Association between prenatal glucocorticoid exposure and adolescent neurodevelopment: An observational follow‐up study

• Published in: Acta obstetricia et gynecologica Scandinavica Vol. 103; no. 8; pp. 1530 - 1540
• Main Authors: Rakers, Florian, Schleussner, Ekkehard, Cornelius, Amani, Kluckow, Steffen, Muth, Isabel, Hoyer, Dirk, Rupprecht, Sven, Schultze, Torsten, Schiecke, Karin, Ligges, Carolin, Schwab, Matthias, Hoyer, Heike
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2024; John Wiley and Sons Inc; Wiley
• Subjects: Adolescent; Adolescent Development - drug effects; Attention Deficit Disorder with Hyperactivity; Attention deficit hyperactivity disorder; Betamethasone; Child development; Cognition - drug effects; Female; fetal physiology; fetal programming; Fetuses; Follow-Up Studies; glucocorticoids; Glucocorticoids - adverse effects; Humans; Hypothalamo-Hypophyseal System - drug effects; Male; Metabolism; neurodevelopment; Neurology; Original; Pituitary-Adrenal System - drug effects; Pregnancy; Premature birth; Prenatal exposure; Prenatal Exposure Delayed Effects; preterm birth; Prospective Studies; Steroids; Teenagers; preterm birth; fetal programming; glucocorticoids; neurodevelopment; fetal physiology
• ISSN: 0001-6349; 1600-0412; 1600-0412
• DOI: 10.1111/aogs.14885

Introduction Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long‐lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8–9 years. This follow‐up study aimed to examine whether these findings persisted into adolescence. Material and Methods Prospective observational follow‐up study involving twenty‐one 14‐ to 15‐year‐old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty‐five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention‐deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus–pituitary–adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. Results No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 vs references 105.9, mean difference −2.0, 95% confidence interval [CI]: −7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress‐induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency–adjusted means: 16.0 Hz vs 17.8 Hz, mean difference −1.83 Hz, 95% CI: −3.21 to −0.45, p = 0.01). Conclusions In 14‐ to 15‐year‐old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow‐up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions. In our follow‐up study on 14‐ to 15‐years‐olds prenatally exposed to glucocorticoid prophylaxis for respiratory distress syndrome, we found that earlier discrepancies in prepubertal IQ scores and autonomic nervous system activity, in comparison to unexposed subjects, do not continue into adolescence.