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

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.

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