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 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002–2004 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 3rd and 4th week (“late elevations”; n=532) of life with neurocognition. Results Early elevations of CRP, TNF-alpha, IL-8, ICAM-1, and EPO 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 CRP (OR:4.0; 95% CI 1.5, 10), IL-8 (OR:5.0; 1.9, 13), ICAM-1 (OR:6.5; 2.6, 16), VEGF-R2 (OR:3.2; 1.2, 8.3), and TSH (OR:3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and VEGF-R2. When four 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 four or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs:2.9–4.8). Conclusion EP children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than EP peers without such elevations to have cognitive impairment at 10 years.

Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm

“…At age 10 years, 966 of these were recruited for an age‐appropriate assessment of cognition, executive function, behaviors, and achievement, 889 (92%) returned for follow up, and 874 were administered the neurocognitive tests (Table 1). Because children who had early systemic inflammation are at heightened risk of cognitive impairment (Kuban et al, 2017), and children who are cognitively impaired do not do well on academic achievement tests, we wanted to restrict our search for any relationship between early systemic inflammation and learning limitations not attributed to global limitation to children who were not cognitively impaired. Thus, the sample for the analyses presented here is restricted to the 666 children who had a DAS‐II verbal IQ ≥ 70 and non‐verbal IQ ≥ 70.…”

The fetus at the tipping point: modifying the outcome of fetal asphyxia

“…Recent data from the Extremely Low Gestational Age Newborns (ELGANs) study measured pro‐inflammatory cytokine patterns in whole blood of preterm infants <28 weeks gestation in the first month of life and demonstrated that elevated systemic levels of pro‐inflammatory cytokines are associated with adverse neurological outcomes up to the age of 10 years (Kuban et al . ), and that both antenatal and postnatal inflammation play a role (Yanni et al . ).…”

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

“…The cause of neurodevelopmental impairment after preterm birth is multifactorial. However, there is compelling evidence that exposure to perinatal infection/inflammation is strongly associated with preterm birth and impaired neurodevelopment [2][3][4]. In recent studies, long-term neurodevelopmental impairment was associated with diffuse injury in the white matter tracts, with evidence of chronic gliosis and impaired oligodendrocyte maturation, but limited cell loss [5,6].…”