Journal of Perinatology (2012) 32, 677–684 r 2012 Nature America, Inc. All rights reserved.



Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?
JE Tyson1, C Pedroza1, J Langer2, C Green1, B Morris3, D Stevenson4, KP Van Meurs4, W Oh5, D Phelps6, M O’Shea7, GE McDavid1, C Grisby8 and R Higgins9, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX, USA; 2RTI International, Research Triangle Park, NC, USA; 3Trinity Mother Frances Hospitals and Clinics, Tyler, TX, USA; 4Stanford University, Palo Alto, CA, USA; 5 Brown University, Providence, RI, USA; 6University of Rochester, Rochester, NY, USA; 7Wake Forest University, Winston-Salem, NC, USA; 8Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA and 9Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

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; p1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.

impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing. Journal of Perinatology (2012) 32, 677–684; doi:10.1038/jp.2012.64; published online 31 May 2012 Keywords: phototherapy; bilirubin; ELBW infant; randomized clinical trial; statistical interaction; Bayesian analysis

Study Design: ELBW infants (n ¼ 1974) were randomized to AgPT or conservative phototherapy at age 12 to 36 h. The effect of AgPT on outcomes (death, impairment, profound impairment, death or impairment (primary outcome), and death or profound impairment) at 18 to 22 months of corrected age was related to BW stratum (501 to 750 g; 751 to 1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses. Result: Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 h age. Among mechanically ventilated infants p750 g BW (n ¼ 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. Conclusion: Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound

Correspondence: Dr JE Tyson, Department of Pediatrics, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 2.106, Houston, TX 77030, USA. E-mail: Received 17 February 2012; revised 10 April 2012; accepted 18 April 2012; published online 31 May 2012

Introduction With the increasingly aggressive care of the most immature newborns, it is important to ensure that the therapies that they receive are both safe and effective. Yet, as Lucey has emphasized,1 ‘these fetal infants are receiving many therapiesy that have never been tested on this unique population.’ In this paper, we address whether aggressive phototherapy (AgPT), a therapy that is widely used in treating extremely lowbirth-weight (ELBW; p1000 g) infants, may increase the mortality of the smallest and sickest infants while reducing their serum bilirubin and risk of bilirubin neurotoxicity and neurodevelopmental impairment. Aggressive use of phototherapy has been encouraged by the neurodevelopmental delay associated with even low serum bilirubin levels among small premature infants in multiple large cohort studies.2 However, phototherapy has been assessed in only two large randomized trials, the most recent by the 16-center Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.3 In this trial, we randomized ELBW infants at 12 to 36 h of age to AgPT (provided at a total serum bilirubin value of 5 mg dlÀ1 or higher in the first week and 7 mg dlÀ1 or higher in the second week) or to conservative phototherapy (ConPT) (provided at a bilirubin value

although nonsignificant. or a score below 70 on the Mental or Psychomotor Development Index of the Bayley Scales of Infant Development II. hemolytic disease) were assessed singly and in combination.20 Profound impairment was defined as a score of p50 for either index or a level of 5 for gross motor function by the modified Palisano criteria.4. Partly because conventional frequentist analyses do not allow the probability of benefit or harm from treatment to be calculated.94. and death or profound impairment at 18 to 22 months of corrected age.5 In this trial. hypoxia.9 or cause oxidative injury or other adverse effects. Exclusion criteria included terminal illness (pH <6. severe hemolytic disease.68. 95% confidence interval ¼ 0.16.21 (Profound impairment was not initially defined as an outcome for the trial. brand of phototherapy lamps. chest compressions.93 to 2. feedings. AgPT did reduce neurodevelopmental impairment at 18 to 22 months of corrected age (after term) (RR ¼ 0. 751 to 1000 g) and randomized using a centralized computer system. Population Infants with a BW of 501 to 1000 g were enrolled 12 to 36 h after birth. Phototherapy was provided at the bilirubin values noted above and administered for at least 24 h whenever started or restarted. major congenital anomaly.74 to 0. hemolysis. and congenital non-bacterial infection. After parental informed consent was obtained.13.89). This paper reports our analyses assessing whether the benefits and hazards of AgPT for the smallest and sickest infants differed from those for other ELBW infants.7 phototherapy may reduce the antioxidant benefits associated with moderate bilirubin levels8. increase in mortality also occurred in the only other major phototherapy trial (the Collaborative Phototherapy trial conducted in the 1970s). hypercapnia.52 to 0.49 (95% confidence interval ¼ 0. profound impairment. Hearing outcomes were determined by the neurological examiner and from parental report. as recently recommended for all clinical trials. However. 95% confidence interval ¼ 0. infection. reduce albumin binding.13–15 The protocol for our Network trial included plans to relate the risks and benefits of AgPT to baseline risk factors including measures of severity of illness. Outcomes at 18 to 22 months of corrected age were assessed by blinded neurological examiners and neurodevelopmental assessors trained to reliability during a 2-day workshop. but was added partly because profound impairment is less likely than less severe impairment to improve with age. Of concern. administration of pressors.8 or persistent bradycardia and hypoxemia for >2 h). 