Neonatal clinicians have long debated how to define neonatal sepsis, a condition—however it is defined—that is a significant cause of neonatal morbidity and mortality worldwide.1,2 There are compelling reasons for defining sepsis in any population. First, accurate longitudinal and comparative sepsis surveillance requires a reproducible definition that can be applied across different centers, databases, regions, and care models. Definitions based on microbiologic culture have allowed for meaningful analysis of large national neonatal databases in the United States.3,4 Second, functional definitions of sepsis can guide early recognition and institution of life-saving clinical interventions. This is especially impactful among populations that are relatively healthy at baseline, for whom a specified degree of laboratory test abnormality, symptomatology, and/or measures of organ dysfunction should prompt specific and time-sensitive interventions such as intravascular volume and antibiotic administration. The International Surviving Sepsis Campaign, for example, provides best practice guidance for clinicians caring for adult patients with sepsis or septic shock.5 Finally, reproducible definitions are optimally required for the conduct of intervention trials of therapeutics to prevent or treat sepsis. To conduct and recruit for antimicrobial trials, for example, clear inclusion criteria, objective parameters to monitor response, and explicit measurable outcomes are critically important.6

Both concern for the consequences of excessive and indiscriminate empiric antibiotic use among newborns (particularly those born preterm), and fear of the often serious and potentially fatal consequences of neonatal infection inform clinical trials addressing prevention, identification, and optimal management of neonatal sepsis.4,7 These trials have variably defined sepsis, leading to an inability to pool trial results and to accurately measure impact. In light of these considerations, Hayes and colleagues aimed to catalog definitions of neonatal sepsis in published randomized controlled trials.8 The authors identified 80 trials from 1986 to 2019, comprising almost 41,000 neonates from multiple international sites. It is worth noting that the trials included are themselves quite heterogeneous, addressing early- and late-onset neonatal sepsis, sepsis treatment and sepsis prevention, and neonatal sepsis both as the primary aim of the study as well as a secondary outcome in trials of obstetric interventions. The sepsis definitions were revealed to be equally varied. Because they did not fall into discrete bins, the authors broke down contingent or algorithmic definitions into their component primary criteria and relevant secondary criteria, and included a sub-analysis of definition qualifiers. The majority relied on microbiological culture and/or clinical signs of infection. Biochemical, hematological, and radiological signs of and clinical risk factors for infection were less frequently utilized. The authors contrasted their findings with adult and pediatric sepsis definitions, which more commonly rely on evidence of organ dysfunction. They conclude by calling for an international consensus-based definition of neonatal sepsis to allow for meta-analysis that might better interpret and translate results to improve outcomes.

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