Effect Of Hydrocortisone Therapy Initiated 7 To 14 Days After Birth On Mortality Or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial
Wes Onland, Filip Cools, André A. Kroon, Karin J. Rademaker, Maruschka P. Merkus, Peter Hendrik Dijk, Henrica L.M. van Straaten, Arjan B te Pas, Thilo Mohns, Els Bruneel, Arno F J Van Heijst, Boris W Kramer, Anne Debeer, Inge A Zonnenberg, Yoann Maréchal, Henry Blom, Katleen Plaskie, Martin Offringa, Anton H. van Kaam
Published 2019 · Medicine
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Importance Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures The primary outcome was a composite of death or BPD assessed at 36 weeks’ postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks’ postmenstrual age. Results Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, −3.6% [95% CI, −12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks’ postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, −8.2% [95% CI, −16.2% to −0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, −4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks’ postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration Netherlands National Trial Register Identifier: NTR2768
This paper references
Pulmonary Effects of Triiodothyronine (T3) and Hydrocortisone (HC) Supplementation in Preterm Infants less than 30 Weeks Gestation: Results of the THORN Trial—Thyroid Hormone Replacement in Neonates
Sumita Biswas (2003)
Circulating neutrophil concentration and respiratory distress in premature infants.
Paula Juliana Ferreira (2000)
Structural and Functional Brain Development After Hydrocortisone Treatment for Neonatal Chronic Lung Disease
Gregory A. Lodygensky (2005)
Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.
Lex W. Doyle (2017)
Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatr
M van der Heide-Jalving (2003)
Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes.
Elizabeth J. Short (2003)
Association of Race/Ethnicity With Very Preterm Neonatal Morbidities
Teresa M. Janevic (2018)
A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants
Tanis R. Fenton (2013)
Early lowdose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial
F Bonsante (2007)
Effects of Higher Versus Lower Dexamethasone Doses on Pulmonary and Neurodevelopmental Sequelae in Preterm Infants at Risk for Chronic Lung Disease: A Meta-analysis
Wes Onland (2008)
Respiratory management of extremely low birth weight infants: survey of neonatal specialists
Sumesh Parat (2016)
Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.
Outi M. Peltoniemi (2005)
Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial
Kristi L. Watterberg (2004)
Home oxygen status and rehospitalisation and primary care requirements of infants with chronic lung disease
Anne Greenough (2002)
Guidelines for Statistical Analysis Plans.
David L. Demets (2017)
Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants.
Henry L. Halliday (2001)
Guidelines on neonatal steroids
HL Halliday (2001)
Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up
Karin J. Rademaker (2007)
Randomized Trials in Vulnerable Populations
Deborah J Cook (2008)
The International Classification of Retinopathy of Prematurity revisited.
Isaac Ben-Sira (2005)
Supporting young adults with hemiplegia: services and costs.
Jennifer K Beecham (2001)
Population-based study of bronchopulmonary dysplasia in very low birth weight infants in Switzerland
Juliane Hentschel (2005)
Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone
Yamini V Virkud (2017)
Pulmonary sequelae and functional limitations in children and adults with bronchopulmonary dysplasia.
Daniel T. Malleske (2018)
Differences in Behavioral Outcome and Motor Development at School Age After Neonatal Treatment for Chronic Lung Disease with Dexamethasone versus Hydrocortisone
Rosa Karemaker (2006)
Neonatologists are using much less dexamethasone
Eric S. Shinwell (2003)
Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children.
Karin J. Rademaker (2007)
Guidelines for statistical analysis plans. JAMA
DL DeMets (2017)
Intractable spastic cerebral palsy in children: a Dutch cost of illness study.
Marjanke A. Hoving (2007)
Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial
Wes Onland (2011)
and the Practice Committee of the ChildNeurology Society
J Neu (2002)
Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk Factors: A Meta-analysis and Meta-regression
E Sabrina Twilhaar (2018)
Population-based risks of mortality and preterm morbidity by gestational age and birth weight
Rebecca J. Baer (2016)
Relative adrenal insufficiency in the preterm and term infant
Elaine Frances Fernandez (2009)
Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants.
Henry L. Halliday (2000)
Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.
Barbara J. Stoll (2015)
Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes.
Nehal A. Parikh (2013)
L Monte (2005)
Cost of Hospitalization for Preterm and Low Birth Weight Infants in the United States
Rebecca B. Russell (2007)
Postnatal corticosteroids for preterm infants--do what we say, not what we do.
Alan H. Jobe (2004)
Open-Label Glucocorticoids Modulate Dexamethasone Trial Results in Preterm Infants
Wes Onland (2010)
Are postnatal steroids ever justified to treat severe bronchopulmonary dysplasia?
