Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy (D-Wheeze)

The goal of this study is to identify a vitamin D supplementation strategy that best promotes the lung, immune, and overall health of black infants born preterm (28-36 weeks gestational age). This is a high risk population that seems to have unique vitamin D needs, and inappropriate supplementation may promote wheezing or allergy. The results of this study will help form nutritional recommendations for the approximately 100,000 black infants born at 30-36 weeks gestational age in the U.S. every year.

Black infants face the highest rates of prematurity in the U.S. (18%), have high rates of prematurity-associated wheezing illnesses, and tend to have lower vitamin D levels. The goal of this [comparative effectiveness] study is to identify a vit. D supplementation strategy that minimizes recurrent wheezing in infancy. Long recognized as important for bone health, a growing body of evidence suggests that vit. D may play a role in the regulation and development of many organ systems. The D pathway regulates lung inflammation and impacts morphogenesis, structure, and cell growth and survival in bronchial smooth muscle. Vit. D exposure has the potential to skew cytokine expression from a Th1 (less allergic) to a Th2 (more allergic) phenotype. Due to their developmental immaturity, preterm infants may be particularly vulnerable to any positive or negative effects of vit. D supplementation on the lung, airway, and immune system. Our preliminary data, supported by the literature, suggests that overly aggressive vit. D supplementation may inadvertently increase wheezing in infancy in black, but not white, preterm infants; however, vit. D deficiency could theoretically also increase wheezing via vulnerability to respiratory pathogens. The proposed study is a randomized clinical trial comparing the effect of two different enteral vitamin D supplementation strategies on recurrent wheezing in infancy in 300 black infants born preterm at 28 0/7-36 6/7 wks gestational age, a population for whom neither vit. D requirements nor optimal vit. D serum levels have been established. The investigators will test two strategies: (I) sustained supplementation until 6 mo. of age adjusted for prematurity, and (II) cessation of supplementation when a minimum dietary intake of 200 IU/day is reached. The specific aims are to characterize the effect of each strategy on (aim 1) recurrent wheezing and (aim 2) allergic sensitization and atopy. The investigators will (aim 3) explore the relationship between vit. D serum levels and recurrent wheezing. The investigators hypothesize that strategy II will be more effective in promoting pulmonary health by minimizing recurrent wheezing, allergic sensitization, and overall healthcare utilization, and will be sufficient to prevent clinical vit. D deficiency. The investigators also hypothesize that optimal vit. D serum levels will be lower than the norms for other populations.

Infants will remain on 400 IU/day of cholecalciferol until 6 months of age adjusted for prematurity, regardless of dietary intake

Once the dietary intake of vitamin D has exceeded 200 IU/Day, the infants will receive placebo until they are 6 months of age adjusted for prematurity

Infants will receive cholecalciferol 400 IU/day PO until they are 6 months of age adjusted for prematurity

Recurrent wheezing was defined as more than 1 episode of wheezing reported during the study period. Separate episodes were defined as occurring at least 2 weeks apart.

Inclusion criteria: 28 0/7-36 6/7 weeks gestational age (GA) at birth; family identifies the child as black or African American; < 28 days of supplemental oxygen (subsequent oxygen therapy for < 72 hrs for a brief subsequent illness or surgery will be allowed); admitted to a participating site NICU, special care nursery, transitional care nursery, or well-baby nursery as a neonate; and < 40 weeks corrected GA at enrollment. Exclusion criteria: BPD (> 28 days of supplemental oxygen); pre-existing diagnosis of moderate to severe osteopenia of prematurity and/or alkaline phosphatase > 700; history of fracture; gastrointestinal surgery, including for NEC; known gastrointestinal malabsorption; major congenital anomaly; congenital pulmonary or airway disorder (e.g., cystic fibrosis, tracheomalacia, swallowing disorder, bronchopulmonary sequestration); documented wheezing or stridor prior to enrollment; previous vit. D supplementation with > 400 IU/day; family plans to move more than 60 miles from CWRU or other pre-defined radius at other sites; baseline hypo- or hypercalcemia, hypo- or hyperphosphatemia; and baseline 25(OH) D level < 10 ng/ml.

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Ledingham L, Tatsuoka C, Minich N, Ross KR, Kerns LA, Wagner CL, Fuloria M, Groh-Wargo S, Zimmerman T, Hibbs AM. Burden of prematurity-associated recurrent wheezing: caregiver missed work in the D-Wheeze trial. J Perinatol. 2021 Jan;41(1):69-76. doi: 10.1038/s41372-020-0729-7. Epub 2020 Jul 21.

Hibbs AM, Ross K, Kerns LA, Wagner C, Fuloria M, Groh-Wargo S, Zimmerman T, Minich N, Tatsuoka C. Effect of Vitamin D Supplementation on Recurrent Wheezing in Black Infants Who Were Born Preterm: The D-Wheeze Randomized Clinical Trial. JAMA. 2018 May 22;319(20):2086-2094. doi: 10.1001/jama.2018.5729. Erratum In: JAMA. 2018 Aug 14;320(6):605.