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Early use of parenteral nutrition in the paediatric intensive care unit (PICU) negatively affects development of executive functions, externalising behaviour, and visual–motor integration 2 years later, compared with omitting parenteral nutrition until PICU day 8 (late parenteral nutrition). The molecular basis of this finding is uncertain. We aimed to test the hypothesis that DNA methylation changes occur during critical illness and that early parenteral nutrition (or a specific macronutrient component hereof) contributes to these changes, which could explain its negative effects on neurocognitive development. This pre-planned secondary analysis of the multicentre PEPaNIC trial (2012–18) included all patients with a last PICU day blood sample (n=825, aged 0–17 years at PICU admission) who were randomly allocated (1:1) to early parenteral nutrition or late parenteral nutrition, as compared with 352 demographically matched healthy children. Investigators were masked to treatment allocation. We used the Infinium Human MethylationEPIC BeadChip to determine the genome-wide peripheral blood leukocyte DNA methylation of 865 859 CpG sites, yielding high-quality results for 403 patients allocated to early parenteral nutrition and for 411 patients allocated to late parenteral nutrition. Applying a false discovery rate of less than 0·05, DNA methylation of patients on the last PICU day was compared with that of healthy children, after excluding all CpG sites differentially methylated upon PICU admission, because these reflected pre-admission conditions and altered leukocyte composition. We used bootstrapped multivariable linear and non-linear regression analyses to assess the effect of early parenteral nutrition versus late parenteral nutrition on illness-induced alterations in DNA methylation and to what extent differentially methylated CpG sites explained impaired neurocognitive development 2 years later. During PICU stay, 159 CpG sites were methylated differently in patients admitted to the PICU than in healthy children, with mean effect sizes of 2·6% (SD 2·5) up to 21·6% (p<0·02). These differentially methylated CpG sites occurred in genes involved in brain development, plasticity, and signalling; neuronal differentiation, migration, and growth; metabolism; transcriptional regulation; physical development and locomotion; and several neurodegenerative and neuropsychiatric diseases. Early parenteral nutrition and, in particular, the dose of amino acids, independently contributed to the differential methylation of 37 (23%) of these 159 CpG sites (p=0·0001 to 0·050), which could explain the adverse effect of early parenteral nutrition on neurocognitive development at 2-year follow-up (R 2 0·61 [SD 0·01]). Early parenteral nutrition during paediatric critical illness altered DNA methylation, which suggests a plausible molecular basis for its negative effect on long-term neurocognitive development. Early administration of amino acids, rather than of glucose or lipids, mostly explained the aberrant DNA methylation—a finding that requires further investigation. European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and European Society for Clinical Nutrition and Metabolism. [ABSTRACT FROM AUTHOR]