Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.

Importance Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezingin the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. Objective To determine whether supplementation of vitamin D 3 during the third trimester of pregnancy reduces the risk of persistent wheezein the offspring. Design, Setting, and Participants 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. Interventions Vitamin D 3 (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 3 as part of usual pregnancy care. Main Outcomes and Measures Age at onset of persistent wheezein 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. Results Of the 581 children, persistent wheezewas diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D 3 group and 57 children (20%) in the control group . Vitamin D 3 supplementation was not associated with the risk of persistent wheeze(hazard ratio [HR], 0.76 [95% CI, 0.52-1.12], P  = .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 3 group vs 7.2 [6.4-8.1] for the control group; incidence risk ratio [IRR], 0.83 [95% CI, 0.71-0.97], P  = .02), and the airway immune profile was up-regulated (principal component analysis, P  = .04). There was no effect on additional end points, including asthma (32 children [12%] in the vitamin D 3 group vs 47 children [14%] in the control group; odds ratio, 0.82 [95% CI, 0.50-1.36], P  = .45), and respiratory tract infections (upper, mean [95% CI]: 5.2 [4.8-5.5] in the vitamin D 3 group vs 5.3 [4.9-5.6] in the control group, IRR, 0.99 [95% CI, 0.90-1.09], P  = .84; lower: 94 children [32%] in the vitamin D 3 group vs 95 children [33%] in the control group, HR, 0.96 [95% CI, 0.72-1.27], P  = .76). Intrauterine deathwas observed in 1 fetus (0%) in the vitamin D 3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D 3 group vs 23 neonates (8%) in the control group. Conclusions and Relevance The use of 2800 IU/d of vitamin D 3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheezein the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. Trial Registration clinicaltrials.gov Identifier:NCT00856947