Neurodevelopmental Outcome and Epigenetic Changes at 2 Years Associated with the Oxygen Load Received upon Postnatal Stabilization: A Pilot Study

Abstract

<b><i>Introduction:</i></b> The oxygen load provided to preterm infants during postnatal stabilization caused significant modifications of DNA methylation in the preterm epigenome. We aimed to assess if there was an association between DNA methylation changes and neurodevelopmental outcomes. <b><i>Methods:</i></b> Preterm infants were followed until 2 years after birth. Dried blood spots were processed, and DNA methylation was measured using the MassARRAY technology of Sequenom. We selected specific genes that corresponded to differentially methylated CpG sites that correlated with the oxygen load at 2 h after birth. Neurodevelopmental outcome was blindly assessed using Bayley-III scale. <b><i>Results:</i></b> Of 32 eligible patients, we completed the methylation analysis in 19 patients and the neurodevelopmental evaluation in 22. Comparison of differential methylation analysis between time 0 (cord blood) and 2 h after birth showed 74 significant CpGs, out of which 14 correlated with the oxygen load received at birth. Out of these 14 genes, only <i>TRAPPC9</i> showed statistically significant differences at 2 years of age between the infants who received &#x3e;500 mL versus &#x3c;500 mL O₂/kg. Premature who received &#x3e;500 mL O₂/kg showed significantly lower motor composite scores. <b><i>Discussion/Conclusions:</i></b> Premature who received higher oxygen load scored lower motor composite scores and showed a hypermethylation pattern of <i>TRAPPC9</i> at 2 years of age. <i>TRAPPC9</i> mutations are associated with neurodevelopmental delay and intellectual disability, so changes in the CpG methylation of this gene and its subsequent expression alteration can produce a similar phenotype. Further studies with a greater sample size are needed to confirm these findings.