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

NICHD Neonatal Research Network

Status and phase: Completed; Phase 3

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

Treatments: Procedure: Aggressive Phototherapy 501-750g; Procedure: Aggressive Phototherapy 751-1000g; Procedure: Conservative Phototherapy 751-1000g; Procedure: Conservative Phototherapy 501-750g

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00114543

M01RR016587 (U.S. NIH Grant/Contract)

M01RR000032 (U.S. NIH Grant/Contract)

M01RR006022 (U.S. NIH Grant/Contract)

U10HD021364 (U.S. NIH Grant/Contract)

U10HD027880 (U.S. NIH Grant/Contract)

U10HD027856 (U.S. NIH Grant/Contract)

U10HD027851 (U.S. NIH Grant/Contract)

U10HD040689 (U.S. NIH Grant/Contract)

M01RR000039 (U.S. NIH Grant/Contract)

M01RR008084 (U.S. NIH Grant/Contract)

U10HD027871 (U.S. NIH Grant/Contract)

U10HD021373 (U.S. NIH Grant/Contract)

M01RR000080 (U.S. NIH Grant/Contract)

U10HD027853 (U.S. NIH Grant/Contract)

M01RR000044 (U.S. NIH Grant/Contract)

M01RR000070 (U.S. NIH Grant/Contract)

U10HD040521 (U.S. NIH Grant/Contract)

U10HD040498 (U.S. NIH Grant/Contract)

M01RR000633 (U.S. NIH Grant/Contract)

U10HD040492 (U.S. NIH Grant/Contract)

M01RR007122 (U.S. NIH Grant/Contract)

M01RR000030 (U.S. NIH Grant/Contract)

M01RR000750 (U.S. NIH Grant/Contract)

U10HD021397 (U.S. NIH Grant/Contract)

NICHD-NRN-0029

U10HD034216 (U.S. NIH Grant/Contract)

U01HD036790 (U.S. NIH Grant/Contract)

U10HD021385 (U.S. NIH Grant/Contract)

U10HD027904 (U.S. NIH Grant/Contract)

U10HD040461 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,974 patients

Sex: All

Ages: 12 to 36 hours old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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1,974 participants in 4 patient groups

Aggressive ELBW

Active Comparator group

Description:

In Aggressive group 1, infants with birth weights 501-750g.

Treatment:

Procedure: Aggressive Phototherapy 501-750g

Aggressive VLBW

Active Comparator group

Description:

In the Aggressive group 2, infants with birth weights 751-1000g.

Treatment:

Procedure: Aggressive Phototherapy 751-1000g

Conservative ELBW

Active Comparator group

Description:

In the Conservative group 1, infants with birth weights 501-750g.

Treatment:

Procedure: Conservative Phototherapy 501-750g

Conservative VLBW

Active Comparator group

Description:

In the Conservative group 2, infants with birth weights 751-1000g.

Treatment:

Procedure: Conservative Phototherapy 751-1000g