Introduction
Glucocorticoid (GC) ‐induced fetal programming of the activity of the hypothalamus–pituitary–adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood.
Material and methods
Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+6 weeks of gestation) compared with 38 non‐exposed, age‐matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention‐deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG).
Results
There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM‐exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high‐frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM‐exposed children had lower IQ scores than the unexposed group. BM‐exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose–response relation between BM exposure and activity of the ANS and IQ was estimated in post‐hoc analyses.
Conclusions
Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life‐saving therapy, but its prescription may warrant a well‐balanced risk–benefit assessment.
Objective: To determine stress-sensitivity and neurodevelopmental
outcome in 8- to 9-year-old children following antenatal exposure to
glucocorticoid (GC) prophylaxis for neonatal respiratory distress
syndrome. Design: Clinical cohort study. Setting: University-based
obstetric clinic in Central Germany. Population: 31 term or near-term
born children whose mothers received single or multiple courses of
betamethasone (BM) to induce fetal lung maturation in threatened preterm
birth compared to 39 non-exposed children. Methods: Multi-system
assessment of the individual stress response together with an analysis
of cognitive, behavioral and electrocortical functioning. Main Outcome
Measures: Activity of the hypothalamus-pituitary-adrenal axis (HPAA,
primary outcome domain) and the autonomic nervous system (ANS, secondary
outcome domain) including markers of heart rate variability (HRV).
Additional endpoints were the cognitive performance (IQ) and
attention-deficit/hyperactivity disorder (ADHD) core symptoms. Results:
HPAA activity was not affected by antenatal GC-exposure. ANS activity in
GC-exposed children shifted towards a higher parasympathetic tone
reflected by a higher overall high-frequency band power of HRV (1313 vs.
762 msec2/Hz, p=0.03). BM-exposed children had lower cognitive
performance (IQ 96.9 vs. 108.0, p<0.01) and a marginally
higher ADHD score (FBB-ADHD scale 5.5 vs. 4.6 points, p=0.04). A
monotonic dose-response relationship between GC-exposure and
stress-induced activity of the ANS and IQ was estimated post-hoc.
Conclusions: Antenatal exposure to supraphysiological concentrations of
BM in the context of threatened preterm birth was associated with
multidimensional changes in stress-sensitivity and neurodevelopment in
later life. As these changes may be dose-dependent, antenatal GC
prophylaxis should be used at the minimum effective dose after a careful
risk-benefit assessment.
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