Effect of postnatal dexamethasone dose on brain injury and inflammation in preterm lambs

Background: Postnatal dexamethasone remains a contentious treatment in preterm infants. High-dose dexamethasone is associated with neurological impairment. Low-dose dexamethasone is a promising alternative, but neurological safety is not established. We examined effects of high- and low-dose postnatal dexamethasone on preterm lamb brain development. Methods: Date-mated ewes received IM medroxyprogesterone (150mg/kg) at 121d gestation and IM betamethasone (5.7mg) 48h and 24h prior to caesarean section at 129d gestation. Preterm lambs were randomised to 3 groups with tapering doses of 1) saline (n=8); 2) low-dose dexamethasone (starting 0.15 mg/kg/d; n=8) or 3) high-dose dexamethasone (starting 0.5 mg/kg/d; n=8). Preterm lambs were managed with standard clinical protocols and euthanased at 7d. Naive end-point fetal controls were delivered at 136d gestation (n=7). Brains were weighed at post-mortem and the right hemisphere was fixed (10% formalin x 24h, then 4% paraformaldehyde).The brain was immersed in 20% sucrose then cryosectioned. IHC markers of inflammation (IBA1, GFAP), proliferation (Ki67), apoptosis (caspase3), and myelination (MBP, Olig2) were examined in the hippocampus and prefrontal cortex. Results: Preterm birth reduced brain weight, reduced apoptosis (caspase3) in the hippocampus dentate gyrus (p < 0.05), and increased microglia (IBA1) immunoreactivity in the prefrontal cortex (p < 0.05) relative to fetal controls. Dexamethasone had no effect on any IHC marker compared to the postnatal saline group. Conclusions: Preterm lambs have altered brain development compared to maturational controls. A 7d postnatal dexamethasone course has no short-term effect on brain development at low-dose or high-dose.