95% confidence interval ¼ 0.10–12 Such problems might increase mortality among the smallest and sickest infants with the thinnest. 95% confidence interval ¼ 0. or other problems that increase bilirubin production. Irradiance was increased within this range at bilirubin thresholds of 13 mg dlÀ1 for infants 501 to 750 g and 15 mg dlÀ1 for infants 751 to 1000 g. death or impairment (primary trial outcome).40) among ELBW infants randomized to phototherapy or no phototherapy. Treatment The protocol stipulated phototherapy administration during the first 14 postnatal days. in the smaller birth weight stratum (501 to 750 g) (RR ¼ 1. Infants were classified as having moderate or severe cerebral palsy if they were unable to walk or required assistive devices.19 Impairment was defined as blindness (no functional vision in either eye). moderate or severe cerebral palsy. A potentially important. They added little beyond mechanical ventilation and FiO2 at 24 h in predicting outcomes at Methods The trial is described in detail elsewhere3 and summarized below. a reduction due almost entirely to a reduction in profound impairment (RR ¼ 0.34). the caregivers selected the fluid regimens. An exchange transfusion was indicated whenever the bilirubin exceeded the threshold after 8 h of intensified phototherapy. Multiple variables that may influence risk of bilirubin neurotoxicity or need for phototherapy (resuscitation drugs.6 Although considered quite safe. most translucent skin and greatest vulnerability to phototoxicity. impairment.96 to 1. The target irradiance level was 15 to 40 mW cmÀ2 nmÀ1.86. and other interventions.18 were stratified by center and BW (501 to 750g.87 to 1.22) This definition was based on prior Network studies23 and selected before any comparison of the outcomes of treatment groups.99). acidosis (pH <7. Conversely. the benefits of phototherapy may be greatest in these infants by preventing bilirubin neurotoxicity associated with hypoalbuminemia. Statistical analyses Baseline severity of Illness. early-onset sepsis. or compromise the blood–brain barrier. As appropriate for an effectiveness trial. infants Journal of Perinatology . the RR was 1.Clinical trials and aggressive phototherapy JE Tyson et al 678 of 8 mg dlÀ1 or higher for 501 to 750 g infants and 10 mg dlÀ1 or higher for 751 to 1000 g infants). indications for mechanical ventilation. We failed to demonstrate that AgPT reduced the primary outcome (death or impairment) (adjusted relative risk (RR) ¼ 0. Outcome assessments The outcomes included death. severe hearing loss (hearing loss for which bilateral hearing aids were prescribed).17 we performed Bayesian as well as frequentist analyses.02). Total serum bilirubin was measured in the first week at least once daily and in the second week when phototherapy had been given in the previous 24 h or the last bilirubin exceeded 7 mg dlÀ1.10). mortality with AgPT was increased. albeit not significantly.

and three-way interaction terms (a prior probability that is skeptical.27 To perform a sensitivity analysis and assess the robustness of the disturbing results for death.55 0.25 Hierarchical models have the statistical advantage of pooling specific subgroup estimates rather than estimating an effect for each subgroup.37.33 (0. RR.01) (Table 1). There was no adjustment for multiple comparisons.65 0.10. Intention-to-treat analyses were performed. N/total N (%) 218/944 (23) 124/343 (36) Frequentist analyses RR 95% Confidence interval (0.0 with 95% credible intervals of 0.05) (0. relative risk.0 (a range that includes the values observed in the great majority of large neonatal trials26 (BN(log RR ¼ 0. about interaction terms but which allows treatment estimates to vary across subgroups). the adjusted RR for each outcome was estimated using robust multilevel Poisson regression analyses (with center as a random effect to account for center variability).10 was used to reduce the risk of false-negative findings.1 at 2%.39) BW 501–750 g. 2. mechanical ventilation. thereby reducing the likelihood of overestimating subgroup differences.0 (%) 60 1 (99% probability of increased mortality) 93 97 49 Posterior probability of RR <0.01 (0.0 and <0.28 Results In all analyses.19 (0. body weight. 1. Death Overall and for all subgroups except one. 1. BW stratum (501 to 750 g. and interaction terms. Journal of Perinatology .24 In the frequentist analyses. 1. a priori. For all main effects in the models. we follow the guidelines developed by Sung et al.9 (%) 22 B0 0. BW. Predictor variables included treatment (AgPT or ConPT). 1. we used a neutral prior distribution centered at an RR ¼ 1.63. In reporting the Bayesian analyses.19 0. 1.83) 0.92 1. ethnicity.90 (that is. However. All interaction terms assumed independent informative Normal prior distributions centered at log RR of zero and separate variance components for the two. 1. In assessing the effects of AgPT on the smallest and sickest infants. Hierarchical analyses were performed using an extended approach of Dixon and Simon. For subgroups with a small sample size or number of adverse outcomes.19) (1.62.56. not ventilated at 24 h age 8/62 (13) 50/310 (16) 17/219 (8) 17/68 (25) 64/329 (19) 12/203 (6) 0.01. (Because of limited power to identify interactions.0 and of an RR <0. the Bayesian and frequentist models produced similar values for the RR.05) (0.5 to 2.19. multilevel Poisson regression models.14) (0.9 with AgPT.72. 501 to 750 g ventilated infants (n ¼ 696) had an increased RR (1.17) (1. 