Vitamin A Supplementation for Extremely-Low-Birth-Weight Infants (Vitamin A)

Randomized Trial of Vitamin A Supplementation for Extremely-Low-Birth-Weight

This multi-site, randomized trial was conducted to determine the safety and effectiveness of a higher dose of vitamin A and determine if this would increase the rate of survival without bronchopulmonary dysplasia (BPD) and reduce the risk of sepsis. Infants with birth weights from 401-1000g and who were on mechanical ventilation or supplemental oxygen at 24-96 hours of age were enrolled. Subjects were randomized to either the Vitamin A or a control group. Infants in the Vitamin A group were given a dose of 5000 IU (0.1 ml) intramuscularly on Mondays, Wednesdays, and Fridays for four weeks. Control infants received a sham procedure rather than placebo injections.

Study Overview

• Status: Completed
• Conditions: Sepsis; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Respiration, Artificial; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Drug: Vitamin A; Other: Sham Procedure

Detailed Description

Infants with extremely low birth weights (≤1,000 g) have low plasma and tissue concentrations of vitamin A, and vitamin A deficiency may predispose these infants to chronic lung disease. A meta-analysis of clinical trials of vitamin A supplementation for preterm infants revealed a 17% increase in the rate of survival without chronic lung disease, which approached statistical significance.

This multi-site, randomized trial was conducted to determine the safety and effectiveness of a higher dose of vitamin A than that used in previous trials in extremely-low-birth-weight (ELBW) infants. We hypothesized that vitamin A supplementation would increase the rate of survival without bronchopulmonary dysplasia and reduce the risk of sepsis.

Infants with birth weights from 401-1000g and who received mechanical ventilation or supplemental oxygen at 24-96 hours of age were enrolled. Subjects were randomized to either the vitamin A or a control group. Infants in the Vitamin A group were given a dose of 5000 IU (0.1 ml) intramuscularly on Mondays, Wednesdays, and Fridays for four weeks. Control infants received a sham procedure rather than placebo injections.

Serum vitamin A was measured in a central laboratory at base line and at 28 days in the first 300 infants. On study day 28 (two to three days after the last treatment and immediately after a blood sample was collected), the relative dose-response was evaluated.

• Study Type: Interventional
• Enrollment (Actual): 807
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20052
      • George Washington University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 4 days (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants wtih birth weights from 401-1,000g
• Receiving mechanical ventilation or supplemental oxygen at 24-96 hours of age

Exclusion Criteria:

• Major congenital anomalies
• Congenital nonbacterial infection
• Infants diagnosed with a terminal illness (as indicated by a pH below 6.80 or by the presence of hypoxia with bradycardia for more than two hours)
• Infants who were to receive vitamin A in a parenteral fat emulsion or in doses exceeding recommendations for multivitamin preparations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental; Vitamin A group.	Drug: Vitamin A; 5,000 IU (0.1 ml) was given on Mondays, Wednesdays, and Fridays for four weeks.
SHAM_COMPARATOR: Control; Sham procedure Control group.	Other: Sham Procedure; Control infants received a sham procedure rather than placebo injections.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic lung disease or death	Chronic lung disease was defined as the need for oxygen at 36 weeks' postmenstrual age.	36 weeks' postmenstrual age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sepsis	Sepsis was defined on the basis of a positive blood culture and treatment with antibiotics for at least five days (unless the infant died within five days).	5 days

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR)
• Investigators: Study Director: Jon E. Tyson, MD MPH, University of Texas Southwestern Medical Center; Principal Investigator: Joel Verter, PhD, George Washington University Biostatistics Center; Study Director: Charles R. Bauer, MD, University of Miami; Principal Investigator: Edward F. Donovan, MD, Case Western Reserve University

Publications and helpful links

General Publications

• Stark AR, Tyson JE, Hibberd PL. Variation among institutional review boards in evaluating the design of a multicenter randomized trial. J Perinatol. 2010 Mar;30(3):163-9. doi: 10.1038/jp.2009.157. Epub 2009 Oct 1.
• Kennedy KA, Stoll BJ, Ehrenkranz RA, Oh W, Wright LL, Stevenson DK, Lemons JA, Sowell A, Mele L, Tyson JE, Verter J. Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network. Early Hum Dev. 1997 Jul 24;49(1):19-31. doi: 10.1016/s0378-3782(97)01869-0.
• Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999 Jun 24;340(25):1962-8. doi: 10.1056/NEJM199906243402505.
• Ambalavanan N, Tyson JE, Kennedy KA, Hansen NI, Vohr BR, Wright LL, Carlo WA; National Institute of Child Health and Human Development Neonatal Research Network. Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months. Pediatrics. 2005 Mar;115(3):e249-54. doi: 10.1542/peds.2004-1812. Epub 2005 Feb 15.
• Rysavy MA, Li L, Tyson JE, Jensen EA, Das A, Ambalavanan N, Laughon MM, Greenberg RG, Patel RM, Pedroza C, Bell EF; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial. J Pediatr. 2021 Sep;236:78-85.e5. doi: 10.1016/j.jpeds.2021.05.022. Epub 2021 May 15.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: January 1, 1996
• Primary Completion (ACTUAL): July 1, 1997
• Study Completion (ACTUAL): July 1, 1999

Study Registration Dates

• First Submitted: September 15, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (ESTIMATE): September 16, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 26, 2017
• Last Update Submitted That Met QC Criteria: September 22, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Prematurity; Chronic Lung Disease; Vitamin A; NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Body Weight; Birth Weight; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin A
• Other Study ID Numbers: NICHD-NRN-0015; U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U01HD019897 (U.S. NIH Grant/Contract); U10HD021415 (U.S. NIH Grant/Contract); U10HD027881 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); M01RR006022 (U.S. NIH Grant/Contract); M01RR000750 (U.S. NIH Grant/Contract); M01RR000070 (U.S. NIH Grant/Contract); M01RR000997 (U.S. NIH Grant/Contract); U10HD021397 (U.S. NIH Grant/Contract); U10HD034167 (U.S. NIH Grant/Contract)