To evaluate whether differences in early nutritional support provided to extremely premature infants mediate the effect of critical illness on later outcomes, we examined whether nutritional support provided to “more critically ill” infants differs from that provided to “less critically ill” infants during the initial weeks of life, and if, after controlling for critical illness, that difference is associated with growth and rates of adverse outcomes. 1366 participants in the NICHD Neonatal Research Network parenteral glutamine supplementation randomized controlled trial who were alive on day of life 7 were stratified by whether they received mechanical ventilation for the first 7 days of life. Compared to more critically ill infants, less critically ill infants received significantly more total nutritional support during each of the first 3 weeks of life, had significantly faster growth velocities, less moderate/severe bronchopulmonary dysplasia, less late-onset sepsis, less death, shorter hospital stays, and better neurodevelopmental outcomes at 18–22 months corrected age. Rates of necrotizing enterocolitis were similar. Adjusted analyses using general linear and logistic regression modeling and a formal mediation framework demonstrated that the influence of critical illness on the risk of adverse outcomes was mediated by total daily energy intake during the first week of life.

Matrix metalloproteinases (MMP) and chemokines appear to be induced by hyperoxia in preclinical studies. We hypothesized that O2 exposure immediately after birth is associated with altered blood spot MMP 9 and β chemokine concentrations. The following analytes were measured on blood spots on days 1 and 3 of life, using luminex technology in 1059 infants (birth weights < 1000 grams) in the NICHD Neonatal Research Network: MMP 9, monocyte chemoattractant protein 1 (MCP 1), macrophage inflammatory proteins (MIP 1α and β), and Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES). Infants administered O2 continually from 6 to 24 hours of life (n=729), when compared to those with < 6 hours exposure (n=330), had significantly lower mean birth weight and higher rate of respiratory distress syndrome (p≤ 0.002). On day 3, MCP 1 was higher and RANTES lower among infants with early prolonged O2 exposure. After adjusting for covariates, prolonged early O2 exposure retained a statistically significant association with higher MCP 1 on day 3 (p=0.003). The consistent association between O2 exposure and MCP 1 among extremely preterm infants suggests that further investigation of its role in oxidative injury is warranted.