0. the latter two variables were used as our illness severity measures.) Each final model included all main effects.9. Accordingly. N/total N (%) All infants BW 501–750 g. the denominator for each outcome was the number of infants randomized whose outcome was known (three infants had a missing value for mechanical ventilation). and inborn/ outborn status). and illness severity to outcome. FiO2 at 24 h age. we repeated the analysis assuming an optimistic prior probability with the RR centered at 0. ventilated at 24 h age 230/946 (24) 153/353 (43) Conservative phototherapy. 1.39) Posterior RR Bayesian analyses 95% Credible interval Posterior probability of RR <1. The same approach was used in conducting secondary analyses for each outcome that included additional predictor variables (gestational age.01) (0.81) 87 85 36 Abbreviations: BW.02. not ventilated at 24 h age BW 751–1000 g. 1. the analyses provided minimal or no evidence that AgPT increased mortality (RR p1. sex.79 1. ventilated at 24 h age BW 751–1000 g.125)). Bayesian models included the same predictors as in the final frequentist.80.82 1. Relation of treatment. a 10% reduction in death with AgPT) and the probability of an RR >1. 95% confidence interval ¼ 1. 751 to 1000 g).97 1. a P >0.29. 1. Bayesian statistics were used to estimate the probability of an RR <1.63.Clinical trials and aggressive phototherapy JE Tyson et al 679 18 to 22 months.39) with only a 1% estimated probability of Table 1 Death Subset Observed data Aggressive phototherapy. Bayesian models shrink the subgroup-specific estimate toward the overall estimate of treatment effect. three-way interactions and constituent terms were assessed with backward elimination of terms with a P >0.01 to 1. The tables include these values and to provide information not obtainable from frequentist statistics the (posterior) probability of an RR <1.

41) Bayesian analyses Posterior 95% Credible RR interval Posterior Posterior probability of probability of RR <1.01) 0. Results similar to those above were found using secondary models that also included gestational age. there was a significant reduction in death or profound impairment (RR ¼ 0.77. ventilated at 24 h age BW 751–1000 g.81 with a 99% estimated probability of a reduction in death or profound impairment.70.55. (0. (0. AgPT did not reduce this outcome among infants in the smaller BW stratum (RR ¼ 0. same values are shown for all infants in both birth weight strata whether ventilated or not ventilated at 24 h age. 1.78 with less than a 50% estimated probability of a reduction in this composite outcome among ventilator-treated infants p750 g and among nonventilated-treated infants 751 to 1000 g. Table 2 Impairment and profound impairmenta Outcome Observed data Aggressive phototherapy. The results consistently favored AgPT (RR ¼ 0.75. 1. (0.9 (%) 71 59 95 97 0. (0. The effect of treatment differed by BW stratum irrespective of mechanical ventilation (P ¼ 0.89) with a 99% estimated probability that AgPT reduced this composite outcome (Table 4).13) 1.52.82 1. relative risk. relative risk. 1. (0. Death or profound impairment Overall.77. (0. P-values >0.01) 1. N/total N (%) 275/902 275/684 119/896 119/678 (30) (40) (13) (18) Frequentist analyses RR 95% Confidence interval (0.58. and thus a 99% estimated probability of increased mortality with AgPT. phototherapy.00 (%) RR <0. (0.05 for an interaction of treatment with birth weight and mechanical ventilation.82. (0. 1.79.Clinical trials and aggressive phototherapy JE Tyson et al 680 decreased mortality.93 1.80 0. all subgroups were combined in the analyses (Table 2). therefore.01) 1.0 (%) 97 96 99 >99 Posterior probability of RR <0. N/total Na (%) N/total Na (%) All infants BW 501–750 g.01) 0.72 0.12) 1. (0.58. and whether the infants were born within or outside their Network center.86 0.91 1. (0. (0.73 (0.91 to 0. upper 95% confidence or credible limits for both of 1.78.97) 1.70 0.86 0. Not ventilated at 24 h age 465/902 (52) 248/347 (71) 22/56 (39) 133/294 (45) 60/203 (30) 493/902 (55) 235/337 (70) 34/65 (52) 171/313 (55) 52/186 (28) Frequentist analyses RR 95% Confidence interval (0. (0. ventilated at 24 h age BW 501–750 g.01) and a 95% estimated probability that the composite outcome of death or impairment was reduced (RR <1.55.31). Impairment or profound impairment Because there was no evidence that treatment effects for these outcomes differed among the patient subgroups (no interaction terms that were significant. N/total N (%) Impairment (All infants) impairment (Survivors only) Profound impairment (all infants) Profound impairment (survivors only) 235/902 (26) 235/672 (35) 80/895 (9) 80/665 (12) Conservative phototherapy. not ventilated at 24 h age BW 751–1000 g.69 0. P <0.00) 1.90 in profound impairment.06 0.91) 0.09) 0.83 1. Table 3 Death or impairment Subset Observed data Conservative Aggressive phototherapy.88 0. (0.98).00) 1. ethnicity. RR.56.97) 1. a No significant interaction was identified. (0.89) among all infants enrolled and among all survivors assessed with 96 to >99% estimated probability of a reduction in impairment or profound impairment and a 95 to 97% probability of an RR <0. The sensitivity analysis gave similar results (96% probability of increased mortality with AgPT for the 501 to 750 g ventilated infants) despite using an optimistic prior (0.90 (%) 95 39 92 99 43 25 1 78 86 17 0.34) Abbreviations: BW.02 (0.89 0.93.0) (Table 3). These findings were associated with a P <0.06).89) Posterior RR Bayesian analyses 95% Credible interval Posterior probability of RR <1.94) 0. body weight.74.88 to 0. Journal of Perinatology . a The total N for the four subgroups does not add to the total overall N because three infants had a missing value for mechanical ventilation.08) 0.70.90 RR for death). Infants >750 g BW had an RR of 0.02 0. the findings differed by subgroup (an interaction of treatment with BW and mechanical ventilation. However.91) Abbreviation: RR.01 0. sex.92. Death or impairment Overall AgPT was associated with a marginally significant and potentially important overall reduction in death or impairment (RR ¼ 0.69 to 0.

