Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial
Authors: Gentle Samuel J. , Rysavy Matthew A. , Li Lei , Laughon Matthew M. , Patel Ravi M. , Jensen Erik A. , Hintz Susan , Ambalavanan Namasivayam , Carlo Waldemar A. , Watterberg Kristi ,   National Institute of Child Health and Human Development Neonatal Research Network, Laptook Abbot R , Keszler Martin , Vohr Betty R , Hensman Angelita M , Vieira Elisa , St. Pierre Lucille , Burke Robert T , Alksinis Barbara , Caskey Melinda , Hoffman Laurie , Johnson Katharine , Keszler Mary L , Knoll Andrea , Leach Teresa M , Little Emily , McGowan Elisabeth C , Stephens Bonnie E , Watson Victoria E , Hibbs Anna Maria , Walsh Michele C , Wilson-Costello Deanne E , Newman Nancy S , Bhola Monika , Payne Allison H , Siner Bonnie S , Yalcinkaya Gulgun , Truog William E , Kilbride Howard W , Gauldin Cheri , Pallotto Eugenia K , Holmes Anne , Johnson Kathy , Scott Allison , Poindexter Brenda B , Schibler Kurt , Merhar Stephanie , Yolton Kimberly , Grisby Cathy , Beiersdorfer Traci , Cahill Tanya E , Dudley Juanita , Gratton Teresa L , Kirker Kristin , Thompson Julia , Wuertz Sandra , Polin Richard A , Cotton Michael , Goldberg Ronald N , Malcolm William F , Goldstein Ricki F , Finkle Joanne , Ashley Patricia L , Fisher Kimberley A , Gustafson Kathryn E , Mago-Shah Deesha , Warren Mollie , Bose Carl L , Bernhardt Janice , Bose Gennie , Wereszczak Janice , Warner Diane , Clark Cindy , Kicklighter Stephen D , Bentley Alexandra , Edwards Laura , Rhodes-Ryan Ginger , White Donna , Carlton David P , Stoll Barbara J , Hale Ellen C , Loggins Yvonne , Bottcher Diane , Carter Sheena L , Kendrick-Allywood Salathiel , Mulligan LaRossa Maureen , Mackie Colleen , Smikle Gloria , Comerford Lynn C , Laursen Judith , Sanders Amy , Maitre Nathalie L , Adams-Chapman Ira , Bremer Andrew A , Wilson Archer Stephanie , Higgins Rosemary D , Tyson Jon E , Khan Amir M , Kennedy Kathleen A , Mosquera Ricardo A , Duncan Andrea F , McDavid Georgia E , Alaniz Nora , Allain Elizabeth , Arldt-McAlister Julie , Sana Boral Debasree , Burson Katrina , Dempsey Allison G , Eason Elizabeth , Evans Patricia W , Garcia Carmen , Green Charles , Hall Donna J , Jiminez Margarita , John Janice , Jones Patrick M , Lillie M. Layne , Martin Karen , Martin Sara C , Mason Carrie M , McKee Shannon L , Poe Michelle , Rennie Kimberly , Rodgers Shawna L , Siddiki Saba Khan , Sperry Daniel , Stephens Emily K , Pierce Tate Patti L , Wright Sharon L , Sanchez Pablo J , Nelin Leif D , Jadcherla Sudarshan R , Slaughter Jonathan L , Luzader Patricia W , Burkhardt Stephanie , Carey Helen , Chao Michelle , Clark Erna , Fearns Erin , Fortney Christine A , Fowler Aubrey , Grothause Jennifer , Gutentag Julie , Hague Cole , McCool Jacqueline , Nelin Mary Ann , Park Courtney , Pietruszewski Lindsay , Purnell Jessica , Shadd Julie , Small Kristi , Stein Melanie , Sullivan Margaret , Sullivan Rox Ann , Timan Christopher J , Yeates Keith O , Yoseff-Salameh Lina , Keim Sarah A , Newton Julia , Levengood Katelyn , Batterson Nancy , Rice Courtney , Moallem Mohannad , Harmon Heidi M , Das Abhik , Wallace Dennis , Banna Carla M , Gantz Marie G , O'Donnell Auman Jeanette , Crawford Margaret M , Gabrio Jenna , Leblond David , Newman Jamie E , Petrie Huitema Carolyn M , vonLehmden Annie , Zaterka-Baxter Kristin M , Li Lei , Van Meurs Krisa P , Stevenson David K , Chock Valerie Y , Ball M. Bethany , Bentley Barbara , Chitkara Ritu , Davis Alexis S , DeAnda Maria Elena , DeBattista Anne M , Earhart Beth , Huffman Lynne C , Krueger Casey E , Lucash Ryan E , Proud Melinda S , Hitchner