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Original Investigation
October 23/30, 2018

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age: A Randomized Clinical Trial

Dale L. Phelps, MD1; Kristi L. Watterberg, MD2; Tracy L. Nolen, DrPH3; et al Carol A. Cole, RPh1; C. Michael Cotten, MD, MHS4; William Oh, MD5; Brenda B. Poindexter, MD, MS6,7; Kristin M. Zaterka-Baxter, RN, BSN3; Abhik Das, PhD8; Conra Backstrom Lacy, RN2; Ann Marie Scorsone, MS1; Michele C. Walsh, MD, MS9; Edward F. Bell, MD10; Kathleen A. Kennedy, MD, MPH11; Kurt Schibler, MD6; Gregory M. Sokol, MD7; Matthew M. Laughon, MD, MPH12; Satyanarayana Lakshminrusimha, MD13; William E. Truog, MD14; Meena Garg, MD15; Waldemar A. Carlo, MD16; Abbot R. Laptook, MD5; Krisa P. Van Meurs, MD17; David P. Carlton, MD18; Amanda Graf, MD19; Sara B. DeMauro, MD, MSCE20; Luc P. Brion, MD21; Seetha Shankaran, MD22; Faruk H. Orge, MD23; Richard J. Olson, MD24; Helen Mintz-Hittner, MD25; Michael B. Yang, MD26; Kathryn M. Haider, MD27; David K. Wallace, MD, MPH28; Mina Chung, MD29; Denise Hug, MD30; Irena Tsui, MD31; Martin S. Cogen, MD32; John P. Donahue, MD, PhD33; Michael Gaynon, MD34; Amy K. Hutchinson, MD35; Don L. Bremer, MD36; Graham Quinn, MD, MSCE37; Yu-Guang He, MD38; William R. Lucas Jr, MD39; Timothy W. Winter, DO40; Stephen D. Kicklighter, MD41; Kartik Kumar, MD11; Patricia R. Chess, MD1; Tarah T. Colaizy, MD, MPH10; Anna Marie Hibbs, MD9; Namasivayam Ambalavanan, MD16; Heidi M. Harmon, MD, MS7; Elisabeth C. McGowan, MD5; Rosemary D. Higgins, MD42; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Author Affiliations
  • 1School of Medicine and Dentistry, University of Rochester, Rochester, New York
  • 2Health Sciences Center, University of New Mexico, Albuquerque
  • 3Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
  • 4Department of Pediatrics, Duke University, Durham, North Carolina
  • 5Department of Pediatrics, Women & Infants’ Hospital, Brown University, Providence, Rhode Island
  • 6Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 7Department of Pediatrics, School of Medicine, Indiana University, Indianapolis
  • 8Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland
  • 9Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
  • 10Department of Pediatrics, University of Iowa, Iowa City
  • 11Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center, Houston
  • 12Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel Hill
  • 13Department of Pediatrics, State University of New York, Buffalo
  • 14Department of Pediatrics, Children’s Mercy Hospital and University of Missouri School of Medicine, Kansas City
  • 15Department of Pediatrics, University of California, Los Angeles
  • 16Division of Neonatology, University of Alabama at Birmingham
  • 17Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
  • 18Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia
  • 19Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio
  • 20Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia
  • 21Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
  • 22Department of Pediatrics, Wayne State University, Detroit, Michigan
  • 23Department of Ophthalmology, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
  • 24Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City
  • 25Department of Ophthalmology and Visual Science, McGovern Medical School, University of Texas Health Science Center, Houston
  • 26Department of Ophthalmology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 27Department of Ophthalmology, School of Medicine, Indiana University, Indianapolis
  • 28Department of Pediatrics, Duke University, Durham, North Carolina
  • 29Department of Ophthalmology, School of Medicine and Dentistry, University of Rochester, Rochester, New York
  • 30Department of Ophthalmology, Children’s Mercy Hospital and University of Missouri School of Medicine, Kansas City
  • 31Department of Ophthalmology, University of California, Los Angeles
  • 32Department of Ophthalmology, University of Alabama at Birmingham
  • 33Alpert Medical School, Women & Infants’ Hospital, Brown University, Providence, Rhode Island
  • 34Department of Ophthalmology, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, California
  • 35Department of Ophthalmology, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia
  • 36Department of Ophthalmology, Nationwide Children’s Hospital, Columbus, Ohio
  • 37Department of Ophthalmology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia
  • 38Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas
  • 39Department of Ophthalmology, Wayne State University, Detroit, Michigan
  • 40Division of Ophthalmology, Department of Surgery, Health Sciences Center, University of New Mexico, Albuquerque
  • 41Department of Pediatrics, Division of Neonatology, WakeMed Health and Hospitals, Raleigh, North Carolina
  • 42Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
JAMA. 2018;320(16):1649-1658. doi:10.1001/jama.2018.14996
Key Points

Question  Does administration of myo-inositol to premature infants for up to 10 weeks reduce the incidence of type 1 retinopathy of prematurity?

Findings  In this randomized clinical trial that included 638 premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 retinopathy of prematurity or death compared with placebo (29% vs 21%, respectively).

Meaning  These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Abstract

Importance  Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety.

Objective  To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks’ gestational age.

Design, Setting, and Participants  Randomized clinical trial included 638 infants younger than 28 weeks’ gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group.

Interventions  A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks.

Main Outcomes and Measures  Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP.

Results  Among 638 infants (mean, 26 weeks’ gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).

Conclusions and Relevance  Among premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

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