<p><strong>OBJECTIVES: </strong>To determine the epidemiology and microbiology of early-onset sepsis (EOS) among very preterm infants using a nationally representative cohort from academic and community hospitals to inform empirical antibiotic guidance, highlight risk factors for infection, and aid in prognostication for infected infants.</p>

<p><strong>METHODS: </strong>Prospective observational study of very preterm infants born weighing 401 to 1500 g or at 22 to 29 weeks' gestational age from January 2018 to December 2019 in 753 Vermont Oxford Network centers. EOS was defined as a culture-confirmed bacterial infection of the blood or cerebrospinal fluid in the 3 days after birth. Demographics, clinical characteristics, and outcomes were compared between infants with and without EOS.</p>

<p><strong>RESULTS: </strong>Of 84 333 included infants, 1139 had EOS for an incidence rate of 13.5 per 1000 very preterm births (99% confidence interval [CI] 12.5-14.6). (538 of 1158; 46.5%) and group B (218 of 1158; 18.8%) were the most common pathogens. Infected infants had longer lengths of stay (median 92 vs 66 days) and lower rates of survival (67.5% vs 90.4%; adjusted risk ratio 0.82 [95% CI 0.79-0.85]) and of survival without morbidity (26.1% vs 59.4%; adjusted risk ratio 0.66 [95% CI 0.60-0.72]).</p>

<p><strong>CONCLUSIONS: </strong>In a nationally representative sample of very preterm infants with EOS from 2018 to 2019, approximately one-third of isolates were neither group B nor . Three-quarters of all infected infants either died or survived with a major medical morbidity. The profoundly negative impact of EOS on very preterm infants highlights the need for novel preventive strategies.</p>