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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 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 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.

Conclusion:

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.

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Acknowledgements

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.gov NCT00114543). Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, 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. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. 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, Natus Medical loaned light-emitting diode phototherapy lights to each center. These lights were used at the discretion of the attending neonatologist in treating infants in either treatment group. The lights were returned to Natus Medical or purchased at a prorated price after the study. Natus Medical played no role in the study design, data collection, data analysis, or manuscript preparation or revision. The authors declare no other potential conflicts of interest.

Dr Tyson drafted the manuscript and no form of payment was given him to produce the manuscript.

Author Contributions

Study concept and design: Tyson, Pedroza, Morris, Oh, Stevenson, Phelps, O’Shea, Higgins.

Acquisition of data: Tyson, Pedroza, Morris, Oh, Stevenson, Phelps, O’Shea, Mc David, Grisby.

Analysis and interpretation of data: Langer, Pedroza, Green, Tyson.

Drafting of the manuscript: Tyson, Pedroza, Green, Langer.

Critical Revision of the manuscript for important intellectual content: Tyson, Pedroza, Green, Morris, Oh, Stevenson, Van Meurs, Phelps, O’Shea, Higgins.

Obtained funding: Tyson, Oh, Stevenson, Phelps, O’Shea, Higgins.

Administrative, technical, or material support: Higgins.

Study supervision: Tyson, Morris.

Additional Contributions: RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the Network, 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. The following investigators, in addition to those listed as authors, participated in this study:

NRN Steering Committee Chair: Alan H Jobe, MD PhD, University of Cincinnati (2001 to 2006); Michael S Caplan, MD, University of Chicago, Pritzker School of Medicine (2006 to present).

Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904)—Abbot R Laptook, MD; Betty R Vohr, MD; Angelita Hensman, BSN RNC; Theresa M Leach, MEd CAES; Martha R Leonard, BA BS; James R Moore, MD; Lucy Noel RN; Bonnie E Stephens, MD; Robert T Burke, MD; Yvette Yatchmink, MD; Rachel V Walden, MD; Victoria E Watson, MS CAS.

Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364, M01 RR80)—Avroy A Fanaroff, MD; Michele C Walsh, MD MS; Deanne Wilson-Costello, MD; Nancy S Newman, RN; Bonnie S Siner, RN.

Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084)—Kurt Schibler, MD; Edward F Donovan, MD; Jean J Steichen, MD; Kate Bridges, MD; Barbara Alexander, RN; Marcia Worley Mersmann, RN CCRC; Holly L Mincey, RN BSN; Jody Hessling, RN; Teresa L Gratton, PA; Kimberly Yolton, PhD.

Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30)—Ronald N Goldberg, MD; C Michael Cotten, MD MHS; Ricki F Goldstein, MD; Kathy J Auten, MSHS; Kimberley A Fisher, PhD FNP-BC IBCLC; Melody B Lohmeyer, RN MSN; Kathryn E Gustafson, PhD; Katherine A Foy, RN.

Emory University, Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39)—Barbara J Stoll, MD; Ira Adams-Chapman, MD; Ellen C Hale, RN BS CCRC.

Eunice Kennedy Shriver National Institute of Child Health and Human Development—Linda L Wright, MD; Elizabeth M McClure, MEd.

Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750)—Brenda B Poindexter, MD MS; James A Lemons, MD; Anna M Dusick, MD; Dianne E Herron, RN; Lucy C Miller, RN BSN CCRC.

RTI International (U10 HD36790)—Abhik Das, PhD; W Kenneth Poole, PhD; Qing Yao, PhD; Betty Hastings; Elizabeth N McClure, MEd; Jamie E Newman, PhD MPH; Rebecca L Perritt, MS; Carolyn M Petrie Huitema, MS; Kristin M Zaterka-Baxter, RN BSN.

Stanford University, Lucile Packard Children′s Hospital (U10 HD27880, M01 RR70)—Susan R Hintz, MD MS Epi; M Bethany Ball, BS CCRC; Joan M Baran, PhD; Barbara Bentley, PsychD MSEd; Lori E Bond, PhD; Ginger K Brudos, PhD; Maria Elena DeAnda, PhD; Anne M DeBattista, RN PNP; Jean G Kohn, MD MPH; Renee P Pyle, PhD; Nicholas H St John, PhD.

