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Structural and Functional Brain Development After Hydrocortisone Treatment for Neonatal Chronic Lung Disease

Gregory A. Lodygensky, MD^*, Karin Rademaker, MD, Slava Zimine, PhD, Marianne Gex-Fabry, MSc^||, Arno F. Lieftink, MA^¶, François Lazeyras, PhD, Floris Groenendaal, MD, PhD, Linda S. de Vries, MD, PhD and Petra S. Huppi, MD^*,#

^* Departments of Pediatrics
Radiology
^|| Department of Psychiatry, University of Geneva, Geneva, Switzerland; Departments of
Neonatology
^¶ Medical Child Psychology, University Medical Center, Utrecht, Netherlands
^# Department of Neurology, Harvard Medical School, Boston, Massachusetts

Objective. There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments.

Methods. Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks.

Results. Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 ± 12.4; term: 109.6 ± 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL), white matter (preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3).

Conclusions. Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.

Key Words: prematurity • hydrocortisone • brain development • MRI

Abbreviations: WISC-R, Wechsler Intelligence Scales for Children-Revised • IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia

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