However.96 to 1. The reduction in bilirubin with phototherapy might increase the susceptibility of ELBW infants to oxidative injury. 0. as in our analysis of ventilated 501 to 750 g infants. suggests the possibility of an increased mortality in the smallest infants in the trial. like those in the Collaborative Phototherapy Trial. 0.89 0.81 Abbreviations: BW. RR ¼ 1.98 0.9 (%) 63 7 89 0. The possibility that AgPT increases mortality of ventilated infants p750 g BW treated is supported by our Bayesian analyses performed to complement the frequentist analyses.87.7 Yet.Clinical trials and aggressive phototherapy JE Tyson et al 681 Table 4 Death or profound impairment Subset Observed data Aggressive phototherapy. like almost all clinical trials.96) Posterior RR Bayesian analyses 95% Credible interval (0. N/total N (%) All infants BW 501–750 ga BW 751–1000ga 310/895 (35) 202/403 (50) 108/492 (22) Conservative phototherapy.12 While larger and healthier infants might escape injury discernible in our trial. a factor likely to make it difficult to identify phototherapy hazards. The use of AgPT for the smallest and sickest newborns might be analogous to use of surgery (rather than radiation or chemotherapy alone) for some cancer patients to improve their long-term outcome despite a greater initial risk of death.10) (0. Because the effects of any therapy may differ considerably in different subgroups.13 These findings have been largely ignored because they were not significant at P <0. 80% of the ConPT group received phototherapy.8. their assessment was preplanned. 1.3 Although the P-value for a two-way interaction between treatment group and BW was not significant (P ¼ 0. the use of composite outcomes may be unavoidable for such questions as the effect of AgPT on survival without impairment when the components (death or impairment) are competing outcomes.69. Even so.80. 0. In contrast. Such analyses do not assess the likelihood that the alternative hypothesis is correct. subgroup analyses are most likely to be valid when. body weight. N/total N (%) 337/896 (38) 200/400 (50) 137/496 (28) Frequentist analyses RR 95% Confidence interval (0.87.32. Our trial.30 Such differences are particularly important in identifying treatment hazards to which the highest risk patients may be especially vulnerable.81 0. and this finding.99) (0. except perhaps in the most vulnerable infants. 0. Discussion Despite concerns about extrapolating treatment effects from larger and healthier infants to the most immature infants.79.96) Posterior probability of RR <1. When.68.31 Bilirubin is reported to be a powerful antioxidant.82). phototoxicity might directly result in oxidative injury to cell membranes or other adverse effects.11. and they are biologically plausible. an error often made in failing to recognize and seriously consider important potential treatment hazards when statistical power is limited. as in our study. we identified a significant three-way interaction suggesting that AgPT increased mortality among ventilated infants p750 g BW.1 phototherapy has been considered both effective and safe in all newborns. the results for each component should be separately analyzed. Bayesian analyses directly assess the question: How likely is the treatment to Journal of Perinatology . relative risk. they are supported by pre-existing evidence. The preselected primary outcome was the composite outcome of death or impairment. a difference equal to the 5% absolute reduction in the number of infants with impairment and only slightly more than the 4% reduction in infants with profound impairment in this BW group. This finding was supported by the sensitivity analysis using an optimistic prior probability. had high power only to identify overall treatment effects using conventional frequentist statistics. a Same values for those ventilated and not ventilated at 24 h age.29 In our Network trial.10) (0. 1. power was limited. subgroup differences should be considered in any trial. preterm infants have been randomly assigned to treatment with phototherapy or no phototherapy in only one large trial.98 0. but also among all low BW (<2500 g) infants (n ¼ 1063.15). the effect of treatment appears to differ for the different components of outcome.0 (%) 99 63 99 Posterior probability of RR <0. confidence interval ¼ 0. However. This Network trial is the only large trial to date of AgPT. We previously reported that the absolute number of deaths among 501 to 750 g infants was 5% greater with aggressive than ConPT. Subgroup analyses must be viewed with skepticism. Frequentist analyses assess the probability that the observed or a larger difference between groups would occur assuming the null hypothesis is correct. The analyses reported herein were conducted to provide the best assessment possible with the available data to evaluate whether the benefits and hazards of AgPT among the smallest and sickest infants differ from those in other ELBW infants. RR.98) (0. Composite outcomes have the disadvantage that treatment may have opposite effects for the outcome components.12 The findings were compatible with a substantial increase in mortality with phototherapy among not only ELBW infants as noted above.11.05. and it was performed decades ago. phototoxicity would be most likely to be identifiable in the most immature infants whose skin readily transmits light and who would be most vulnerable to oxidative injury.9 Moreover.10.88 0.

