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

Dale L. Phelps, Kristi L. Watterberg, Tracy L. Nolen, Carol A. Cole, C. Michael Cotten, William Oh, Brenda B. Poindexter, Kristin M. Zaterka-Baxter, Abhik Das, Conra Backstrom Lacy, Ann Marie Scorsone, Michele C. Walsh, Edward F. Bell, Kathleen A. Kennedy, Kurt Schibler, Gregory M. Sokol, Matthew M. Laughon, Satyanarayana Lakshminrusimha, William E. Truog, Meena GargWaldemar A. Carlo, Abbot R. Laptook, Krisa P. Van Meurs, David P. Carlton, Amanda Graf, Sara B. Demauro, Luc P. Brion, Seetha Shankaran, Faruk H. Orge, Richard J. Olson, Helen Mintz-Hittner, Michael B. Yang, Kathryn M. Haider, David K. Wallace, Mina Chung, Denise Hug, Irena Tsui, Martin S. Cogen, John P. Donahue, Michael Gaynon, Amy K. Hutchinson, Don L. Bremer, Graham Quinn, Yu Guang He, William R. Lucas, Timothy W. Winter, Stephen D. Kicklighter, Kartik Kumar, Patricia R. Chess, Tarah T. Colaizy, Anna Marie Hibbs, Namasivayam Ambalavanan, Heidi M. Harmon, Elisabeth C. McGowan, Rosemary D. Higgins

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1649-1658
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume320
Issue number16
DOIs
StatePublished - Oct 23 2018
Externally publishedYes

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Retinopathy of Prematurity
Inositol
Premature Infants
Gestational Age
Randomized Controlled Trials
Placebos
Outcome Assessment (Health Care)
Hemorrhage
Neonatal Intensive Care
Necrotizing Enterocolitis
Hypotension
Cause of Death
Perfusion
Safety
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity among Preterm Infants <28 Weeks' Gestational Age : A Randomized Clinical Trial. / Phelps, Dale L.; Watterberg, Kristi L.; Nolen, Tracy L.; Cole, Carol A.; Cotten, C. Michael; Oh, William; Poindexter, Brenda B.; Zaterka-Baxter, Kristin M.; Das, Abhik; Lacy, Conra Backstrom; Scorsone, Ann Marie; Walsh, Michele C.; Bell, Edward F.; Kennedy, Kathleen A.; Schibler, Kurt; Sokol, Gregory M.; Laughon, Matthew M.; Lakshminrusimha, Satyanarayana; Truog, William E.; Garg, Meena; Carlo, Waldemar A.; Laptook, Abbot R.; Van Meurs, Krisa P.; Carlton, David P.; Graf, Amanda; Demauro, Sara B.; Brion, Luc P.; Shankaran, Seetha; Orge, Faruk H.; Olson, Richard J.; Mintz-Hittner, Helen; Yang, Michael B.; Haider, Kathryn M.; Wallace, David K.; Chung, Mina; Hug, Denise; Tsui, Irena; Cogen, Martin S.; Donahue, John P.; Gaynon, Michael; Hutchinson, Amy K.; Bremer, Don L.; Quinn, Graham; He, Yu Guang; Lucas, William R.; Winter, Timothy W.; Kicklighter, Stephen D.; Kumar, Kartik; Chess, Patricia R.; Colaizy, Tarah T.; Hibbs, Anna Marie; Ambalavanan, Namasivayam; Harmon, Heidi M.; McGowan, Elisabeth C.; Higgins, Rosemary D.

In: JAMA - Journal of the American Medical Association, Vol. 320, No. 16, 23.10.2018, p. 1649-1658.

