Enteral Zinc to Improve Growth in Infants at Risk for Bronchopulmonary Dysplasia

Multiple factors contribute to growth failure in infants with BPD, including poor nutrient stores, inadequate intake, increased losses, and increased needs. Furthermore, compared to infants without BPD, those with BPD have increased resting metabolic rates and energy expenditure. Growth deficits manifest as lower weight, length, and head circumference, as well as changes in body composition. These deficits precede the development of BPD and persist post-discharge. While similar rates of growth are observed in very low birth weight infants with and without BPD once receiving equal calories, catch up growth does not occur in the BPD group. Thus, early growth deficits remained uncompensated.

After iron, zinc is the most metabolically active trace element in the human body. It has a critical role in growth, through its actions on growth hormone, IGF-1, IGFBP-3, and bone metabolism. Prematurity is a risk factor for zinc deficiency, as 60% of zinc accretion occurs in the third trimester. Impaired intake and absorption or excess excretion can further increase this risk. Finally, periods of rapid growth, as seen in preterm infants, increase the need for zinc.

Biochemically, zinc deficiency is defined by a serum zinc level less than 55mcg/dl. However, while zinc depletion is associated with deficiency, the opposite may not be true. For example, in starving patients, clinical symptoms of zinc deficiency occur during re-feeding, suggesting overall requirements are related to needs, regardless of overall zinc status. This may be the case in preterm infants, who may have a subclinical deficiency despite serum zinc level. Thus, zinc deficiency should be considered in infants with poor growth despite receiving adequate protein and calories.

The objective of this study is to determine whether enteral zinc supplementation leads to improved growth in infants at risk for bronchopulmonary dysplasia (BPD). The investigator's hypothesis is that enteral zinc supplementation in very preterm infants at high risk for BPD will significantly improve growth compared to standard of care.

Study Overview

• Status: Terminated
• Conditions: Bronchopulmonary Dysplasia; Growth Failure; Infant,Premature
• Intervention / Treatment: Dietary supplement: Zinc Acetate; Other: No supplemental zinc

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 4 weeks (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 23 0/7 to 29 6/7 weeks GA
2. Birth weight 501 to 1000g, inclusive
3. 14 to 28 days of life, inclusive
4. 14 day BPD risk score ≥ 50% for death or moderate-severe BPD, calculated using the algorithm on the Neonatal Research Network website (https://neonatal.rti.org/index.cfm?fuseaction=BPDCalculator.start).-

Exclusion Criteria:

1. Major congenital and/or chromosomal anomalies
2. Inability to reach 80ml/kg/day enteral feeds by 28 days of life

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Zinc plus standard of care; Infants will receive daily doses of zinc at 2mg/kg from enrollment through 35 6/7 weeks corrected gestational age.	Dietary supplement: Zinc Acetate; Zinc Acetate given with elemental zinc dose of 2mg/kg given orally only daily through 35 6/7 weeks corrected gestational age
Placebo Comparator: Standard of care only; Infants will not receive any doses of zinc through 35 6/7 weeks corrected gestational age	Other: No supplemental zinc; Infants will receive standard of care, which is currently no supplemental zinc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth rate for weight (g/kg/day) from birth to 36+0 weeks corrected gestational age (CGA)	Average daily changes in weight from birth to 36+0 CGA will be calculated and compared between both arms.	Birth to 36+0 weeks corrected gestational age
Growth rate for weight (g/kg/day) from birth to 40+0 weeks CGA	Average daily changes in weight from birth to 40+0 CGA (or discharge, whichever happens first) will be calculated and compared between both arms.	Birth to 40+0 weeks corrected gestational age
Growth rate for length (cm/week) from birth to 36+0 weeks CGA	Average weekly changes in length from birth to 36+0 weeks CGA will be calculated and compared between both arms.	Birth to 36+0 weeks corrected gestational age
Growth rate for length (cm/week) from birth to 40+0 weeks CGA	Average weekly changes in length from birth to 40+0 weeks (or discharge, whichever happens first) CGA will be calculated and compared between both arms.	Birth to 40+0 weeks corrected gestational age
Growth rate for head circumference (cm/week) from birth to 36+0 weeks CGA	Average weekly changes in head circumference from birth to 36+0 weeks CGA will be calculated and compared between both arms.	Birth to 36+0 weeks corrected gestational age
Growth rate for head circumference (cm/week) from birth to 40+0 weeks CGA	Average weekly changes in head circumference from birth to 40+0 weeks CGA (or discharge, whichever happens first) will be calculated and compared between both arms.	Birth to 40+0 weeks corrected gestational age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure changes in serum insulin-like growth factor 1 (IGF-1)	Differences in baseline, 28 days after study intervention initiation, and 36 weeks CGA will be compared between both arms	Study day 0 to 36 weeks corrected gestational age
Measure changes in serum insulin-like growth factor binding protein 3 (IGFBP-3)	Differences in baseline, 28 days after study intervention initiation, and 36 weeks CGA will be compared between both arms	Study day 0 to 36 weeks corrected gestational age
Measure rates of severe BPD diagnoses at 36+0 weeks CGA	Infants will be screened per the NICHD 2001 criteria for severe BPD at 36+0 weeks CGA and these rates will be compared between the two arms.	36+0 weeks corrected gestational age
Measure changes in bone quality per tibial ultrasound	Differences in baseline, 28 days after study intervention initiation, and 36 weeks CGA will be compared between both arms	Study day 0 to 36 weeks corrected gestational age

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Intermountain Research and Medical Foundation
• Investigators: Principal Investigator: Bradley Yoder, MD, University of Utah

Publications and helpful links

General Publications

• Staub E, Evers K, Askie LM. Enteral zinc supplementation for prevention of morbidity and mortality in preterm neonates. Cochrane Database Syst Rev. 2021 Mar 12;3(3):CD012797. doi: 10.1002/14651858.CD012797.pub2.
• Vazquez-Gomis R, Bosch-Gimenez V, Juste-Ruiz M, Vazquez-Gomis C, Izquierdo-Fos I, Pastor-Rosado J. Zinc concentration in preterm newborns at term age, a prospective observational study. BMJ Paediatr Open. 2019 Sep 13;3(1):e000527. doi: 10.1136/bmjpo-2019-000527. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2018
• Primary Completion (Actual): May 25, 2022
• Study Completion (Actual): August 25, 2022

Study Registration Dates

• First Submitted: April 24, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 5, 2023
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: zinc
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Failure to Thrive; Physiological Effects of Drugs; Trace Elements; Micronutrients; Zinc
• Other Study ID Numbers: 102434

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No