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

Abstract

Objectives: To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age.

Study design: A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition.

Results: Early elevations of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8).

Conclusions: Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.

Keywords: cognition; extremely preterm infants; inflammation-related proteins; school age.