Research output: Contribution to journalArticle

Phelps, DL, Watterberg, KL, Nolen, TL, Cole, CA, Cotten, CM, Oh, W, Poindexter, BB, Zaterka-Baxter, KM, Das, A, Lacy, CB, Scorsone, AM, Walsh, MC, Bell, EF, Kennedy, KA, Schibler, K, Sokol, GM, Laughon, MM, Lakshminrusimha, S, Truog, WE, Garg, M, Carlo, WA, Laptook, AR, Van Meurs, KP, Carlton, DP, Graf, A, Demauro, SB, Brion, LP, Shankaran, S, Orge, FH, Olson, RJ, Mintz-Hittner, H, Yang, MB, Haider, KM, Wallace, DK, Chung, M, Hug, D, Tsui, I, Cogen, MS, Donahue, JP, Gaynon, M, Hutchinson, AK, Bremer, DL, Quinn, G, He, YG, Lucas, WR, Winter, TW, Kicklighter, SD, Kumar, K, Chess, PR, Colaizy, TT, Hibbs, AM, Ambalavanan, N, Harmon, HM, McGowan, EC & Higgins, RD 2018, 'Effects of Myo-inositol on Type 1 Retinopathy of Prematurity among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 320, no. 16, pp. 1649-1658. https://doi.org/10.1001/jama.2018.14996
Phelps, Dale L. ; Watterberg, Kristi L. ; Nolen, Tracy L. ; Cole, Carol A. ; Cotten, C. Michael ; Oh, William ; Poindexter, Brenda B. ; Zaterka-Baxter, Kristin M. ; Das, Abhik ; Lacy, Conra Backstrom ; Scorsone, Ann Marie ; Walsh, Michele C. ; Bell, Edward F. ; Kennedy, Kathleen A. ; Schibler, Kurt ; Sokol, Gregory M. ; Laughon, Matthew M. ; Lakshminrusimha, Satyanarayana ; Truog, William E. ; Garg, Meena ; Carlo, Waldemar A. ; Laptook, Abbot R. ; Van Meurs, Krisa P. ; Carlton, David P. ; Graf, Amanda ; Demauro, Sara B. ; Brion, Luc P. ; Shankaran, Seetha ; Orge, Faruk H. ; Olson, Richard J. ; Mintz-Hittner, Helen ; Yang, Michael B. ; Haider, Kathryn M. ; Wallace, David K. ; Chung, Mina ; Hug, Denise ; Tsui, Irena ; Cogen, Martin S. ; Donahue, John P. ; Gaynon, Michael ; Hutchinson, Amy K. ; Bremer, Don L. ; Quinn, Graham ; He, Yu Guang ; Lucas, William R. ; Winter, Timothy W. ; Kicklighter, Stephen D. ; Kumar, Kartik ; Chess, Patricia R. ; Colaizy, Tarah T. ; Hibbs, Anna Marie ; Ambalavanan, Namasivayam ; Harmon, Heidi M. ; McGowan, Elisabeth C. ; Higgins, Rosemary D. / Effects of Myo-inositol on Type 1 Retinopathy of Prematurity among Preterm Infants <28 Weeks' Gestational Age : A Randomized Clinical Trial. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 320, No. 16. pp. 1649-1658.
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title = "Effects of Myo-inositol on Type 1 Retinopathy of Prematurity among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial",
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.",
author = "Phelps, {Dale L.} and Watterberg, {Kristi L.} and Nolen, {Tracy L.} and Cole, {Carol A.} and Cotten, {C. Michael} and William Oh and Poindexter, {Brenda B.} and Zaterka-Baxter, {Kristin M.} and Abhik Das and Lacy, {Conra Backstrom} and Scorsone, {Ann Marie} and Walsh, {Michele C.} and Bell, {Edward F.} and Kennedy, {Kathleen A.} and Kurt Schibler and Sokol, {Gregory M.} and Laughon, {Matthew M.} and Satyanarayana Lakshminrusimha and Truog, {William E.} and Meena Garg and Carlo, {Waldemar A.} and Laptook, {Abbot R.} and {Van Meurs}, {Krisa P.} and Carlton, {David P.} and Amanda Graf and Demauro, {Sara B.} and Brion, {Luc P.} and Seetha Shankaran and Orge, {Faruk H.} and Olson, {Richard J.} and Helen Mintz-Hittner and Yang, {Michael B.} and Haider, {Kathryn M.} and Wallace, {David K.} and Mina Chung and Denise Hug and Irena Tsui and Cogen, {Martin S.} and Donahue, {John P.} and Michael Gaynon and Hutchinson, {Amy K.} and Bremer, {Don L.} and Graham Quinn and He, {Yu Guang} and Lucas, {William R.} and Winter, {Timothy W.} and Kicklighter, {Stephen D.} and Kartik Kumar and Chess, {Patricia R.} and Colaizy, {Tarah T.} and Hibbs, {Anna Marie} and Namasivayam Ambalavanan and Harmon, {Heidi M.} and McGowan, {Elisabeth C.} and Higgins, {Rosemary D.}",
year = "2018",
month = "10",
day = "23",
doi = "10.1001/jama.2018.14996",
language = "English (US)",
volume = "320",
pages = "1649--1658",
journal = "JAMA - Journal of the American Medical Association",
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TY - JOUR

T1 - Effects of Myo-inositol on Type 1 Retinopathy of Prematurity among Preterm Infants <28 Weeks' Gestational Age

T2 - A Randomized Clinical Trial

AU - Phelps, Dale L.

AU - Watterberg, Kristi L.

AU - Nolen, Tracy L.

AU - Cole, Carol A.

AU - Cotten, C. Michael

AU - Oh, William

AU - Poindexter, Brenda B.

AU - Zaterka-Baxter, Kristin M.

AU - Das, Abhik

AU - Lacy, Conra Backstrom

AU - Scorsone, Ann Marie

AU - Walsh, Michele C.

AU - Bell, Edward F.

AU - Kennedy, Kathleen A.

AU - Schibler, Kurt

AU - Sokol, Gregory M.

AU - Laughon, Matthew M.

AU - Lakshminrusimha, Satyanarayana

AU - Truog, William E.

AU - Garg, Meena

AU - Carlo, Waldemar A.

AU - Laptook, Abbot R.

AU - Van Meurs, Krisa P.

AU - Carlton, David P.

AU - Graf, Amanda

AU - Demauro, Sara B.

AU - Brion, Luc P.

AU - Shankaran, Seetha

AU - Orge, Faruk H.

AU - Olson, Richard J.

AU - Mintz-Hittner, Helen

AU - Yang, Michael B.

AU - Haider, Kathryn M.

AU - Wallace, David K.

AU - Chung, Mina

AU - Hug, Denise

AU - Tsui, Irena

AU - Cogen, Martin S.

AU - Donahue, John P.

AU - Gaynon, Michael

AU - Hutchinson, Amy K.

AU - Bremer, Don L.

AU - Quinn, Graham

AU - He, Yu Guang

AU - Lucas, William R.

AU - Winter, Timothy W.

AU - Kicklighter, Stephen D.

AU - Kumar, Kartik

AU - Chess, Patricia R.

AU - Colaizy, Tarah T.

AU - Hibbs, Anna Marie

AU - Ambalavanan, Namasivayam

AU - Harmon, Heidi M.

AU - McGowan, Elisabeth C.

AU - Higgins, Rosemary D.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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.

AB - 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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U2 - 10.1001/jama.2018.14996

DO - 10.1001/jama.2018.14996

M3 - Article

C2 - 30357297

AN - SCOPUS:85055461939

VL - 320

SP - 1649

EP - 1658

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 16

ER -