Reichert Elizabeth N , Sivakumar Dharshi , Taylor Heather , Weiss Hali E , Peralta-Carcelen Myriam , Collins Monica V , Cosby Shirley S , Biasini Fred J , Domnanovich Kristy A , McNair Tara E , Phillips Vivien A , Whitley Sally , York Chapman Sheree , Devaskar Uday , Chanlaw Teresa , Geller Rachel , Garg Meena , Purdy Isabell B , Bell Edward F , Colaizy Tarah T , Widness John A , Brumbaugh Jane E , Johnson Karen J , Walker Jacky R , Goeke Claire A , Schmelzel Mendi L , Eastman Diane L , Baack Michelle L , Meyer Lauritz R , Hogden Laurie A , Henning Megan M , Elenkiwich Chelsey , Broadbent Megan , Van Muyden Sarah , Ellsbury Dan L , Campbell Donia B , Tud Tracy L , Fuller Janell , Beauman Sundquist , Backstrom Lacy Conra , Ruffner Hanson Mary , Hartenberger Carol , Kuan Elizabeth , Lowe Sandra Jean R. , Sokol Gregory M , Papile Lu Ann , Harmon Heidi , Hines Abbey C , Lytle Carolyn , Herron Dianne E , Gunn Susan , Smiley Lucy , Dawn Wilson Leslie , DeMauro Sara B , Schmidt Barbara , Eichenwald Eric C , Kirpalani Haresh , Abbasi Sorava , Mancini Toni , Chaudhary Aasma S , Cucinotta Dara M , Bernbaum Judy C , Freeman Duncan Andrea , Dysart Kevin , Gerdes Marsha , Hurt Hallam , Snyder Jonathan , Ziolkowski Kristina , D'Angio Carl T , Guillet Ronnie , Myers Gary J , Binion Kyle , Chess Patricia R , Fallone Caitlin , Farooq Osman , Kent Alison , Maffett Dee , Merzbach Joan , Orme Constance , Sacilowski Michael G , Sabaratnam Premini , Scorsone Ann Marie , Wadkins Holly I M , Wynn Karen , Yost Kelley , Reynolds Anne Marie , Lakshminrusimha Satyan , Chandrasekharan Praveen , Guilford Stephanie , Hartley-McAndrews Michelle E , Williams Ashley , Zorn William , Li Emily , Donato Jennifer , McKee Kimberly G , Coleman Kelly R , Bean Stephen A , Coleman Carol A , Horihan Cassandra A , Wyckoff Myra H , Brion Luc P , Heyne Roy J , Vasil Diana M , Adams Sally S , Chen Liiun , De Leon Maria M , Eubanks Frances , Guzman Alicia , Heyne Elizabeth , Lee Lizette E , Madden Linda A , McDougald E Rebecca , Pavageau Lara , Sepulveda Pollieanna , Twell Boatman Cathy , Tolentino-Plata Kristine , Vera Azucena , Waterbury Jillian , Yoder Bradley A , Ohls Robin K , Baserga Mariana , Winter Sarah , Minton Stephen D , Sheffield Mark J , Rau Carrie A , Baker Shawna , Burnett Jill , Christensen Susan , Cole Bledsoe Laura , Cunningham Sean , Davis Brandy , Elmont Jennifer O , Hall Becky , Loertscher Manndi C , Marchant Trisha , Maxon Earl , McGrath Kandace M , Mickelsen Hena G , Morshedzadeh Galina , Parry D Melody , Reich Brixen A , Schaefer Susan T , Stout Kelly , Stuart Ashley L , Weaver-Lewis Kimberlee , Woodbury Kathryn D , Shankaran Seetha , Chawla Sanjay , Natarajan Girija , Sood Beena G , Bara Rebecca , Agarwal Prashant , Bajaj Monika , Childs Kirsten , February Melissa , Goldston Laura , Johnson Mary E , Panaitescu Bogdan , Hinz Woldt Eunice , Barks John , Carlson Martha , Christensen Mary K , White Diane F , Wiggins Stephanie A 
Published: May 2023

Importance

Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.

Objective

To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.

Design, Setting, and Participants

This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023.

Intervention

Infants were randomized to 10 days of hydrocortisone or placebo treatment.

Main Outcomes and Measures

Infants’ baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up.

Results

Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4.

Conclusions and Relevance

In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death.

Trial Registration

ClinicalTrials.gov Identifier: NCT01353313