Procedural pain and brain development in premature newborns

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.<br/><br/>Methods: Infants born very preterm (N ¼ 86; 24–32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were<br/>analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery.<br/><br/>Results: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (b ¼ 0.0002, p ¼ 0.028) and reduced subcortical gray matter NAA/choline (b ¼ 0.0006, p ¼ 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.<br/><br/>Interpretation: Early procedural pain in very preterm infants may contribute to impaired brain development.