Eric C. Eichenwald (2007)
Impact of a Physiologic Definition on Bronchopulmonary Dysplasia Rates
Michele C. Walsh (2004)
Changes in the Use of Postnatal Steroids for Bronchopulmonary Dysplasia in 3 Large Neonatal Networks
Michele C. Walsh (2006)
Risk factors for post-neonatal intensive care unit discharge mortality among extremely low birth weight infants.
Lilia C De Jesus (2012)
超出生体重児に対する早期デキサメサゾン投与の有用性 : National Institute of Child Health and Human Development Neonatal research Network報告 (海外誌掲載論文の和文概要とそれに対するコメント)
Stark Ar (2001)
Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia
Kristi L. Watterberg (2010)
Very low birth weight outcomes of the National Institute of Child health and human development neonatal research
JA Lemons (1995)
Speech and language outcomes of children with bronchopulmonary dysplasia.
Barbara A. Lewis (2002)
Early Dexamethasone—Attempting To Prevent Chronic Lung Disease
Robert A. Sinkin (2000)
A preliminary study into the economic burden of cerebral palsy in China.
Bin Wang (2008)
Finding the Optimal Postnatal Dexamethasone Regimen for Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Systematic Review of Placebo-Controlled Trials
Wes Onland (2009)
Mortality and Neonatal Morbidity Among Infants 501 to 1500 Grams From 2000 to 2009
Jeffrey D. Horbar (2012)
Bronchopulmonary Dysplasia in Very Low Birth Weight Subjects and Lung Function in Late Adolescence
Lex William Doyle (2006)
Lung and Brain Damage in Preterm Newborns
Olaf Dammann (2004)
Leslie A. Parker (1995)
Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.
Kristi L. Watterberg (1999)
Growth and Neurodevelopmental Outcomes After Early Low-Dose Hydrocortisone Treatment in Extremely Low Birth Weight Infants
Kristi L. Watterberg (2007)
Role of neutrophils in lung vascular injury and edema after premature birth in lambs.
David P. Carlton (1997)
Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants.
Ann L. Jefferies (2012)
Evidence-Based Neonatal Unit Practices and Determinants of Postnatal Corticosteroid-Use in Preterm Births below 30 Weeks GA in Europe. A Population-Based Cohort Study
Alexandra Nuytten (2017)
Gender Differences in Respiratory Morbidity and Mortality of Preterm Neonates
Courtney Townsel (2017)
The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs
Keith Barrington (2001)
Safety, Reliability, and Validity of a Physiologic Definition of Bronchopulmonary Dysplasia
Michele C. Walsh (2003)
Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
Laura R. Ment (2002)
Fetal and neonatal mortality risks of multiple births.
Greg R. Alexander (2005)
Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.
Henry L. Halliday (2000)
Serious adverse events in academic critical care research
Deborah J Cook (2008)
Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system.
Elizabeth J. Short (2007)
Effects of Neonatal Corticosteroid Treatment on Hippocampal Synaptic Function
Chiung-Chun Huang (2007)
Bronchopulmonary Dysplasia: Executive Summary of a Workshop
Rosemary D. Higgins (2018)
Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.
Lex W. Doyle (2017)
Chorioamnionitis and neonatal outcome in preterm infants: a clinical overview
Lorenza Pugni (2016)
Long-term pulmonary sequelae of severe bronchopulmonary dysplasia.
S V Jacob (1998)
Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992.
Lex William Doyle (2006)
Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): statistical analysis plan
Wes Onland (2018)
Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes.
Michele C. Walsh (2005)
Preschool healthcare utilisation related to home oxygen status
Anne Greenough (2006)
Practice parameter: Neuroimaging of the neonate Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society
Laura R. Ment (2002)
Risk factors for post - neonatal intensive care unit dischargemortality among extremely low birth weight infants
LC DeJesus (2012)
Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial
Olivier Baud (2016)
Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids
Colm P. Travers (2018)
This paper is referenced by
Long-term effects of postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia: Balancing the risks and benefits.
Jeanie L. Y. Cheong (2019)
The Impact of Postnatal Systemic Steroids on the Growth of Preterm Infants: A Multicenter Cohort Study
Carlos Zozaya (2019)
Bias Attributable to Composite Outcome
Fredi Alexander Diaz-Quijano (2020)
Very low-dose dexamethasone to facilitate extubation of preterm babies at risk of bronchopulmonary dysplasia: the MINIDEX feasibility RCT
Helen Yates (2019)
Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury
Ji Hye Kwon (2019)
Update on Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia.
Marco Filippone (2019)
Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis
Ian Paul Morris (2019)
Aktuelles in der Neonatologie
Mario Ruediger (2019)
Bronchopulmonary dysplasia: how can we improve its outcomes?
Tae-Jung Sung (2019)
Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes
Heidi M. Harmon (2020)
Bernard Thébaud (2019)
Treatment and respiratory support modes for neonates with respiratory distress syndrome
Theodore Dassios (2020)