or clinical instability prompting the use of respiratory or pressor support.1. a positive blood culture. Mc David. the findings from the Network trialFthe only large trial of AgPT yet performedFsuggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International. evidence of treatment heterogeneity like we identified in our analyses would generate a hypothesis to be tested in future trials. O’Shea. Morris. Author Contributions Study concept and design: Tyson. Pedroza. and analyzed the data for this study. These concerns do not apply to our analyses. there may never be another large trial comparing phototherapy to no phototherapy or AgPT to ConPT in ELBW infants. and thus do not contradict our analyses. . pressor therapy. NCT00114543).29 In this instance. or apnea and bradycardia requiring bag and mask ventilation or intubation during the prior 24 h)).36 higher plasma bilirubin levels on day 5 were associated with a higher risk of death or impairment among unstable infants (infants who at 5 days had any of the various risk factors (primarily mechanical ventilation but also blood pH <7. We decided against doing this partly because the findings with 684 such infants randomized suggested that any increase in survival with ConPT would be almost entirely offset by an increase in survivors with profound impairment. Grisby. These analyses did not involve any assessment of the effect of AgPT. Stevenson.’ It remains to be determined whether the approach would avoid an increase in mortality while maintaining the reduction in profound impairment with AgPT in the Network trial. Oh. data analysis.33 These analyses may be most helpful in estimating treatment benefits and hazards when power is limited as in subgroup analyses. These treatment approaches could then be rigorously tested by comparing them to AgPT in a large randomized trial. partly because the manufacturing changes in phototherapy lamps since the prior Collaborative Phototherapy have substantially increased the irradiance levels that they deliver (mean of 22 to 23 mW cmÀ2 nmÀ1 each day as measured at the infant’s skin during the Network trial3). Natus Medical loaned light-emitting diode phototherapy lights to each center. O’Shea. Acknowledgments The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network’s Phototherapy Trial (ClinicalTrials. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. We considered whether to extend the Network trial to randomize additional infants <750 g BW to more precisely assess the risks and benefits of AgPT and ConPT in this subgroup. Clinical instability at age 5 days may be the resultFnot the causeFof bilirubin toxicity that resulted in hypoventilation. The lights were returned to Natus Medical or purchased at a prorated price after the study. These lights were used at the discretion of the attending neonatologist in treating infants in either treatment group. This relationship was not observed among stable infants. Irradiance levels can be increased. The authors declare no other potential conflicts of interest. As for other neonatal therapies. Concerns about Bayesian analyses have largely been concerns that the prior probability would be derived from methodologically weak studies and be overly optimistic. Acquisition of data: Tyson. the data coordinating center (DCC) for the network. In summary. Oh. The appropriate irradiance levels and how they Journal of Perinatology would be best achieved is unclear.35 In recent observational analyses of the Network trial.34. which stored.Clinical trials and aggressive phototherapy JE Tyson et al 682 have benefit/harm?16–18. phototherapy should not be assumed to have the same risks and benefits in the smallest and sickest infants as in more mature infants. This study was supported by grants from the National Institutes of Health and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Tyson drafted the manuscript and no form of payment was given him to produce the manuscript.4–6 and the values for RR were similar in the Bayesian and frequentist analyses and identified a high probability that AgPT increases mortality while reducing profound impairment. data collection. Dr Abhik Das (DCC Principal Investigator) and Mr John Langer (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. or manuscript preparation or revision. The presence or absence of these problems may simply be a marker for infants who experienced bilirubin toxicity or phototoxicity. Ordinarily.17 Bayesian analyses allow prior estimates of treatment effect to be updated using new data in estimating the (posterior) probability of benefit. Stevenson. Pedroza. Conflict of interest The authors declare no conflict of interest. The mortality findings in the Network trial prompted Watchko and Maisels37 to conclude that ‘In infants <750 g. On behalf of the NRN. if necessary. an outcome that some people consider worse than death. or more surface yexposed to phototherapy if the bilirubin rises. managed. Phelps. Natus Medical played no role in the study design. have the limitations inherent in observational analyses for making treatment inferences. The posterior probability that AgPT increased mortality was estimated using a neutral prior probability despite the evidence of an increased mortality in the one large prior trial of phototherapy. Phelps. Higgins.32. it seems prudent to initiate phototherapy at lower irradiance levels. Our results indicate an urgent need to develop other treatment approaches using lower irradiance levels or other treatment methods38 that may reduce severe bilirubin neurotoxicity without risking an increase in the mortality of these infants. recurrent apnea.