University of Alabama at Birmingham Health System and Children's Hospital of Alabama (U10 HD34216, M01 RR32)—Waldemar A Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Monica V Collins, RN BSN MaEd; Shirley S Cosby, RN BSN; Vivien A Phillips, RN BSN.

University of California—San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) – Neil N Finer, MD; Yvonne E Vaucher, MD MPH; Maynard R Rasmussen MD; Paul R Wozniak MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Martha G Fuller, RN MSN; Wade Rich, BSHS RRT.

University of Miami Holtz Children's Hospital (U10 HD21397, M01 RR16587)—Charles R Bauer, MD; Shahnaz Duara, MD; Silvia Hiriart-Fajardo, MD; Ruth Everett-Thomas, RN BSN; Mary Allison, RN; Alexis N Diaz, BA; Silvia Frade Eguaras, Yamiley C Gideon, BA; Alexandra Stoerger, BA; Andrea Garcia, MA; Kasey Hamlin-Smith, PhD.

University of Rochester Medical Center, Golisano Children's Hospital (U10 HD40521, M01 RR44, UL1 RR24160)—Ronnie Guillet, MD PhD; Gary J Myers, MD; Linda J Reubens, RN CCRC; Erica Burnell, RN; Mary Rowan, RN; Diane Hust, MS RN CS; Rosemary L Jensen; Kelly Yost, PhD; Lauren Zwetsch, RN MS PNP; Julie Babish Johnson, MSW; Emily Kushner, MA; Joan Merzbach, LMSW.

University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas (U10 HD40689, M01 RR633)—Walid A Salhab, MD; Pablo J Sánchez, MD; Charles R Rosenfeld, MD; Abbot R Laptook, MD; Roy J Heyne, MD; Sally S Adams, MS RN CPNP; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T Heyne, PsyD PA-C; Jackie F Hickman, RN; Linda A Madden, RN CPNP; Susie Madison, RN; Nancy A Miller, RN; Janet S Morgan, RN; Catherine Twell Boatman, MS CIMI.

University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373, KL2 RR24149, UL1 RR24148)—Kathleen A Kennedy, MD MPH; Pamela J Bradt, MD MPH; Patricia W Evans, MD; Terri Major-Kincade, MD MPH; Laura L Whitely, MD; Nora I Alaniz, BS; Esther G Akpa, RN BSN; Patty A Cluff, RN; Susan Dieterich, PhD; Anna E Lis, RN BSN; Georgia E McDavid, RN; Stacy Reddoch, BA; Maegan C Simmons, RN; Patti L Pierce Tate, RCP; Sharon L Wright, MT(ASCP).

Wake Forest University, Baptist Medical Center, Brenner Children's Hospital, and Forsyth Medical Center (U10 HD40498, M01 RR7122)—Lisa K Washburn, MD; Robert G Dillard, MD; Nancy J Peters, RN CCRP; Barbara G Jackson, RN BSN; Korinne Chiu, MA; Deborah Evans Allred, MA LPA; Donald J Goldstein, PhD; Raquel Halfond, MA; Carroll Peterson, MA; Ellen L Waldrep, MS; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD.

Wayne State University, Hutzel Women's Hospital, Children's Hospital of Michigan, and Sinai-Grace Hospital (U10 HD21385)—Seetha Shankaran, MD; Yvette R Johnson, MD MPH; Athina Pappas, MD; Rebecca Bara, RN BSN; Geraldine Muran, RN BSN; Deborah Kennedy, RN BSN; Laura A Goldston, MA.

Yale University, Yale-New Haven Children's Hospital and Bridgeport Hospital (U10 HD27871, UL1 RR24139, MO1 RR125, M01 RR6022)—Richard A Ehrenkranz, MD; Patricia Gettner, RN; Harris C Jacobs, MD; Christine G Butler, MD; Patricia Cervone, RN; Monica Konstantino, RN BSN; Elaine Romano, MSN; JoAnn Poulsen, RN; Joanne Williams, RN; Sheila Greisman, RN.

Note: All persons named in the Acknowledgement above have provided written permission to be named.

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Tyson, J., Pedroza, C., Langer, J. et al. Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?. J Perinatol 32, 677–684 (2012). https://doi.org/10.1038/jp.2012.64

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