Trial of Aggressive Versus Conservative Phototherapy in Infants <1,000 Grams Birth Weight (Phototherapy)

A Randomized Trial of Aggressive or Conservative Phototherapy for Extremely Low Birth Weight Infants

This multi-center, randomized clinical trial compared different bilirubin levels as thresholds for timing of phototherapy in extremely low birth weight infants. The primary hypothesis was that there would be no difference in death or neurodevelopmental impairment at 18-22 months corrected age in infants treated by either aggressive or conservative threshold limits. 1,978 infants were enrolled.

Study Overview

• Status: Completed
• Conditions: Hyperbilirubinemia, Neonatal; Jaundice, Neonatal; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Procedure: Aggressive Phototherapy 501-750g; Procedure: Aggressive Phototherapy 751-1000g; Procedure: Conservative Phototherapy 501-750g; Procedure: Conservative Phototherapy 751-1000g

Detailed Description

In NICHD Neonatal Research Network (NRN) centers in 2002, phototherapy was administered to 94 percent of the extremely low birth weight (ELBW) infants who survive more than 12 hours. Yet, it is unclear what level of bilirubin in the blood is harmful for these very tiny infants -- no data existed from large or recent clinical trials to define the risks, benefits, and appropriate indications for phototherapy in these infants. The largest and most recent trial was the NICHD Collaborative Phototherapy Trial which involved infants treated in 1974-1976 and included only 77 ELBW infants. Data from this study and others suggested that phototherapy could have important hazards as well as benefits for ELBW infants.

This NRN study used two different bilirubin levels as thresholds for timing of phototherapy in 1,978 extremely low birth weight infants, examining the primary hypothesis that there would be no difference in death or neurodevelopmental impairment at 18-22 months corrected age between the aggressively and conservatively treated groups.

Enrolled infants were stratified by birth weight (501-750g and 751-1,000g) and randomized to receive phototherapy regimens based on either an aggressive threshold or a conservative threshold of total serum bilirubin.

In the Aggressive group:

• 501-750 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 5 mg/dl for day of life 1-14.
• 751-1,000 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 5 mg/dl for day of life 1-7 and 7 mg/dl for day of life 8-14.

In the Conservative group:

• 501-750 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 8 mg/dl for day of life 1-14.
• 751-1,000 grams birth weight infants, phototherapy was started, stopped, and restarted based on a total serum bilirubin threshold level of 10 mg/dl for day of life 1-14.

The phototherapy regimens are designed to fall within the range of clinical practice and to assure a sizable difference between groups in total serum bilirubin levels and duration of phototherapy.

The primary outcome was death or neurodevelopmental impairment at 18-22 months corrected age determined at an outpatient clinic visit. Secondary outcomes included death, abnormal neurodevelopmental outcome, severe hearing loss, cerebral palsy, blindness, and important medical outcomes.

• Study Type: Interventional
• Enrollment (Actual): 1974
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Diego, California, United States, 92103-8774
      • University of California at San Diego
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale 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
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Charlotte, North Carolina, United States, 27157
      • Wake Forest University
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • 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
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 hours to 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• 501-1000 grams birth weight
• 12-36 hours postnatal age

Exclusion criteria:

• Terminal condition (pH <6.8 for >2 hours OR persistent bradycardia, heart rate <100 bpm, associated with hypoxia for >2 hours]
• Prior use of phototherapy
• Major congenital anomaly
• Hydrops fetalis or severe hemolytic disease diagnosed in-utero
• Overt congenital nonbacterial infection
• Parental refusal or inability to provide consent
• Attending physician refusal
• Parents who are considered unlikely to return for follow-up evaluation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aggressive ELBW; In Aggressive group 1, infants with birth weights 501-750g.	Procedure: Aggressive Phototherapy 501-750g; Phototherapy started, stopped, and/or restarted when total serum bilirubin levels reach 5 mg/dl during days of life 1-14.
Active Comparator: Aggressive VLBW; In the Aggressive group 2, infants with birth weights 751-1000g.	Procedure: Aggressive Phototherapy 751-1000g; Phototherapy started, stopped, and/or restarted when total serum bilirubin levels reach 5 mg/dl during days of life 1-7, and started, stopped, and/or restarted when levels reach 7 mg/dl during days of life 8-14.
Active Comparator: Conservative ELBW; In the Conservative group 1, infants with birth weights 501-750g.	Procedure: Conservative Phototherapy 501-750g; Phototherapy started, stopped, and/or restarted when total serum bilirubin levels reach ≥8.0 mg/dl during days of life 1-14.
Active Comparator: Conservative VLBW; In the Conservative group 2, infants with birth weights 751-1000g.	Procedure: Conservative Phototherapy 751-1000g; Phototherapy started, stopped, and/or restarted when total serum bilirubin levels reach ≥10.0 mg/dl during days of life 1-14.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Death or neurodevelopmental impairment (MDI <70; PDI <70; cerebral palsy; blindness; or severe hearing loss)	0-22 months corrected age