Pritzker School of Medicine (2006 to present). Nicholas H St John. Sheila Greisman. RN MS PNP. Lucy Noel RN. Kimberly Yolton. Pedroza. BS. Renee P Pyle. PhD. Rachel V Walden. Gaynelle Hensley. Sally S Adams. Nora I Alaniz. PhD. RN. Hutzel Women’s Hospital. Kristin M ZaterkaBaxter. Qing Yao. PhD. RN. Kathryn E Gustafson. Clarence Demetrio. University of Rochester Medical Center. MD MPH. MD. MD. Deborah Evans Allred. Michael S Caplan. MD. Stevenson. MD. RN. MD. RN. Stanford University. C Michael Cotten. PhD. Jean G Kohn. RTI International (U10 HD36790)FAbhik Das. Children’s Hospital of Michigan. RCP. MD MPH. Deborah Kennedy. Vivien A Phillips. University of Texas Health Science Center at Houston Medical School. Riley Hospital for Children. Duke University School of Medicine. Michele C Walsh. RN. PhD. Alexandra Stoerger. M01 RR750)FBrenda B Poindexter. Pedroza. Morris. MD MPH. PsyD PA-C. University Hospital. Oh. BSN RNC. or material support: Higgins. Tyson. Patty A Cluff. and Emory University Hospital Midtown (U10 HD27851. Rebecca Bara. Donald J Goldstein. Yvonne E Vaucher. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216. Susie Madison. MD MS. RN BSN. MD. Elizabeth T Heyne. Phelps. M01 RR32)FWaldemar A Carlo. MD. and Wishard Health Services (U10 HD27856. RN. Bonnie E Stephens. RN. RN CCRC. PhD. RN BSN. MD. University of Cincinnati (2001 to 2006). RN. RN. Elizabeth N McClure. Anna E Lis. Catherine Twell Boatman. Drafting of the manuscript: Tyson. RN. RN BSN. Roy J Heyne. Ellen C Hale. MA. MD. MS RN CPNP. RN BSN. MD MS. MD. MS RN CS. MD. Janet S Morgan. participated in this study: NRN Steering Committee Chair: Alan H Jobe. MD MPH. Edward F Donovan. RR633)FWalid A Salhab. University Hospital. RN BSN CCRC. Joan M Baran. MSN. PhD FNP-BC IBCLC. MD. The following investigators. M01 RR44. Susan Dieterich. MD. Melissa Whalen Morris. MEd. MD. MD. Rosemary L Jensen. MA. Monica Konstantino. RN BSN. RN. Anna M Dusick. Ira Adams-Chapman. RN BSN MaEd. Rebecca L Perritt. Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentFLinda L Wright. PsychD MSEd. MD MHS. RN. Langer. BA. Barbara Bentley. PhD. M01 RR7122)FLisa K Washburn. Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904)FAbbot R Laptook. Administrative. Katherine A Foy. Diane Hust. Robert T Burke. Yvette R Johnson. PhD. University Hospital. Wayne State University. Grady Memorial Hospital. RN BSN. technical. MD. PA. Robert G Dillard. and Sinai-Grace Hospital (U10 HD21385)FSeetha Shankaran. PhD. Carolyn M Petrie Huitema. MD. Emily Kushner. MD. M01 RR16587)FCharles R Bauer. MD MS Epi. RN BS CCRC. Golisano Children’s Hospital (U10 HD40521. Theresa M Leach. MD. Cincinnati Children’s Hospital Medical Center. BS CCRC. M01 RR70)FSusan R Hintz. Gary J Myers. Nancy S Newman. and Forsyth Medical Center (U10 HD40498. Sharon L Wright. PhD. MD. MD. Yale-New Haven Children’s Hospital and Bridgeport Hospital (U10 HD27871. Marcia Worley Mersmann. Critical Revision of the manuscript for important intellectual content: Tyson. MD. Patricia Gettner. MD. Barbara G Jackson. University of CaliforniaFSan Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) – Neil N Finer. Rainbow Babies & Children’s Hospital (U10 HD21364. RN PNP. Kate Bridges. MD. RN. Alexis N Diaz. MD. MD. and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373. M01 RR39)FBarbara J Stoll. LMSW. Harris C Jacobs. which stored. Kathy Arnell. Nancy A Miller. MS CIMI. MD. Shahnaz Duara. RN BSN. Georgia E McDavid. MD. Jody Hessling. Ruth Everett-Thomas. Kimberley A Fisher. Dianne E Herron. M01 RR6022)FRichard A Ehrenkranz. Paul R Wozniak MD. Elaine Romano. Myriam Peralta-Carcelen. Brenner Children’s Hospital. MD MPH. Yamiley C Gideon. MT(ASCP). PhD. RN. Patricia W Evans. Dr Abhik Das (DCC Principal Investigator) and Ms Nellie Hansen (DCC Statistician) at RTU International had full access to all the data in the Phototherapy Trial and take responsibility for the integrity of the data. managed. Jamie E Newman. MD. Green. and Good Samaritan Hospital (U10 HD27853. Joan Merzbach. Yale University. MA. Lucile Packard Children0 s Hospital (U10 HD27880. Kelly Yost. University of Chicago. Baptist Medical Center. Lucy C Miller. MD. MD.Clinical trials and aggressive phototherapy JE Tyson et al 683 Analysis and interpretation of data: Langer. Pablo J Sa Abbot R Laptook. Jackie F Hickman. MD MPH. Jean