Antenatal dexamethasone before asphyxia promotes cystic neural injury in preterm fetal sheep by inducing hyperglycemia

Abstract

Antenatal glucocorticoid therapy significantly improves the short-term systemic outcomes of prematurely born infants, but there is limited information available on their impact on neurodevelopmental outcomes in at-risk preterm babies exposed to perinatal asphyxia. Preterm fetal sheep (0.7 of gestation) were exposed to a maternal injection of 12 mg dexamethasone or saline followed 4 h later by asphyxia induced by 25 min of complete umbilical cord occlusion. In a subsequent study, fetuses received titrated glucose infusions followed 4 h later by asphyxia to examine the hypothesis that hyperglycemia mediated the effects of dexamethasone. Post-mortems were performed 7 days after asphyxia for cerebral histology. Maternal dexamethasone before asphyxia was associated with severe, cystic brain injury compared to diffuse injury after saline injection, with increased numbers of seizures, worse recovery of brain activity, and increased arterial glucose levels before, during, and after asphyxia. Glucose infusions before asphyxia replicated these adverse outcomes, with a strong correlation between greater increases in glucose before asphyxia and greater neural injury. These findings strongly suggest that dexamethasone exposure and hyperglycemia can transform diffuse injury into cystic brain injury after asphyxia in preterm fetal sheep.

Keywords: Glucocorticoids; asphyxia; hyperglycemia; periventricular leukomalacia; premature birth.

Figure 1.

(a) Neurophysiological adaptation to asphyxia (1 min mean ± SEM). (b) Rate of change of cortical impedance during asphyxia (1 min mean ± SEM). (c) Raw EEG patterns at approximately 15 min during asphyxia. Note heavy suppression in the saline-asphyxia group and low frequency rolling activity with dexamethasone and glucose treatment. *p < 0.05, dexamethasone-asphyxia vs. saline-asphyxia; #p < 0.05, glucose-asphyxia vs. saline-asphyxia.

Figure 2.

Neurophysiological parameters before asphyxia and during recovery. The period of asphyxia is not shown. Ψp < 0.05, effect of asphyxia; Φp < 0.05, effect of dexamethasone treatment; #p < 0.05, glucose-asphyxia vs. saline-asphyxia.

Figure 3.

(a) Post-asphyxial seizures with corresponding spectral edge frequency (SEF). Note the different scales used. (b) EEG patterns at 7 days recovery.

Figure 4.

(a) Area of intact tissue in five brain regions 7 days after asphyxia. Bars indicate mean ± SEM. †p < 0.05, vs. saline-sham; ‡p < 0.05, vs. dexamethasone-sham; *p < 0.05, saline-asphyxia vs. dexamethasone-asphyxia; #p < 0.05, saline-asphyxia vs. glucose-asphyxia. (b) Left panels: coronal histological sections. Note severe injury of the thalamus, white matter and absence of the hippocampus in the dexamethasone-asphyxia and glucose-asphyxia groups. Scale bar = 10 mm. Right panels: enlarged sagittal gyri. Note severe injury of the cortex and intragyral white matter. Scale bar = 10 mm.

Figure 5.

Association of increased arterial glucose levels before asphyxia with reduced intact areas.