Vitamin D Supplementation for Extremely Preterm Infants

Early Vitamin D Supplementation for Prevention of Respiratory Morbidity in Extremely Preterm Infants: A Randomized Clinical Trial

The study hypothesis states that giving early enteral Vitamin D supplementation to preterm infants will decrease respiratory morbidity in extremely preterm infants.

After informed consent obtained, infants will be randomized using computer-generated stratified randomization codes by the pharmacy. Clinicians, researcher, and primary caregivers will be masked. Subjects will be randomly assigned to one of the treatment arms or to a placebo concurrent control. Early vitamin D supplementation/placebo will be initiated within the first 7 days after birth. Premature infants will be randomized to receive one of the 3 fixed doses of vitamin D: either placebo (zero dose), 200 IU/day, or 800 IU/day. The supplementation will be started within 72 hours of enteral feeds being initiated and will continue until postnatal day 28. After this period of supplementation, routine supplementation will be conducted in all groups. Remnant cord blood samples will be analyzed for vitamin D levels (serum hydroxyvitamin D [25(OH)D]. Two circulating vitamin D concentrations (25(OH)D concentrations) will be measured on postnatal days 14 and 28. Urine samples will be collected weekly, to determine calcium excretion if high serum calcium concentrations are found. Supplementation will be discontinued and infant will exit the study if surgical necrotizing enterocolitis/bowel perforation is diagnosed, if 25 (OH)D concentrations >60ng/mL (>150nmol/L; potentially toxic) are detected or, if infant NPO for greater than 24 hours. If infant made briefly NPO (<24h) for feeding intolerance, suspected sepsis, hypotension,hemodynamically significant PDA, or respiratory difficulties, enteral vitamin D will not be discontinued. All infants will be followed to discharge for primary, secondary outcomes as well as adverse events.

200 IU/day given orally once per day as one of 4 doses of 0.5ml each given every 6 hours. Other 3 doses will be placebo (sterile water). Duration of 28 postnatal days

800 IU/day given orally per day as 4 doses of 200 IU/0.5ml each every 6 hours. Duration of 28 postnatal days

The total number of days alive and off respiratory support. Respiratory support is defined as need of supplemental oxygen and/or positive pressure ventilation to maintain normal target oxygen saturations (88-95%).

Serum vitamin D levels determined by enzyme immunoassay obtained from whole blood (remnant sample or obtained during clinical blood draw)

Number of episodes of culture proven or clinically suspected sepsis episodes treated with antibiotics for at least 5 days

A physiologic oxygen challenge test will be administered to infants from 36.0 weeks gestation to 37.0 weeks gestation to determine a need for supplemental oxygen to keep saturation levels between 88-95%.

Counted as number of days on which an infant is on mechanical ventilation for any part of a calendar day

Radiographic documentation of pneumatosis or intestinal perforation or treatment course for clinical necrotizing enterocolitis per Bell's stage greater than 1.

Serum calcium measurement per blood obtained either centrally or by heel stick, performed for clinical care. High serum calcium level is greater than 3 mmol/l of total calcium or total calcium of >12 mg/dL, or ionized calcium >2 mml/L.

Calcium measurement per urine, random sampling. High level (>95%tile) urine calcium to creatinine ratio is >3.8 mmol/mmol.

Inclusion Criteria: Infants admitted to the Regional Newborn ICU of the University of Alabama with gestational age between 23-27 completed weeks Exclusion Criteria: Major congenital/chromosomal anomalies Moribund infant with low likelihood of survival, in opinion of the clinical team

Huey SL, Acharya N, Silver A, Sheni R, Yu EA, Pena-Rosas JP, Mehta S. Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD012875. doi: 10.1002/14651858.CD012875.pub2.

Fort P, Salas AA, Nicola T, Craig CM, Carlo WA, Ambalavanan N. A Comparison of 3 Vitamin D Dosing Regimens in Extremely Preterm Infants: A Randomized Controlled Trial. J Pediatr. 2016 Jul;174:132-138.e1. doi: 10.1016/j.jpeds.2016.03.028. Epub 2016 Apr 11.