J Steichen. BA BS. MD. On behalf of the Network. Joanne Williams. Ginger K Brudos. Angelita Hensman. Shirley S Cosby. Barbara Alexander. MD. MS. Ricki F Goldstein. M01 RR8084)FKurt Schibler. MSHS. RN. JoAnn Poulsen. Andrea Garcia. KL2 RR24149. and Durham Regional Hospital (U10 HD40492. Maegan C Simmons. Holly L Mincey. Methodist Hospital. the data coordinating center (DCC) for the network. Maynard R Rasmussen MD. Martha G Fuller. Linda A Madden. MD. MA. Gail Wiley Hounshell. Alicia Guzman. Kasey Hamlin-Smith. MA. Laura L Whitely. James A Lemons. PhD. RN. Yvette Yatchmink. Case Western Reserve University. Lori E Bond. RN CCRP. Laura A Goldston. Kathy J Auten. Patricia Cervone. and Children’s Medical Center Dallas (U10 HD40689. Teresa L Gratton. Betty Hastings. PhD. MS. Martha R Leonard. Elizabeth M McClure. PhD. MA. Mary Rowan. MEd CAES. MD. University of Miami Holtz Children’s Hospital (U10 HD21397. Korinne Chiu. Linda J Reubens. Higgins. Charles R Rosenfeld. Children’s Memorial Hermann Hospital. Stacy Reddoch. Additional Contributions: RTI International. Geraldine Muran. Nancy J Peters. Alamance Regional Medical Center. Wake Forest University. Melody B Lohmeyer. Deanne Wilson-Costello. RN MSN. MD MPH. Maria Elena DeAnda. M01 RR30)FRonald N Goldberg. RN. in addition to those listed as authors. RN. MD PhD. MSW. Raquel Halfond. MA LPA. RN. Bonnie S Siner. BA. PhD. Silvia Frade Eguaras. Pedroza. Emory University. M Bethany Ball. MD. Namasivayam Ambalavanan. O’Shea. PhD MPH. MD. RNC. W Kenneth Poole. BA. Green. MA. RN BSN. Athina Pappas. MD. RN BSN. Terri Major-Kincade. RN MSN. UL1 RR24148)FKathleen A Kennedy. University of Texas Southwestern Medical Center at Dallas. BSHS RRT. RN CPNP. UL1 RR24139. Lauren Zwetsch. Patti L Pierce Tate. BA. Children’s Healthcare of Atlanta. Stevenson. Indiana University. Higgins. MD. Ellen L Waldrep. MD. Phelps. RN CCRC. Monica V Collins. Morris. Wade Rich. MS. MO1 RR125. Victoria E Watson. RN. Erica Burnell. Silvia Hiriart-Fajardo. Mary Allison. Betty R Vohr. Parkland Health & Hospital System. Anne M DeBattista. Study supervision: Tyson. MS CAS. UL1 RR24160)FRonnie Guillet. Green. MD PhD. RN BSN. Esther G Akpa. RN BSN. Pamela J Bradt. Julie Babish Johnson. RN. RN. M01 RR80)FAvroy A Fanaroff. MD. MEd. Van Meurs. M01 ´ nchez. Journal of Perinatology . Carroll Peterson. MD. RN BSN. Obtained funding: Tyson. Oh. O’Shea. PhD. RN. Christine G Butler. James R Moore. and analyzed the data for this study.

Tin mesoporphyrin for the prevention of severe neonatal hyperbilirubinemia. 14: 403–416. 14 Hansen TWR. conservative phototherapy for infants with ELBW. 16 Spiegelhalter DJ. 3 Morris BH. Ames BN. 35 Saigal S. Spennati GF et al. J Clin Epidemiol 2009. Pediatrics 1985. Morris BH. Stoll BJ et al. UK. 28 Sung L. Clin Trials 2011. Bilirubin is an antioxidant of possible physiological importance. 33 Goodman SN. Epidemiology 1990. 235(4792): 1043–1046. Intensive care for extreme prematurityFmoving beyond gestational age. 38 Wong RJ. Perritt R. Aggressive vs. Human experimentation in perinatology. Acta Paediatr 2010. Bracken MB (eds). 1993. In vitro and in vivo effects of erythrocyte phototherapy on newborns. Introduction to Bayesian methods I: measuring the strength of evidence. Formation of photoproducts and cytotoxicity of bilirubin irradiated with turquoise and blue phototherapy light. 311(7020): 1621–1625. 5 Lipsitz PJ. Neonatal hyperbilirubinemia In: Klaus MH. Walter S. 28(5): 326–333. BMJ 1999. Users’ Guides To The Medical Literature: A Manual For Evidence-Based Clinical Practice. 31 Oxman A. 27 Jones HE. Schluchter M. Pediatrics 2005. 32 McGrayne SB. NeoReviews 2007. 2001. Stevenson DK. Mechanisms of bilirubin toxicity: clinical implications. Tyson JE. 13 Wennberg RP. Rosenbaum PL. 324–362. Stability of maternal preferences for pediatric health states in the perinatal period and 1 year later. AMA Press: Chicago. 8(2): 129–143. Koren G. Laupacis A. Fanaroff AA. Development and reliability of a system to classify gross motor function in children with cerebral palsy. 4 Brown AK. Association between peak serum bilirubin and neurodevelopmental outcomes in ELBW infants. 20 Bayley N. 8 Gopinathan V. 22 Hack M. 15: 136–140. Racine A. Langer J. Pediatrics 2004. Bilirubin and ascorbate antioxidant activity in neonatal plasma. Ahlfors CE. 15 Bender GJ. Bryla DA. BMJ 1995. Cochrane neonatal systematic reviews: a survey of the evidence for neonatal therapies. 