Randomized Controlled Trial of Enteral Vitamin D Supplementation (ViDES) in Infants <28 Weeks Gestational Age or <1000 Grams Birth Weight: Study Protocol.

Background: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. Methods: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 grams birth weight at a large academic center in the United States.Infants are stratified by birth weight and randomized within 96 hours after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth.We hypothesize that the higher and early vitamin D dose (800 IU/d with early feeding) compared to placebo plus routine dose (400 IU/d with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at one month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes) and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes.The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. Discussion: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterminfants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. Trial registration: ClinicalTrials.gov registered on July 14, 2022 (NCT05459298).

Randomized controlled trial of enteral vitamin D supplementation (ViDES) in infants <28 weeks gestational age or <1000 g birth weight: study protocol.

BACKGROUND: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. METHODS: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 g birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 h after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/day with early feeding) compared to placebo plus routine dose (400 IU/day with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at 1 month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes), and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. DISCUSSION: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterm infants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. TRIAL REGISTRATION: ClinicalTrials.gov NCT05459298. Registered on July 14, 2022.

Practical approaches for supporting informed consent in neonatal clinical trials.

The survival and health of preterm and critically ill infants have markedly improved over the past 50 years, supported by well-conducted neonatal research. However, newborn research is difficult to undertake for many reasons, and obtaining informed consent for research in this population presents several unique ethical and logistical challenges. In this article, we explore methods to facilitate the consent process, including the role of checklists to support meaningful informed consent for neonatal clinical trials. CONCLUSION: The authors provide practical guidance on the design and implementation of an effective consent checklist tailored for use in neonatal clinical research.

Fatty acid concentrations in preterm infants fed the exclusive human milk diet: a prospective cohort study.

OBJECTIVE: Quantify blood fatty acids and growth outcomes in preterm infants fed the exclusive human milk diet. METHODS: A prospective cohort study of 30 infants 24-34 weeks gestation and ≤1250 g fed the exclusive human milk diet. Blood fatty acids were quantified at two time points. Comparisons were made using two-sample t-tests and Wilcoxon rank sum. RESULTS: Donor human milk-fed (n = 12) compared to mother's own milk-fed infants (n = 18) from birth to after 28 days of life, had an increased interval change of linoleic to docosahexaenoic acid ratio (5.5 vs. -1.1 mole percent ratio, p = 0.034). Docosahexaenoic and eicosapentaenoic acid interval changes were similar between groups. The arachidonic acid change was similar between groups (-2.3 vs. -0.9 mole percent, p = 0.37), however, both experienced a negative change across time. At 36 weeks postmenstrual age, growth velocities were similar for groups. CONCLUSION: An exclusive human milk diet maintains birth docosahexaenoic and eicosapentaenoic acid concentrations. However, the postnatal deficit in arachidonic acid was not prevented.

Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. METHODS: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. DISCUSSION: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. TRIAL REGISTRATION: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022).

Red Blood Cell Transfusion Thresholds for Anemia of Prematurity.

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants.

Fecal Elastase in Preterm Infants to Predict Growth Outcomes.

OBJECTIVES: Preterm infants are born functionally pancreatic insufficient with decreased pancreatic production of lipase and proteases. Developmental pancreatic insufficiency (PI) may contribute to reduced nutrient absorption and growth failure. We sought to determine longitudinal fecal elastase (ELA1) levels in a cohort of preterm infants and whether levels are associated with growth outcomes. METHODS: Prospective observational study of 30 infants 24-34 weeks gestational age and birth weight ≤1250 g fed the exclusive human milk diet, consisting of human milk with human milk-based fortifier. ELA1 was quantified by ELISA during the first 2 weeks of life [Early; 7.5 ± 1.8 days of life (DOL)] and after attainment of full, fortified feedings (Late; 63.6 ± 24.1 DOL). RESULTS: Early ELA1 levels were 192.2 ± 96.4 µg/g, and Late ELA1 levels were 268.0 ± 80.3 µg/g, 39.4% higher (P = 0.01). Infants with early PI (ELA1 < 200 µg/g) were more likely male and of lower gestational age, weight, length, and head circumference at birth. These variables, but not PI status, independently predicted somatic growth. CONCLUSIONS: Fecal ELA1 in preterm infants fed exclusive human milk diet increases with postnatal age. Although pancreatic function in preterm infants may serve as a biological contributor to early postnatal growth failure, additional studies using fecal ELA1 as a predictive biomarker for growth failure are needed in larger cohorts.