Effect of Vitamin D<sub>3</sub>Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring
Authors: Bo L. Chawes, Klaus Bønnelykke, Jakob Stokholm, Nadja H. Vissing, Elín Bjarnadóttir, Ann-Marie M. Schoos, Helene M. Wolsk, Tine Marie Pedersen, Rebecca K. Vinding, Sunna Thorsteinsdóttir, Lambang Arianto, Henrik W. Hallas, Lene Heickendorff, Susanne Brix, Morten A. Rasmussen, Hans Bisgaard
Journal: JAMA (2016)

<h3>Importance</h3> Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. <h3>Objective</h3> To determine whether supplementation of vitamin D<sub>3</sub>during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. <h3>Design, Setting, and Participants</h3> A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014. <h3>Interventions</h3> Vitamin D<sub>3</sub>(2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D<sub>3</sub>as part of usual pregnancy care. <h3>Main Outcomes and Measures</h3> Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed. <h3>Results</h3> Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D<sub>3</sub>group and 57 children (20%) in the control group . Vitamin D<sub>3</sub>supplementation was not associated with the risk of persistent wheeze (hazard ratio [HR], 0.76 [95% CI, 0.52-1.12],<i>P</i> = .16), but the number of episodes of troublesome lung symptoms was reduced (mean episodes [95% CI]: 5.9 [5.2-6.6] for the vitamin D<sub>3</sub>group vs 7.2 [6.4-8.1] for the control group; incidence risk ratio [IRR], 0.83 [95% CI, 0.71-0.97],<i>P</i> = .02), and the airway immune profile was up-regulated (principal component analysis,<i>P</i> = .04). There was no effect on additional end points, including asthma (32 children [12%] in the vitamin D<sub>3</sub>group vs 47 children [14%] in the control group; odds ratio, 0.82 [95% CI, 0.50-1.36],<i>P</i> = .45), and respiratory tract infections (upper, mean [95% CI]: 5.2 [4.8-5.5] in the vitamin D<sub>3</sub>group vs 5.3 [4.9-5.6] in the control group, IRR, 0.99 [95% CI, 0.90-1.09],<i>P</i> = .84; lower: 94 children [32%] in the vitamin D<sub>3</sub>group vs 95 children [33%] in the control group, HR, 0.96 [95% CI, 0.72-1.27],<i>P</i> = .76). Intrauterine death was observed in 1 fetus (0%) in the vitamin D<sub>3</sub>group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D<sub>3</sub>group vs 23 neonates (8%) in the control group. <h3>Conclusions and Relevance</h3> The use of 2800 IU/d of vitamin D<sub>3</sub>during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00856947