The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns

Abstract

We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration. Methods In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing 6 functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14 and evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and, at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers (M-CHAT) screen, and, in a subset of these children from 12 of 14 sites (n= 826), an attention problem identified with the Child Behavior Checklist (CBCL). Results The risk of abnormal brain structure and function overall was increased among children who had recurrent/persistent elevations of the 25 protein. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index (MDI) on the Bayley Scales of Infant Development-II, microcephaly, and a CBCL-defined attention problem increased with higher numbers of these recurrently/persistently elevated proteins. Interpretation Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely premature.

Neurodevelopmental outcomes in postnatal growth-restricted preterm infants with postnatal head-sparing

“…For example, elevated levels of inflammation-related proteins in the first two weeks of life in infants born < 28 weeks increase the odds of microcephaly and lower Mental Developmental Index scores on the BSID-II at 2 years of age. 27 Likewise, preterm infants with proven neonatal sepsis or necrotizing enterocolitis demonstrate structural changes in the brain and smaller head circumferences at 2 years of age. 28 Moreover, adverse neurodevelopmental outcomes and poor head growth have been associated with neonatal infection in extremely low birthweight infants.…”

The Human Microbiome during Bacterial Vaginosis

“…In contrast, Lactobacillus colonization of the placenta was associated with low odds of an inflammatory response in newborns. In turn, the patterns of maternal microbedependent systemic inflammation were associated with developmental delay in psychomotor function, brain damage, and a myriad of inflammation-driven complications in very-early-gestational-age children studied up to 9 years of age (131)(132)(133)(134)(135)(136)(137).…”

Urinary Levels of IL-1β and GDNF in Preterm Neonates as Potential Biomarkers of Motor Development: A Prospective Study

“…This was an unexpected finding, as typically this cytokine is associated with CNS damage [35, 42, 51, 57]. However, the inflammatory response may have a physiological function in brain development and may exert protective role in the CNS [17, 50, 52, 53, 58].…”