Secondary Outcome Measures

Outcome Measure	Time Frame
Patent ductus arteriosus requiring drug or surgical treatment	36 weeks post conceptual age
Retinopathy of prematurity	36 weeks post conceptual age
Bronchopulmonary dysplasia (BPD)	36 weeks post conceptual age
Ventilator settings and FiO2 at 36 weeks	36 weeks post conceptual age
Necrotizing enterocolitis (NEC)	120 days old or at discharge
Intraventricular hemorrhage (IVH) by grade	120 days old or at discharge
Periventricular leukomalacia	120 days old or at discharge
Sepsis	120 days old or at discharge
Hearing assessments	120 days old or at discharge

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Ronnie Guillet, MD PhD, University of Rochester; Principal Investigator: Brenda H. Morris, MD, The University of Texas Health Science Center, Houston; Principal Investigator: Shahnaz Duara, MD, University of Miami

Publications and helpful links

General Publications

• Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008 Oct 30;359(18):1885-96. doi: 10.1056/NEJMoa0803024.
• Ahlfors CE, Vreman HJ, Wong RJ, Bender GJ, Oh W, Morris BH, Stevenson DK; Phototherapy Subcommittee; National Institute of Child Health and Development (NICHD) Neonatal Research Network. Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns. Clin Biochem. 2007 Feb;40(3-4):261-7. doi: 10.1016/j.clinbiochem.2006.09.006. Epub 2006 Sep 29. Erratum In: Clin Biochem. 2009 Apr;42(6):547.
• Bender GJ, Cashore WJ, Oh W. Ontogeny of bilirubin-binding capacity and the effect of clinical status in premature infants born at less than 1300 grams. Pediatrics. 2007 Nov;120(5):1067-73. doi: 10.1542/peds.2006-3024.
• Oh W, Stevenson DK, Tyson JE, Morris BH, Ahlfors CE, Bender GJ, Wong RJ, Perritt R, Vohr BR, Van Meurs KP, Vreman HJ, Das A, Phelps DL, O'Shea TM, Higgins RD; NICHD Neonatal Research Network Bethesda MD. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr. 2010 May;99(5):673-678. doi: 10.1111/j.1651-2227.2010.01688.x. Epub 2010 Jan 25. Erratum In: Acta Paediatr. 2013 Mar;102(3):326.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: September 1, 2002
• Primary Completion (Actual): April 1, 2005
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: June 15, 2005
• First Submitted That Met QC Criteria: June 15, 2005
• First Posted (Estimate): June 16, 2005

Study Record Updates

• Last Update Posted (Actual): March 22, 2019
• Last Update Submitted That Met QC Criteria: March 20, 2019
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Prematurity; Phototherapy; Bilirubin; NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); Neurodevelopmental outcome
• Additional Relevant MeSH Terms: Pathologic Processes; Infant, Newborn, Diseases; Skin Manifestations; Body Weight; Birth Weight; Jaundice; Hyperbilirubinemia; Hyperbilirubinemia, Neonatal; Jaundice, Neonatal
• Other Study ID Numbers: NICHD-NRN-0029; M01RR000633 (U.S. NIH Grant/Contract); 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); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (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); U10HD021397 (U.S. NIH Grant/Contract); U10HD040461 (U.S. NIH Grant/Contract); U10HD040498 (U.S. NIH Grant/Contract); U10HD040521 (U.S. NIH Grant/Contract); M01RR000032 (U.S. NIH Grant/Contract); M01RR000039 (U.S. NIH Grant/Contract); M01RR000044 (U.S. NIH Grant/Contract); M01RR000080 (U.S. NIH Grant/Contract); M01RR007122 (U.S. NIH Grant/Contract); M01RR016587 (U.S. NIH Grant/Contract); M01RR000030 (U.S. NIH Grant/Contract); U01HD036790 (U.S. NIH Grant/Contract)