Effect of prenatal high-dose vitamin D on childhood atopic dermatitis is modified by maternal cotinine metabolome: A secondary analysis of a randomized clinical trial

BACKGROUND: Tobacco exposure has been shown to modulate the effect of vitamin D on the risk of atopic diseases. However, randomized clinical trials investigating the potential effect modification between tobacco exposure and vitamin D supplementation on atopic disease risk are lacking.

OBJECTIVE: We sought to investigate the potential effect modification from maternal tobacco exposure on the effect of prenatal high-dose vitamin D supplementation on the risk of child atopic dermatitis, asthma, and allergic rhinitis.

METHODS: A post hoc analysis in the double-blinded COPSAC2010 randomized clinical trial (NCT00856947) including 581 mother-child pairs randomized to 2800 IU/d (high-dose) versus 400 IU/d (standard-dose) from pregnancy week 24. Maternal blood metabolomic profiling was performed at inclusion, reflecting maternal tobacco exposure using a supervised sparse partial least squares model.

RESULTS: We found a significant effect modification from the maternal cotinine metabolome score (Pinteraction < .01) where high-dose vitamin D reduced atopic dermatitis until the age of 6 years in offspring from mothers with highest (fourth quartile) cotinine metabolome score: crude; hazard ratio = 0.46 (0.23-0.93), P = .03, and adjusted for sex, birth season, socioeconomic circumstances, living environment, air pollution, maternal diet, vitamin D levels, and fish oil intervention; hazard ratio = 0.36 (0.15-0.85), P = .02. Similarly, significant effect modification was demonstrated on the risk of asthma (Pinteraction = .03) until the age of 6 years but not allergic rhinitis (Pinteraction = .08) at the age of 6 years.

CONCLUSIONS: This exploratory study of prespecified randomized clinical trial outcomes demonstrates effect modifications of the maternal tobacco exposure metabolome on the primary preventive effect of prenatal high-dose vitamin D on offspring atopic disease risk, suggesting a potential personalized prevention strategy targeting mothers exposed to tobacco smoking.