Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?

Abstract

Objective Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT. Study Design ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses. Results Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment. Conclusions Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

Let there be light—but should there be less?

“…The Neonatal Research Network have taken a new look at their data using a Bayesian approach to the statistical analyses. 17 They now find that the relative risk of death in the 501 to 750 g birth weight subgroup treated with aggressive phototherapy was 1.19 (95% confidence interval 1.01 to 1.39), with a 99% estimated probability of increased mortality. On the other hand, the likelihood of impairment or profound impairment was significantly reduced in both weight groups (501 to 750 and 751 to 1000 g).…”

“…With this in mind, the recommendation to start phototherapy at lower irradiance in ELBW infants <750 g birth weight may need further discussion. 17,18 Indeed, the same may be true for the use of prophylactic vs targeted phototherapy, because this would also result in longer light exposure. Conversely, could it be argued that treatment for neonatal jaundice should be as brief as possible, but maximally effective during periods of exposure?…”

“…19 Others have also chosen graphs 15,20 or used birth weights in lieu of gestational ages. 15 The recommendations are clearly influenced by the results from the Neonatal Research Network, 16,17 and recommend phototherapy at lower levels than others have opted for. 15 Also, in infants with birth weight <750 g, the authors recommend starting phototherapy with lower irradiance, and to increase irradiance only if the initial irradiance fails to keep the serum bilirubin at safe levels.…”

“…That being the case, should decisions about treatment be at the whim of individual physicians, or are the babies better served with more uniform practices? The results from the Neonatal Research Network 16,17 remind us that we need to start thinking about phototherapy as a 'drug' to be administered in appropriate dosage, as is indeed our approach to most other things we do for sick infants.…”

“…This highlights some of the challenges in understanding and interpreting the network results. 16,17 The Neonatal Research Network enrolled almost 2000 premature infants, and few, if any, others in the world have the capability to execute a study of this size. Nevertheless, it was necessary to employ innovative statistical tools to arrive at a conclusion of increased mortality in the 501 to 750 g birth weight group.…”