Proinflammatory state and metabolic dysregulation linking delayed feeding progression to extrauterine restricted head growth in extremely preterm infants.

BACKGROUND: Growth of head circumference is critically associated with neurodevelopmental outcomes. Extrauterine growth restriction of head circumference from birth to term-equivalent age is linked to impaired neurodevelopment. This study examined whether a proinflammatory state and metabolic dysregulation characterize the association between delayed feeding progression and extrauterine restricted head growth in extremely preterm infants. METHODS: This cohort study included infants born ≤ 28 weeks' gestation between 2019 and 2021. Feeding progression trajectories, categorized as improvement or delayed improvement based on daily enteral feeding milk volumes during the first 8 weeks, were analyzed using kmlShape. Plasma metabolomics were assessed at 36 weeks postmenstrual age, and head growth and brain MRI were evaluated at term-equivalent age. RESULTS: Among the 98 extremely preterm infants, 62 (63%) demonstrated improvement in feeding progression, while 36 (37%) had delayed improvement. Compared to the feeding improvement group, the delayed feeding improvement group had higher rates of gastrointestinal morbidities, including necrotizing enterocolitis (NEC) of Bell stage II or higher (17% vs. 2%, p = 0.009) and abdominal surgery for non-NEC events (25% vs. 8%, p = 0.021) during admission, and a significantly increased risk of extrauterine growth restriction in head circumference by term-equivalent age (47% vs. 23%, p = 0.021). The multivariable analysis showed delayed feeding improvement was also a significant risk associated with the delta z-scores below - 1.5 in head circumference (adjusted odds ratio [aOR]: 5.26 [95% CI 1.66-16.65]). MRI examinations revealed significantly smaller residual brain volumes involving total brain tissue volume, brainstem, and cerebellum in the delayed improvement group. Untargeted plasma metabolomics showed elevated levels of hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandins, bile acids and immune markers, and reduced levels of L-tyrosine, phenylpyruvic acid, L-tryptophan metabolism, and L-carnitine biosynthesis were found in the delayed improvement group compared to that in the improvement group. CONCLUSIONS: Proinflammatory and dysregulated metabolic state following early delayed feeding progression were associated with impaired extrauterine head growth, highlighting the potential role of the immature gut-brain axis in preterm infants.