NEC incidence. This finding supports the use of the studied probiotic as an effective preventive strategy for NEC, although its effects on broader mortality outcomes remain uncertain.