Abstract
Postnatal glucocorticoids such as dexamethasone are effective in promoting lung development in preterm infants, but are prescribed cautiously due to concerns of neurological harm. We developed an analysis pipeline for post-mortem magnetic resonance imaging (MRI) to assess brain development and hence the neurological safety profile of postnatal dexamethasone in preterm lambs. Lambs were delivered via caesarean section at 129 days’ (d) gestation (full term ≈ 150 d) with saline-vehicle control (Saline, n = 9), low-dose tapered dexamethasone (cumulative dose = 0.75 mg/kg, n = 8), or high-dose tapered dexamethasone (cumulative dose = 2.67 mg/kg, n = 8), for seven days. Naïve fetal lambs (136 d gestation) were used as end-point maturation controls. The left-brain hemispheres were immersion-fixed in 10 % formalin (24 h), followed by paraformaldehyde (>6 months). Image sequences were empirically optimized for T1- and T2-weighted MRI and analysed using accessible methods. Spontaneous lesions detected in the white matter of the frontal cortex, temporo-parietal cortex, occipital lobe, and deep to the parahippocampal gyrus were confirmed with histology. Neither postnatal dexamethasone treatment nor gestation showed any associations with lesion incidence, frontal cortex (total, white, or grey matter) or hippocampal volume (all p > 0.05). Postnatal dexamethasone did not appear to adversely affect neurodevelopment. Our post-mortem MRI analysis pipeline is suitable for other animal models of brain development.
Highlights
Immaturity of the lung and prolonged mechanical ventilation is a risk factor for the development of chronic lung disease in preterm infants
We aimed to develop a workflow pipeline for the ex vivo examination of preterm lamb brains, and to use the resulting magnetic resonance imaging (MRI) derived tissue volumes to examine the effects of early postnatal glucocorticoid therapy on brain growth and the development of neuropathology
For all reported measures below, we examined whether tissue age at time of scanning had an effect on outcome measures in the preterm animals
Summary
Immaturity of the lung and prolonged mechanical ventilation is a risk factor for the development of chronic lung disease in preterm infants. Early extubation and the use of non-invasive respiratory support is a key goal of contemporary neonatal clinical practice Postnatal glucocorticoids, such as dexamethasone, promote lung development and facilitate extubation in infants with severe lung disease [2,3], but are prescribed cautiously, because of concerns of increased risk for poor neurodevelopment [3]. The supraphysiological doses of dexamethasone administered to preterm infants two decades ago reduced cortical grey matter, cerebral volume and cerebellar volume at term-equivalent age [4,5]; and resulted in smaller hippocampi at 2 years’ corrected postnatal age [6] Some of these changes persist into adolescence [7]. Meta-regression analyses show that postnatal dexamethasone may be beneficial for neurodevelopment in infants at high risk of chronic lung disease, and harmful for infants at low risk, independent of dose [11,12]
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