The timing of antenatal glucocorticoids determines the receptor sensitivity in preterm infants

Approximately 15 million babies are born too early each year, corresponding to a global preterm birth rate of about 11%. The antenatal glucocorticoid (aGC) therapy is indicated to more than 90% of their mothers when there is a risk of preterm delivery between 24 and 34 weeks of gestation. Synthetic GCs (sGC) accelerate fetal lung maturation and reduce the risk of respiratory distress syndrome (RDS), the leading cause of mortality in preterm infants. However, this treatment has been associated with an increased vulnerability to develop neurobehavioral and immune disorders later in life, effects attributed to permanent changes in the stress axis activity and in the homeostasis of endogenous GCs. In the present study, we assessed the effect of the antenatal administration of aGCs in preterm babies with a special focus on the influence of the time of exposure. We found that preterm infants exposed to aGCs in the late evening (i.e.: out-of-phase relative to the maternal daily cortisol rhythms) exhibited reduced GR sensitivity in peripheral blood mononuclear cells (PBMCs). By comparing the transcriptome of PBMCs we found significant changes in genes involved in antibody production and B cell signaling, leucocyte migration and proliferation, antigen presentation and cellular stress responses. Our data suggests that the aGCs exposure in the morning, in-phase and aligned with the maternal GC rhythms, would be advisable in the clinics to minimize these secondary effects and improve the capacity of preterm infants to fight against pathogens during the first weeks of life. Overall design: The RNA samples were obtained from peripheral blood mononuclear cells (PBMCs) from 13 term babies (controls) and 34 premature babies exposed to antenatal glucocorticoids (aGCs). We further devided the aGCs exposed babies' samples depending on the time of day in which the mother was exposed. Babies exposed to aGCs in the morning are grouped as in-phase (IP, n=17) (with the maternal circadian rhythms) and babies exposed in the evening are grouped as out-of-phase (OP, n=17).