The Association of Infant Urinary Adrenal Steroids with the Risk of Childhood Asthma Development

Background Adrenal steroids play important roles in early life development. However, our understanding of the effects of perinatal adrenal steroids on the development of childhood asthma is incomplete. Objective This study aimed to evaluate the associations between early life adrenal steroid levels and childhood asthma. Methods Participants included INSPIRE birth cohort children with untargeted urinary metabolomics data measured during early infancy (n=264) and nasal immune mediator data measured concurrently at age 2-6 months (n=76). A total of 11 adrenal steroid compounds identified using untargeted metabolomics and 6 asthma-relevant nasal immune mediators from multiplex assays were a priori selected. Current asthma at ages 5 and 6 years was ascertained using validated questionnaires. Associations were tested using logistic and linear regression with confounders adjustment. Results Pregnenetriol disulfate (adjusted odd ratio, aOR= 0.20, 95%CI= [0.06, 0.68]) and 3a,21-dihydroxy-5b-pregnane-11,20-dione-21-glucuronide (aOR= 0.34, 95%CI= [0.14, 0.75]) were inversely associated with childhood asthma at 5 and 6 years after multiple testing adjustment. There was a significant interaction effect of pregnanediol-3-glucuronide by sex (aOR=0.11, 95%CI=[0.02, 0.51], for females) on childhood asthma. Pregnenetriol disulfate was inversely associated with GM-CSF (b=-0.45, q-value=0.05). 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide was inversely associated with IL-4 (b=-0.29, q-value=0.02), IL-5 (b=-0.35, q-value=0.006), IL-13 (b=-0.26, q-value=0.02), GM-CSF (b=-0.35, q-value=0.006), and FGF-b(b=-0.24, q-value=0.01) after multiple testing adjustment. Conclusion The inverse association between adrenal steroids downstream of progesterone and 17-hydroxypregnenolone and odds of childhood asthma and nasopharyngeal Type 2 immune biomarkers suggest that increased early life adrenal steroids may suppress Type 2 inflammation and protect against the development of childhood asthma.