Effect of Vitamin D Supplementation on Recurrent Wheezing in Black Infants Who Were Born Preterm: The D-Wheeze Randomized Clinical Trial

Abstract

Importance: Black infants born preterm face high rates of recurrent wheezing throughout infancy. Vitamin D supplementation has the potential to positively or negatively affect wheezing through modulation of the pulmonary and immune systems.

Objective: To assess the effectiveness of 2 vitamin D dosing strategies in preventing recurrent wheezing.

Design, setting, and participants: A randomized clinical trial enrolled 300 black infants born at 28 to 36 weeks' gestation between January 2013 and January 2016 at 4 sites in the United States, and followed them up through March 2017. Randomization was stratified by site and maternal milk exposure.

Interventions: Patients were enrolled prior to discharge from the neonatal intensive care unit or newborn nursery and received open-label multivitamin until they were consuming 200 IU/d of cholecalciferol from formula or fortifier added to human milk, after which they received either 400 IU/d of cholecalciferol until 6 months of age adjusted for prematurity (sustained supplementation) or placebo (diet-limited supplementation). One-hundred fifty three infants were randomized to the sustained group, and 147 were randomized to the diet-limited group.

Main outcomes and measures: Recurrent wheezing by 12 months' adjusted age was the primary outcome.

Results: Among 300 patients who were randomized (mean gestational age, 33 weeks; median birth weight, 1.9 kg), 277 (92.3%) completed the trial. Recurrent wheezing was experienced by 31.1% of infants in the sustained supplementation group and 41.8% of infants in the diet-limited supplementation group (difference, -10.7% [95% CI, -27.4% to -2.9%]; relative risk, 0.66 [95% CI, 0.47 to 0.94]). Upper and lower respiratory tract infections were among the most commonly reported adverse events. Upper respiratory infections were experienced by 84 of 153 infants (54.9%) in the sustained group and 83 of 147 infants (56.5%) in the diet-limited group (difference, -1.6% [95% CI, -17.1% to 7.0%]). Lower respiratory infections were experienced by 33 of 153 infants (21.6%) in the sustained group and 37 of 147 infants (25.2%) in the diet-limited group (difference, -3.6% [95% CI, -16.4% to 4.4%]).

Conclusions and relevance: Among black infants born preterm, sustained supplementation with vitamin D, compared with diet-limited supplementation, resulted in a reduced risk of recurrent wheezing by 12 months' adjusted age. Future research is needed to better understand the mechanisms and longer-term effects of vitamin D supplementation on wheezing in children born preterm.

Trial registration: ClinicalTrials.gov Identifier: NCT01601847.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Hibbs, Kerns, and Zimmerman reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) and Office of Dietary Supplements (ODS). Dr Ross reported receiving grants and/or nonfinancial support from the National Institutes of Health, ODS, Boehringer Ingelheim, Teva, GlaxoSmithKline, Merck, Flamel, and Jazz Pharmaceuticals, and Otsuka Pharma/Pharmavite. Dr Wagner reported receiving grants and/or personal fees from the National Institutes of Health/NHLBI and Church & Dwight Inc, for which she serves as a scientific consultant. Dr Groh-Wargo reported receiving speaker honoraria from Abbott Nutrition. Dr Tatsuoka reported receiving grants from the National Institutes of Health, ODS, National Science Foundation, and Biogen. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in the D-Wheeze Study

If all of the eligibility laboratory tests had not been obtained as part of clinical care, infants were consented prior to obtaining study eligibility laboratory tests. If they continued to be eligible, they were then randomized to the sustained or diet-limited group. In both groups, infants received an open-label multivitamin, which provided 400 IU/d of vitamin D until they were receiving 200 IU/d or more from formula or human milk fortifiers. When they were ingesting 200 IU/d or more of vitamin D, they received blinded study drug, which provided 400 IU/d of cholecalciferol (sustained group) or placebo (diet-limited group). Study drug was continued until 6 months’ adjusted gestational age, unless the infant continued to be exclusively fed human milk. In both groups, infants were provided open-label multivitamin if they were exclusively fed maternal milk, up to 12 months’ adjusted gestational age. Two-hundred eighteen infants were enrolled at University Hospitals Cleveland Medical Center (Cleveland, Ohio), 39 infants were enrolled at Medical University of South Carolina (Charleston), 38 infants were enrolled at Montefiore Medical Center (Bronx, New York), and 5 infants were enrolled at MetroHealth Medical Center (Cleveland, Ohio). aLaboratory tests included calcium, phosphorus, alkaline phosphatase, and 25-hydroxyvitamin D.

Figure 2.. 25-Hydroxyvitamin D (25[OH]D) Levels at Baseline (A) and 3 Months’ Adjusted Age (B), By Recurrent Wheezing and Randomization Group

Recurrent wheezing is defined as 2 or more episodes of wheezing during the study period. Box and whisker plots are shown. The extreme horizontal bar for the upper whisker represents the largest value in the respective group that is within 1.5 times the interquartile range or the first quartile, while for the lower whisker, it is the smaller value within 1.5 times the interquartile range of the third quartile. The middle horizontal line in the box represents the median. Values beyond the range of box and whiskers are denoted as points. The 25(OH)D levels at baseline ranged from 10.0 to 71.0 ng/mL in the sustained group and 10.0 to 50.0 ng/mL in the diet-limited group. At 3 months’ adjusted gestational age, the levels ranged from 20.0 to 76.0 ng/mL in the sustained group and 17.0 to 73.0 ng/mL in the diet-limited group. Infants were eligible for enrollment with 25(OH)D levels of 10.0 to 80.0 ng/mL. At 3 months, levels outside of the range of 15.0 to 80.0 ng/mL were treated as adverse events and would have triggered a medical monitor review. At baseline, the sample sizes were 42 and 56 in the sustained and diet-limited groups, respectively, for recurrent wheezing and 93 and 78 for no recurrent wheezing; at 3 months, sample sizes were 42 and 55 in the sustained and diet-limited groups, respectively, for recurrent wheezing and 88 and 78 for no recurrent wheezing.