Phototherapy for preterm newborns—historical controversies and RCT evidence

Abstract

: The Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight randomized controlled trial (A-v-C RCT), published in 2008, was designed to address two long standing intertwined controversies about bilirubin and phototherapy in preterm newborns. The older controversy, dating from the 1950s, was whether ‘low’ bilirubin levels might cause CNS injury in preterm newborns. The newer and less well-known controversy began when scrutiny of the 1974–1976 NICHD Collaborative Phototherapy Trial revealed that the results were consistent with increased mortality risk in the phototherapy arm for ELBW newborns: relative risk (RR) 1.49, 95% CI: 0.93, 2.40. The results of the A-v-C RCT fueled rather than settled the controversy regarding safety of phototherapy for ELBW newborns: mortality was higher with aggressive phototherapy in the 501–750 g stratum, but the strength of the association was not strong enough that the evidence of causation would be considered indisputable (RR 1.13, 95% CI: 0.96, 1.34). By contrast, the A-v-C RCT essentially proved that mean peak total serum bilirubin (TSB) levels ~10 mg/dL (~171 mmol/L) can cause lasting CNS injury in ELBW newborns: RR 0.86 (95% CI: 0.74, 0.99) for neurodevelopmental impairment (NDI) with aggressive phototherapy and mean peak TSB 7.0±1.8 mg/dL versus 9.8±2.1 mg/dL with conservative phototherapy (120±31 versus 168±36 mmol/L). For profound NDI, the RR was 0.68 (95% CI: 0.52, 0.89), and by Bayesian analysis the probability that aggressive phototherapy reduced profound NDI was 0.99. A recently begun large multicenter RCT evaluating cycled phototherapy as a means to reduce exposure to phototherapy in newborns with birth weight <751 g or gestational age <27 weeks could resolve the mortality risk controversy.