Effects of antenatal glucocorticoids on the developing brain

Abstract

Glucocorticoids (GCs) regulate distinct physiological processes in the developing fetus, in particular accelerating organ maturation that enables the fetus to survive outside the womb. In preterm birth, the developing fetus does not receive sufficient exposure to endogenous GCs in utero for proper organ development predisposing the neonate to complications including intraventricular hemorrhage, respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC). Synthetic GCs (sGCs) have proven useful in the prevention of these complications since they are able to promote the rapid maturation of underdeveloped organs present in the fetus. While these drugs have proven to be clinically effective in the prevention of IVH, RDS and NEC, they may also trigger adverse developmental side effects. This review will examine the current clinical use of antenatal sGC therapy in preterm birth, their placental metabolism, and their effects on the developing brain.

Keywords: Antenatal; Glucocorticoids; Neurodevelopment; Preterm birth.

Figure 1. Cerebral cortical development

The cellular organization of the human and mouse cerebral cortex follow a similar developmental pattern. VZ: ventricular zone, SVZ: subventricular zone, IZ: intermediate zone, SP: subplate, CP: cortical plate, MZ: marginal zone. (I-VI: invidual layers of the cortex). On the upper portion of the figure, the timeline for antenatal synthetic glucocorticoid (sGC) administration is depicted. Different cell types are represented by different colors. (Progression of human architectural organization adapted from: Volpe, J Neurology of the Newborn, Fifth ed. p. 83; Mrzljak L, Uylings HBM, Kostovic I, et al: Prenatal development of neurons in the human prefrontal cortex. I. A qualitative Golgi study, J Comp Neurol 271:355-386, 1988)

Figure 2. Comparison of human and mouse brain development

The top panel depicts the timing of human brain development. Gestational age is defined by gestational weeks (GW) which is split into the trimesters of human pregnancy. Above, the timing of neurogenesis, gliogenesis, migration, synaptogenesis and apoptosis are depicted by the length of the rectangles. The timing of antennal sGC therapy is depicted similarly. The bottom panel depicts the timing of mouse brain development. Gestational age is defined by embryonic days (E). The major developmental milestones are depicted similarly to the top panel. (Figure created from data from the following sources: Oomen, C. A. et al. 2009; Braun, M., et al. 2003., Jiang, X. et al. 2015; Pressler, R. et al. 2013; Knuesel, I. et al. 2014. O'Rahilly, R. et al. 2006; Rakic, P. 1977; Carpenter, M. K. et al. 2001; Bayatti, N. et al. 2008; Simonati, A. et al. 1999; Rakic, P, 1974; Chan W.Y. et al. 2002.)