Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

Objective-Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.Methods-Infants born very preterm (n=86, 24-32 weeks gestational age) were followed prospectively from birth, and studied with MRI, 3D MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI): scan 1 early in life (median 32.1 weeks) and scan 2 at termequivalent age (median 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/ choline), lactate to choline ratios, average diffusivity (D AV ) and white matter fractional anisotropy (FA) from up to seven white and four subcortical grey matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analysed using generalized estimating equation modelling adjusting for clinical confounders such as illness severity, morphine exposure, brain-injury and surgery.Results-After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β= −0.0002, p=0.028) and reduced subcortical grey matter NAA/choline (β= −0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.Interpretation-Early procedural pain in very preterm infants may contribute to impaired brain development.

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