Association of fentanyl-induced microbiome changes and neurodevelopmental outcomes in preterm infants

Fentanyl is an appropriate and common medication in hospitalized extremely preterm infants. Opiates such as fentanyl may alter gut microbiome development and subsequent neurodevelopmental outcomes. We compare a cohort of preterm infants with and without postnatal fentanyl exposure, using their hospitalization stool samples and neurodevelopmental outcomes. The study examines the association between fentanyl exposure, fecal microbiome changes during NICU stay, and neurodevelopmental outcomes up to 8 years of age. Fentanyl exposure during NICU hospitalization is associated with a decrease in fecal microbiome richness (adjusted p = 0.02), depletion in the microbial taxa Actinobacteriota, Bacteroidia and Peptostreptococcaceae, increase in constipation, an increase of microbiome derived metabolites involved in inflammation and gastrointestinal (GI) homeostasis, and altered microbial virulence (i.e. factors that contribute to pathogenicity). Increased fentanyl exposure is associated with worse cognitive scores on the Bayley Scales of Infant and Toddler Development at 2 years of age and the intelligence quotient composite score on the Wechsler Preschool and Primary Scale of Intelligence at 3-8 years of age. Microbiome virulence mediated the association between fentanyl and cognitive outcomes at 2 years old. Increased duration of postnatal fentanyl exposure in preterm infants is associated with gut microbiome changes (i.e. richness and virulence) and later cognitive impairment at 2 and 3-8 years of age.