1. This 6-year follow up of the Vitamin D Antenatal Asthma Reduction Trial found no significant difference in the incidence of asthma or recurrent wheeze between children whose mothers received daily vitamin D versus placebo. This result contrasts with the between-group difference detected at early time points in the original trial.
2. While measures of airway resistance were lower in the vitamin D group as assessed by impulse oscillometry, these differences were small and require further validation.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Asthma is estimated to affect over 5% of the global population, and its early onset necessitates the identification of antenatal and early-life risk factors. In murine models, vitamin D deficiency during pregnancy has been shown to stunt airway development and cause alveolar simplification, and a meta-analysis of data from two trials, including the Vitamin D Antenatal Asthma Reduction Trial (VDAART) indicated a protective effect of prenatal supplementation at 3 years. This study tracked VDAART participants for a further 3 years, finding that the decreased incidence noted at the end of the original study had disappeared by 6 years. After stratifying event times according to level of vitamin D in the mother’s serum, it was discovered that 25-hydroxyvitamin D levels of <20 ng per milliliter were associated with a higher risk of asthma or recurrent wheeze. Supplementation had no effect on eczema, allergic rhinitis, or lower respiratory tract infection, but airway resistance was found to be marginally lower in the vitamin D group after adjusting for variables including ethnicity, sex, and clinical center. One limitation of this study was that the correspondence between those who had asthma at 3 years and those who had asthma at 6 years was somewhat weak, meaning that the effect detected in the original study may have been due to overdiagnosis. Additionally, supplementation was not continued postnatally, precluding analysis of any combined effects.
In-Depth [randomized controlled trial]: In the multicenter, double-blind, placebo-controlled VDAAR Trial, 876 women were randomly assigned in a 1:1 ratio to receive daily a multivitamin along with either 4000 IU vitamin D or placebo. 806 children were tracked for 3 years and included in the original analysis, and a nonsignificant reduction of 6.1% in incidence of the primary outcome (asthma, recurrent wheezing, or both) was noted (P=0.051). In this 6-year follow-up, this difference was no longer present, with 176 children (43.5%) in the vitamin D group and 184 (45.9%) in the control group meeting the criteria for the primary outcome (interval-censored hazard ratio [control vs. vitamin D], 1.12; P=0.25). The correspondence between the children who had the primary outcome at 3 years and the children who had the outcome at 6 years was only fair-to-moderate (Cohen’s kappa, 0.51). Following stratification of event time based on quartile of mean prenatal level of vitamin D recorded in the mother’s serum, a protective effect was discovered, with 25-hydroxyvitamin D levels of less than 20 ng per milliliter correlating with a higher risk (hazard ratio [top vs. bottom quartile], 0.74; 95% confidence interval [CI], 0.54 to 1.02). No significant differences were detected in the secondary outcomes of eczema with rash (effect, 0.2 percentage points; 95% CI, -6.4 to 7.1 percentage points), allergic rhinitis (effect, -5.1; 95% CI, -12.5 to 2.4), and lower respiratory tract infection (effect, -2.4; 95% CI, -10.0 to 5.1).
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