Procedural pain and brain development in premature newborns

Abstract

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 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 analyzed using generalized estimating equation modeling 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 gray 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.

Figure 1. Study profile

MRI= magnetic resonance imaging

Figure 2. Diffusion tensor imaging and regions of interest

The figure shows the axial diffusion tensor imaging encoded anisotropy colour map and the seven white (1–7; FA and D_AV analysed) and four grey matter (8–11; only D_AV analysed) regions of interest (ROIs) that were analysed in a premature newborn with normal magnetic resonance imaging and born at 26^+6/7 weeks gestation and scanned at 29^+3/7 weeks postmenstrual age, at (A) the high centrum semiovale, (B) the basal ganglia and (D) the hippocampal area. The values of each region were averaged bilaterally: high white matter ([1] anterior, [2] central, [3] posterior), (4) genu of the corpus callosum, (5) posterior limb of the internal capsule, (6) splenium of the corpus callosum, (7) optic radiations, (8) caudate, (9) lentiform nuclei, (10) thalamus and (11) hippocampus. The colour convention used to display the predominant diffusion direction has red representing right-left, green representing anterior-posterior and blue representing superior-inferior anatomical directions. (C) represents mean fractional anisotropy (FA) for the optic radiations (ROI 7) for infants with low (below median: grey colour) or high (above median: black colour) numbers of skin-breaking procedures at scan 1 (triangles) and scan 2 (circles).

Figure 3. Proton magnetic resonance imaging and regions of interest

The figure shows the magnetic resonance (MR) spectroscopic imaging and the four white (1–3, 7) and three grey (8–10) regions of interest that were analysed at the level of (A) the high centrum semiovale and (B) the basal ganglia. The values of each region were averaged bilaterally: high white matter ([1] anterior, [2] central and [3] posterior), (7) optic radiations, (8) caudate, (9) lentiform nuclei and (10) thalamus as in Figure 2. (C) represents the mean NAA/choline ratio for the thalamus (ROI 10) for infants with low (below median: grey colour) or high (above median: black colour) numbers of skin-breaking procedures at scan 1 (triangles) and scan 2 (circles). The spectrum of the right thalamus is shown in D. Cho = choline; Cr = creatine; NAA = N-acetylaspartate; Lac = lactate.