Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

Abstract

Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.

Controversies in preterm brain injury

“…Steroids in the neonatal period may impair cerebellar growth (Tam, Chau et al 2011), but several additional studies suggest that hydrocortisone does not reduce brain volumes or cause neurological deficits(Rademaker, Rijpert et al 2006, Kersbergen, de Vries et al 2013) while dexamethasone exposure has been linked to long-term adverse neurodevelopment(Doyle, Ehrenkranz et al 2010). Complicating the conclusions that can be drawn from these observational studies, experiments in rodents and sheep show a wide range of effects when steroid exposure is used in preterm HI models (Bennet, Davidson et al 2012). In addition, long-term reprogramming of the developing hypothalamic-pituitary axis by both endogenous and exogenous glucocorticoids is an area of active investigation with implications for neuropsychological as well as cardiovascular and metabolic health (Reynolds 2013).…”

“…Hydrocortisone is now in use as a more physiological steroid choice for both bronchopulmonary dysplasia and treatment of the adrenal insufficiency frequently seen in extremely preterm infants(Fernandez and Watterberg 2009). Both human and animal data suggest that the beneficial effects of steroids may be counter-balanced by potential disturbances in neurodevelopment, depending on the timing, duration and type of steroid used (Bennet, Davidson et al 2012). For example, betamethasone before delivery may decrease WMI (Agarwal, Chiswick et al 2002), but may increase risk of attention deficit disorders later in life (Khalife, Glover et al 2013).…”

Antenatal Dexamethasone after Asphyxia Increases Neural Injury in Preterm Fetal Sheep

“…Thus it is vital to understand how maternal glucocorticoids affect recovery from perinatal brain injury. Studies in newborn rodents suggest little effect of glucocorticoids after HI, as reviewed [11]. In near-term fetal sheep, at an age when brain maturity is broadly equivalent to term infants, maternal dexamethasone treatment 48 hours before cerebral ischemia did not modify the pattern of injury [12].…”

Steroids and Injury to the Developing Brain

“…66 The effects of glucocorticoids on hypoxic-ischemic brain injury were elegantly summarized in a recent review by Bennet and colleagues. 67 …”