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

CONTEXT: The global preterm birth rate is about 11%. Most premature infants (PI) receive antenatal glucocorticoids (aGCs) to accelerate fetal lung maturation; however, this treatment increases the vulnerability for immune disorders later in life. OBJECTIVE: We hypothesized that aGCs given at the "wrong" time of day determines vulnerability. We compared the effect of aGCs in PIs exposed in the morning (in-phase, IP with the maternal circadian rhythms) and in the evening (out-of-phase, OP) to controls (C). METHODS: We collected data and blood samples from infants enrolled in a population-based cohort study. Groups are balanced by gestational age, birth weight, and sex. Infants were divided depending on the time of maternal cortisol peak. Exclusion criteria were established by the cohort; additionally, infants born before gestational week 24 and exposed to postnatal GCs were excluded. The study was run in subcohorts; GC receptor (GR) sensitivity was assessed in 6 IPs and 6 OPs. RNA sequencing, RNA expression, and DNA methylation were assessed in peripheral blood cells from 13 Cs, 17 IPs, and 17 OPs. All samples were obtained on average 10 days after birth. RESULTS: OP infants exhibited reduced GR sensitivity and suppressed expression of genes involved in antibody production, leukocyte migration, antigen presentation. CONCLUSION: aGC exposure aligned with maternal GC rhythms; therefore, it would be advisable to improve PIs' capacity to fight against pathogens during the first weeks of life.