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Original Investigation |

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

Bo L. Chawes, MD, PhD1; Klaus Bønnelykke, MD, PhD1; Jakob Stokholm, MD, PhD1,2; Nadja H. Vissing, MD, PhD1; Elín Bjarnadóttir, MD1,2; Ann-Marie M. Schoos, MD, PhD1; Helene M. Wolsk, MD1; Tine Marie Pedersen, MD1,2; Rebecca K. Vinding, MD1,2; Sunna Thorsteinsdóttir, MD1; Lambang Arianto, MD1; Henrik W. Hallas, MD1; Lene Heickendorff, MD, DMSc3; Susanne Brix, MSc, PhD4; Morten A. Rasmussen, MSc, PhD1,5; Hans Bisgaard, MD, DMSc1
[+] Author Affiliations
1Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
2Department of Pediatrics, Naestved Hospital, Naestved, Denmark
3Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
4Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark
5Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
JAMA. 2016;315(4):353-361. doi:10.1001/jama.2015.18318.
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Importance  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.

Objective  To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in 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 D3 (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 D3 as part of usual pregnancy care.

Main Outcomes and Measures  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.

Results  Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group . Vitamin D3 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 D3 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 D3 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 D3 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 D3 group vs 95 children [33%] in the control group, HR, 0.96 [95% CI, 0.72-1.27], P = .76). Intrauterine death was observed in 1 fetus (0%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group.

Conclusions and Relevance  The use of 2800 IU/d of vitamin D3 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.

Trial Registration  clinicaltrials.gov Identifier: NCT00856947

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Figure 1.
Flow of Participants Through the COPSAC2010 Vitamin D RCT

COPSAC indicates Copenhagen Prospective Studies on Asthma in Childhood; RCT, randomized clinical trial.

aExclusion criterions were gestational age above week 26, any endocrine, cardiovascular, or nephrological disorders, or vitamin D intake more than 600 IU per day.

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Figure 2.
Effect of Vitamin D3 Supplementation on Risk of Persistent Wheeze in Children in the COPSAC2010 Vitamin D RCT

COPSAC indicates Copenhagen Prospective Studies on Asthma in Childhood; HR, hazard ratio; RCT, randomized clinical trial. P values were evaluated using the Wald test.

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Figure 3.
Effect of Maternal Serum Vitamin D3 Level at 1 Week Postpartum (n = 573) on Risk of Persistent Wheeze in Children in the COPSAC2010 Vitamin D RCT

COPSAC indicates Copenhagen Prospective Studies on Asthma in Childhood; HR, hazard ratio; RCT, randomized clinical trial. To convert vitamin D to nmol/L, multiply by 2.496. The HR describes risk of persistent wheeze per 4 ng/mL increase in maternal serum vitamin D level after intervention. Mean (range) of tertiles: lower tertile, 20 ng/mL (6-29); middle tertile, 35 ng/mL (29-41); upper tertile, 53 ng/mL (42-103). P values were evaluated using the Wald test.

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Figure 4.
Effect of Vitamin D3 Supplementation on the Neonatal Airway Immune Profile in the COPSAC2010 Vitamin D RCT

COPSAC indicates Copenhagen Prospective Studies on Asthma in Childhood; IFN, interferon; IL, interleukin; PCA, principal component analysis; RCT, randomized clinical trial; TGF, transforming growth factor; TNF, tumor necrosis factor. Panel A, 0/0 is the base for interpreting how well a particular mediator is explained. Increasing length of the arrows from 0/0 corresponds to an increased proportion of the mediator being explained by the model. Principal component 1 reflects the overall immune activity regardless of individual mediators, accounting for 54% of the variation in data. Principal component 2 reflects a pattern related to pertubation of CCL17, CCL2, CCL11, CCL13, and TGF-1β vs IL-12p70, IL-10, IL-13, IL-5, IFN-γ, IL-1β, TNF-α, IL-4, IL-2, and IL-17α, accounting for additionally 8% of the variation. Thus, children with loading values above 0 on principal component 2 have an immune profile skewed toward CCL17, CCL2, CCL11, CCL13, and TGF-1β, whereas children with loading values below 0 have an immune profile skewed toward IL-12p70, IL-10, IL-13, IL-5, IFN-γ, IL-1β, TNF-α, IL-4, IL-2, and IL-17α. Panel B, each point corresponds to a child, and 2 points closely positioned indicate a similar profile. The ellipses reflect the 2-dimensional distribution of children in the vitamin D3 group (orange) vs control group (blue), for which 0/0 is the multivariate average of the distribution. Principal component 1 reflects a significant discrepancy between the groups (P = .04), pointing at generally higher airway immune activity in children from mothers supplemented with vitamin D3 during pregnancy.

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