Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age

J Pediatr. 2018 Oct;201:40-48.e4. doi: 10.1016/j.jpeds.2018.05.021. Epub 2018 Jul 18.


Objectives: To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years.

Study design: We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment.

Results: Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins.

Conclusions: Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

Keywords: early life risks and protectors of later cognition; extreme prematurity; inflammation and neurotrophins.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiopoietin-1 / blood
  • Brain-Derived Neurotrophic Factor / blood
  • Chemokine CCL5 / blood
  • Child
  • Child Development*
  • Cognition
  • Cognition Disorders / blood*
  • Cognition Disorders / epidemiology*
  • Executive Function
  • Female
  • Humans
  • Infant, Extremely Premature / blood*
  • Infant, Newborn
  • Male
  • Nerve Growth Factors / blood*
  • Prospective Studies
  • Risk
  • Severity of Illness Index
  • T-Lymphocytes / metabolism
  • United States / epidemiology


  • Angiopoietin-1
  • Brain-Derived Neurotrophic Factor
  • Chemokine CCL5
  • Nerve Growth Factors