Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation

Abstract

Background Systemic inflammation during the first two postnatal weeks in extremely preterm newborns (< 28 weeks gestation) has been associated with an increased risk of neurodevelopmental dysfunctions. Little is known, however, about the relationship between systemic inflammation during the third and fourth postnatal weeks and subsequent development. Methods We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N = 749) and 28 (N = 697) from infants born before the 28th week of gestation and assessed at age 2 years. We then sought the developmental correlates of top quartile concentrations for gestational age and day the specimen was collected. Odds ratios and 95% confidence intervals were calculated from regular or multinomial logistic regression models (as appropriate). Results Top quartile concentrations of CRP, IL-1β, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with ventriculomegaly (when in the NICU) and microcephaly at age 2 years. Top quartile concentrations of CRP, SAA, IL-6, TNF-R2, IL-8, and ICAM-1 were associated with Mental Development Index (MDI) of the Bayley-II < 55, while top quartile concentrations of CRP, TNF-α (inversely), IL-8, and ICAM-1 were associated with Psychomotor Development Index (PDI) < 55 Conclusion Extremely preterm newborns who had systemic inflammation during the third and fourth postnatal weeks were at increased risk of ventriculomegaly during the months after birth, and of microcephaly, and low Bayley Scale scores at 2 years of age.

Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm

“…(14, 15) Now we provide evidence that elevation of circulating inflammation-associated proteins detectable in the 3 rd and 4 th postnatal weeks contribute to risk of cognitive impairment beyond the risk posed by the presence of such proteins in the first 2 weeks of life (28) . This observation coupled with our previous report, which shows little association of Day 1 inflammatory protein elevations with 2-year cognitive outcomes (14) , suggests that in addition to exposures that initiate an inflammatory process in utero, postnatal exposures also might initiate inflammation that predicts later cognitive deficits.…”

“…(14, 15) Moreover, concentrations of inflammation-related proteins in blood spot samples collected in the 3 rd and 4 th weeks of life were associated with two-year outcomes beyond associations with protein concentrations from the first two postnatal weeks alone. (16) …”

Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

“…The predominant form of NWMI is a diffuse injury to myelin tracts (Counsell et al, ) that involves inflammation and gliosis, a reactive response by microglia and astrocytes (Inder et al, ; Pekny and Nilsson, ; Riddle et al, ; Supramaniam et al, ; Verney et al, ) that can be triggered by systemic processes such as infection (Deng, ; Deng et al, ; Hagberg et al, ; Malaeb and Dammann, ). Increased markers of inflammation in the neonatal period are strongly associated with the development of cerebral palsy, NWMI and poor neurological outcomes (Dammann and Leviton, ; Leviton et al, ). Although it had been thought that inflammation led to NWMI by depleting the oligodendrocyte progenitor cell (OPC) pool (Back, ), more recent histologic studies using markers of discrete stages of OPC development in NWMI reveal that OPCs are present but arrested in a pre‐myelinating and immature state (Billiards et al, ; Buser et al, ; Verney et al, ).…”

Neurocognitive Outcomes at 10 Years of Age in Extremely Preterm Newborns with Late-Onset Bacteremia

“…(3, 12, 13) Late-onset bacteremia was associated with a stronger inflammatory response than early bacteremia. (14) These observations prompted us to question whether late-onset bacteremia accounted for some of the apparent increased risk of neurocognitive impairments among children born preterm.…”