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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Hyperbilirubinemia, Neonatal, Jaundice, Neonatal, Infant, Newborn, Infant, Low Birth Weight, Infant, Small for Gestational Age, Infant, Premature

Intervention / Treatment
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* Procedure: Aggressive Phototherapy 501-750g
* Procedure: Aggressive Phototherapy 751-1000g
* Procedure: Conservative Phototherapy 501-750g
* Procedure: Conservative Phototherapy 751-1000g


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Hours
Maximum Age: 36 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Bilirubin, Phototherapy, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Prematurity, Neurodevelopmental outcome