Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial

Abstract

Importance: Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring.

Objective: To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood.

Design, setting, and participants: The Vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States. Enrollment began in October 2009 and completed follow-up in January 2015. Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were randomized at 10 to 18 weeks' gestation. Five participants were deemed ineligible shortly after randomization and were discontinued.

Interventions: Four hundred forty women were randomized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D, and 436 women were randomized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D.

Main outcomes and measures: Coprimary outcomes of (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third trimester maternal 25-hydroxyvitamin D levels.

Results: Eight hundred ten infants were born in the study, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%-28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%-73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6-1.0; P = .051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%-47.5%, P < .001).

Conclusions and relevance: In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important.

Trial registration: clinicaltrials.gov Identifier: NCT00920621.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Litonjua reported receiving personal fees from UpToDate Inc and Springer Humana Press. Dr McElrath reported receiving grants from the National Institutes of Health (NIH). Dr O’Connor reported receiving grants from the NIH. Dr Bacharier reported receiving grants from the NIH and National Heart, Lung, and Blood Institute (NHBLI), and personal fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, and Vectura. Dr Zeiger reported receiving grants from the NHBLI, AstraZeneca, Aerocrine, MedImmune, Genentech, Merck, and GlaxoSmithKline and personal fees from Genentech, Novartis, GlaxoSmithKline, and TEVA. Dr Hornsby reported receiving an NIH ancillary grant. Dr Hawrylowicz reported receiving an NIH ancillary grant, a fellowhip grant from Wellcome Trust Clinical Training Research Fellowship, grant G100758 from the Medical Research Council Centre, and grants from Asthma UK, the Lord Leonard and Lady Estelle Wolfson Foundation, and the Alpha 1 Foundation. No other disclosures were reported.

Figures

Figure 1.. The VDAART Participant Flow

IVF indicates in vitro fertilization.

Figure 2.. Asthma or Recurrent Wheeze-Free Proportion by Treatment

Kaplan-Meier survival estimates. Error bars indicate 95% CI estimates at intervals of 1, 2, and 3 years. Estimates were obtained from nonparametric maximum likelihood estimation, with optimal nonparametric testing with interval-censored response times. These interval-censored response times lead to gaps in the curves, which we have denoted with diagonal lines. The hazard ratio for the time to first event of asthma or recurrent wheeze was 0.8 (95% CI, 0.6–1.0; P value = .051).