Necrotizing enterocolitis (NEC) is a devastating disease affecting approximately 7% to 10% of infants born less than 1500 g (very low birth weight), with those born weighing less than 1000 g being at highest risk.1 Infants diagnosed with NEC have an overall mortality rate close to 25%, with survivors being at an increased risk for both short- and long-term complications including short bowel syndrome, intestinal strictures, late-onset sepsis, cholestasis, and developmental delays.2,3 Thus, there is a significant need for preventive strategies aimed at reducing the risk of NEC among vulnerable preterm infants in the neonatal intensive care unit (NICU).

Although the exact etiology of NEC is unknown, it is likely related to intestinal injury and inflammation as well as intestinal microbial dysbiosis.4 Abnormal intestinal microbial development occurs because of antibiotic exposure, lack of enteral feeds, exposure to nutrition other than mother's own milk, and contact with the NICU environment, which is colonized with potentially pathogenic bacteria.5 Dysbiosis is associated with intestinal inflammation and can damage the intestinal epithelial barrier resulting in an increased risk of NEC with previous research supporting the presence of intestinal dysbiosis prior to the onset of NEC.6

Probiotics are live nonpathogenic bacteria, which colonize the intestinal tract and promote a more commensal intestinal microbiome. In addition, they function to decrease inflammation, improve immune cell regulation, strengthen the gut barrier, and upregulate cytoprotective genes.7 Providing probiotics to preterm infants may decrease the incidence of NEC and is currently one of the most studied interventions in the NICU. A 2020 Cochrane meta-analysis, which included 56 randomized controlled trials and 10 812 preterm infants, found that probiotics were associated with a reduced risk of NEC and infection and a shorter hospital stay.8 An additional 2021 meta-analysis of 30 high-quality nonrandomized studies with included 77 018 infants found that probiotic use was associated with reduced NEC, mortality, and late-onset sepsis.9 Combined, these reviews included nearly 90 000 infants (both randomized controlled trials and observational studies) and overall supported the use of probiotics for the prevention of NEC.

Based upon the vast amount of research supporting the use of probiotics to reduce the incidence of NEC, one would expect their use to be standard care in NICUs. Yet, only approximately 10% of units provide probiotics to infants as a strategy to reduce NEC.10 This lack of universal acceptance is likely related to the absence of Federal Drug Administration regulation, heterogeneity among studies including the use of different types and combinations of probiotics, and safety concerns. In addition, statements by the American Academy of Pediatrics11 and the Canadian Paediatric Society12 advocate caution regarding the routine use of probiotics in preterm infants especially those weighing less than 1000 g.

Probiotics are typically regulated as dietary supplements. However, when used for treatment or disease prevention, dietary supplements are required to meet higher regulatory standards including identification of the specific microbe for use, evidence that this microbe is administered at the indicated dose, and evidence of safety. When probiotics are not regulated as a pharmaceutical-grade product, the actual probiotic content may vary from those advertised on the product label. In fact, when 16 different commercially available probiotic products were evaluated to determine whether they contained Bifidobacterium as advertised, only 1 contained exactly the same Bifidobacterium organism as advertised on the label and variability existed between product lot and pill. One product contained none of the organisms listed on the label.13

Published studies regarding the use of probiotics to prevent NEC in preterm infants have significant methodologic differences. Numerous different strains and combinations of probiotics have been included and pooling such data in a meta-analysis may be problematic. In addition, previous studies have included infants of varying gestational ages including those older than 32 weeks who are at minimal risk of developing NEC. Such heterogeneity among studies suggests caution in interpretation of results regarding the benefits of probiotics.

Safety concerns regarding the use of probiotics in preterm infants generally surround the potential for sepsis associated with the bacterial strain contained in the probiotic or from pathogens present in the probiotic product due to contamination.14 In addition, the most recent large randomized controlled trials have not shown a reduction in NEC among infants born at the earliest gestational ages who are at greatest risk of both NEC and probiotic-related complications.15,16 Finally, little information exists regarding the long-term safety of probiotic use in this population.

The combination of extensive research supporting the routine use of probiotics in preterm infants and caution against their use has led to confusion among clinicians regarding whether or not to include probiotics in their routine care of preterm infants. Potential options regarding the use of probiotics in an individual unit include (1) waiting for the result of recently completed or ongoing studies evaluating the safety and tolerability of pharmaceutical-grade probiotics; (2) waiting for Federal Drug Administration approval; or (3) acceptance that the evidence is "good enough" and implement the use of probiotics in NICU protocols.17 However, units implementing probiotics into their routine care should standardize their practice to ensure effectiveness and safely. Development of protocols that explicitly specify which infants are eligible, the specific probiotic product and dose to use, and precise start and stop times is essential. Careful documentation of outcomes, adverse events, and safety is also necessary. Finally, NICUs should discuss potential risks and benefits with parents and consider a formalized consent process.

Necrotizing enterocolitis is a devastating disease that significantly increases the mortality and morbidity of preterm infants in the NICU emphasizing the urgent need for preventive strategies. However, because any preventive strategy requires treatment of all at risk infants, exposure of numerous infants to probiotics is necessary to prevent a single case of NEC. Therefore, prior to implementation of probiotics into routine care, it is necessary that NICUs develop and ensure health provider compliance with detailed policies and protocols to maximize infant safety.

-Leslie A. Parker, PhD, APRN, FAANP, FAAN

College of Nursing

University of Florida

Gainesville, Florida

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