Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Epigenetic Scores (EpiScores) are relatively stable DNA methylation (DNAm)-based proxies of circulating proteins that can capture health-related exposures such as chronic inflammation. EpiScore of C-reactive protein (DNAm CRP) is associated with inflammatory burden in early life, atypical brain development following preterm birth (encephalopathy of prematurity), and adult cognitive ability. To evaluate the utility of EpiScores for predicting cognition in children born preterm, we investigated relations between 43 neonatal saliva-based EpiScores known to associate with low gestational age, and cognition assessed at 2 and 5 years of age in a cohort of 232 preterm and term-born children.

DNAm CRP was negatively associated with 5-year Mullen Scales of Early Learning Composite (ELC) (β = −0.273, p = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, βinteraction = 0.181). EpiScores of CRTAM, NCAM1 and SLITRK5 were also associated with 5-year ELC in the full cohort (absolute β range 0.219 to 0.267, Bonferroni-adjusted p-values <0.01). For preterm children, associations for DNAm CRP (β = −0.318, p = 0.021) and DNAm CRTAM (β = −0.307, p = 0.006) with 5-year ELC remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.

LM has received speaker and consultancy fees from Illumina. REM is a scientific advisor to the Epigenetic Clock Development Foundation and to Optima partners. All other authors declare that they have no competing interests.

RS is supported by the Translational Neuroscience PhD Programme at the University of Edinburgh, funded by Wellcome (218493/Z/19/Z). SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). The Theirworld Edinburgh Birth Cohort (TEBC) was initiated and is maintained by Theirworld (www.theirworld.org). This work was supported through the PRENCOG study (PReterm birth as a determinant of Neurodevelopment and COGnition in children), funded by a UKRI Medical Research Council Programme Grant, MR/X003434/1.

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