Postnatal infection is associated with widespread abnormalities of brain development in premature newborns

Abstract

Introduction: Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns.

Results: In 34/117 newborns studied, clinical signs were accompanied by positive cultures whereas 17 had clinical signs of sepsis alone. White matter injury (WMI) was identified in 34 newborns. In multivariate regression models, infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (D(AV)), and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection.

Discussion: These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain development. These abnormalities extend beyond brain injuries apparent with conventional magnetic resonance injury (MRI).

Methods: 117 preterm newborns (24-32 wk gestation) were studied prospectively at a median of 32.0 and 40.3 wk ostmenstrual age with MRI (WMI, hemorrhage), magnetic resonance (MR) spectroscopy (metabolism), and diffusion tensor imaging (microstructure). Newborns were categorized as having "no infection," "clinical infection," or "positive-culture infection." We compared brain injuries as well as metabolic and microstructural development across these infection groups.

Figure 1. Proton magnetic resonance imaging and regions of interest

As shown in Figure 1, brain metabolic development was assessed using magnetic resonance spectroscopic imaging in 8 regions of interest at the level of (A) the high centrum semi-ovale and (B) the basal ganglia: high white matter ((1) anterior, (2) central, and (3) posterior), (4) caudate, (5) lentiform nuclei, (6) thalamus, (7) optic radiations, (8) calcarine region. The values of each region were averaged bilaterally. The arrow shows the spectrum of the left frontal white matter. This example is taken from a premature newborn with a normal MR imaging and born at 27 weeks gestation and scanned at 28 weeks postmenstrual age. Legend: Cho=Choline; Cr=Creatine; NAA=N-acetylaspartate; Lac=Lactate.

Figure 2. Diffusion tensor imaging and regions of interest

As shown in Figure 2, brain microstructural development was assessed using diffusion tensor imaging in 12 regions of interest at the level of (A) the high centrum semi-ovale, (B) the basal ganglia, and (C) the midbrain, and include these: high white matter ((1) anterior, (2) central, and (3) posterior), (4) genu of the corpus callosum, (5) posterior limb of the internal capsule, (6) splenium of the corpus callosum, (7) optic radiation, (8) caudate, (9) lentiform nuclei, (10) thalamus, (11) calcarine region, and (12) hippocampus. The values of each region were averaged bilaterally. This example is taken from a premature newborn with a normal MR imaging and born at 27 weeks gestation and scanned at 28 weeks postmenstrual age. The color convention used to display the predominant diffusion direction has red representing right–left, green representing anterior-posterior, and blue representing superior-inferior anatomical directions.

Figure 3. Fractional Anisotropy: Infected Newborns Relative to Non-Infected Newborns

The mean difference, with 95% confidence intervals, is plotted for the overall effect and each region of interest in the white matter. Abbrevations: WM=white matter, CC=corpus callosum, PLIC=posterior limb of the internal capsule.