39(4): 214–223. Vreman HJ. Seven items were identified for inclusion when reporting a Bayesian analysis of a clinical study. 319(7208): 508–512. 2(4): 282–290. Simon R. 116: 333–341. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of ELBW children at school age. Biometrics 1991. 94: 1448–1454. 9 Stocker R. 358(16): 1672–1681. Feeny DH. Acta Paediatr 2005. Part 2): 422–426. Braunholtz D. 359(18): 1885–1896. Neurodevelopmental outcomes of ELBW infants <32 weeks’ gestation between 1993 and 1998. Evaluation of comparative treatment trials. Cartar L. Hayden J. 75(2. Gartner LM. 34(7): 702–722. Cell Mol Neurobiol 2000. Green C. 112(4): 773–779. Med Care 1996. Clin Perinatol 1987. pp 553–565. Cashore WJ. Russell D. Summarizing the evidence: when to believe a subgroup analysis In: Guyatt G. 30 Kraemer HC. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. 29(4): 765–778. 75(2. Neuenschwander B. p 532. 25 Dixon DO. 23 Tyson JE. Glazer AN. 99(5): 673–678. Stevenson DK. Christensen T. Horbar JD. Pediatrics 2007. 36 Oh W. Sem Fetal Neonatal Med 2010. Fetal infants: thoughts about what to do. 47(3): 871–881. Arch Pediatr Adolesc Med 2003. The blood–brain barrier and bilirubin encephalopathy. Di Giulo A. Stoskopf BL. 21 Palisano R. Tyson JE. Journal of Perinatology . 58: 261–268. Ontogeny of bilirubin-binding capacity and the effect of clinical status in premature infants born at less than 1300 grams. Psychological Corporation: New York. Clinical trials and rare diseases: a way out of a conundrum. NY. Austin PC. Assessing clinical benefits and risks for patients. Bayesian models for subgroup analysis in clinical trials. 34 Torrance GW. Phelps DL. JAMA 2010. Science 1987. Wu PYK. Bracken MB. McDonald SA. Hux JE. Pediatrics 2003. 19 Vohr BR. 20(1): 97–109. rather than statistical effects on measures. Taylor HG. Guyatt G. Neonatal and infant mortality in relation to phototherapy. Tomlinson GA. Pediatrics 2005. Fanaroff AA (eds). Rosenbaum P. 62(1): 13–21. Milner AD. Oh W. 1(1): 43–46. No adjustments are needed for multiple comparisons. 2002. Galuppi B. Effective Care of the Newborn Infant. Barr RD. 2 Oh W. 29 Silverman WA. Bayesian statistical inference enhances the interpretation of contemporary randomized controlled trials. Beattie WS. Soll RF. 30(2): 285–304. 304(6): 683–684. 120(5): 1067–1073.e5.Clinical trials and aggressive phototherapy JE Tyson et al 684 Note: All persons named in the Acknowledgement above have provided written permission to be named. Burrows E. 2011. Chapter 22. Wong RJ. Miller NJ. Maisels MJ. 6 Maisels MJ. The Theory That Would Not Die. Clin Perinatol 2002. Greenberg ML. Frank E. Bryla DA. Oxford University Press: Oxford. Feldman BM. 1360–2. Clin Perinatol 2003. Multiattribute utility function for a comprehensive health status classification: Health Utilities Index Mark 2. 8(2): 77–84. 113(6): 1819. FEBS Lett 1994. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in ELBW infants. Pediatrics 1985. Bayesian subset analysis. An introduction to Bayesian methods in health technology assessment. Drotar D. 5th edn. Stevenson DK. Farello G. Vohr BR. Haughton DE. Tozzi-Ciancarelli MG. 26 Sinclair JC. Bender GJ et al. Table 47. Bhutani VK. Poole WK. Wilson-Costello D et al. Enduring controversies in the management of hyperbilirubinemia in preterm infants. Biol Neonate 1989. Neonatal jaundice In: Sinclair JC. Care of the High-risk Neonate. IL. Yamamoto Y. 10 Tozzi E. 18 Wijeysundera DN. 12 Roll EB. Wright LL. 11 Vreman HJ. Wood E. J Clin Epidemiol 2005. N Engl J Med 2008. Ohlssen DI. Furlong WJ. 349(2): 197–200. Part 2): 393–400. 7 Maisels MJ. McDonagh AF. Wang Q. Tyson JE. 1992. Rice-Evans CA. Kim MH. Zhang Y. 116(3): 635–643. Phototherapy: current methods and future directions. Oh W. 17 Lilford RJ. Drummond R (eds). CT. 37 Watchko JF. Yale University Press: New Haven. 24 Rothman KJ. Semin Perinatol 2004. Bayley Scales of Infant Development II. Dev Med Child Neurol 1997. Branson M. WB Saunders: Philadelphia. Abrams KR. References 1 Lucey JF. 56(4): 204–209. Higgins RD. O’Shea TM et al. Stevenson DK. Streiner DL. Clin Trials 2005. Thornton JG. Myles JP. N Engl J Med 2008. Parikh NA. Jones DR. 157(3): 261–269. D’Alfonso A.

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