Extended Caffeine for Apnea in Moderately Preterm Infants
Authors: Waldemar A. Carlo, Eric C. Eichenwald, Benjamin A. Carper, Edward F. Bell, Martin Keszler, Ravi M. Patel, Pablo J. Sánchez, Ronald N. Goldberg, Carl T. D’Angio, Krisa P. Van Meurs, Anna Maria Hibbs, Namasivayam Ambalavanan, Shirley S. Cosby, Nancy S. Newman, Betty R. Vohr, Michele C. Walsh, Abhik Das, Robin K. Ohls, Janell Fuller, Matthew A. Rysavy, Sarvin Ghavam, Luc P. Brion, Karen M. Puopolo, Ryan Moore, Michelle L. Baack, Tarah T. Colaizy, Mariana Baserga, Ahmed F. Osman, Stephanie L. Merhar, Brenda B. Poindexter, Sara B. DeMauro, Vasanth Kumar, C. Michael Cotten, Rachel L. Benz, Cindie L. Buie, Katie M. Foshee, Samuel J. Gentle, Tara E. McNair, Lee A. Merin, Sharon E. Owen, Ariel A. Salas, Vivek S. Shukla, Colm P. Travers, Sandra M. Turner, Pren Fort, Angelita M. Hensman, Abbot R. Laptook, Kim Porras, Lucille St. Pierre, Elisa Vieira, Satyan Lakshminrusimha, Emily Li, Anne Marie Reynolds, Kelsey Voelker, Deanne E. Wilson-Costello, Arlene Zadell, Juanita Dudley, Amy Graber-Pels, Cathy Grisby, Jae Kim, Kristin Kirker, Greg Muthig, Lisa Radcliff, Cynthia Reid, David Russell, Kurt Schibler, Julia Thompson, Sandra Wuertz, Richard A. Polin, Natalie Dellavalle, Joanne Duran, Frances Eubanks, Sonia Gonzales, Michelle Harrod, Mina Kim, Miosotis Mejia, Diana M. Vasil, Myra H. Wyckoff, Patricia L. Ashley, Kimberley A. Fisher, Deesha Mago-Shah, Joanne Probst, Mollie Warren, Diane I. Bottcher, David P. Carlton, Salathiel Kendrick-Allwood, Judith Laursen, Yvonne C. Loggins, Colleen Mackie, Irma Seabrook, Gabriela Dominguez, Donna J. Hall, Amir M. Khan, Apoorva Mahatme, Karen Martin, Ilse Reyna, Matthew A. Rysavy, Emily K. Stephens, Barbara J. Stoll, Jon E. Tyson, Jaleesa Wade, Michelle White, Brenda J. Coulter, Claire A. Goeke, Karen J. Johnson, Mendi L. Schmelzel, Bailey M. Schrimper, Jacky R. Walker, Lisa Gaetano, Nancy Batterson, Hallie Baugher, Demi R. Beckford, Kristin L. Benninger, Cara Boyle, Chelsea Cobe, Brittany DeSantis, Eduardo Finol Mark, Sudarshan R. Jadcherla, Jordan Knox, Patricia Luzader, Laura Marzec, Jacqueline McCool, Bethany Miller, Tanvi Naik, Leif D. Nelin, Theresa Pennington, Jessica Purnell, Joanie Randle, Megan Resetar, Jessica Schiering, Himangini Singh Dixit, Jonathan L. Slaughter, Kristi L. Small, Melanie Stein, Rox Ann Sullivan, Kyrstin Warnimont, Eli Zettler, Andrew A. Bremer, Stephanie Wilson Archer, Soraya Abbasi, Lauren Booth, Christine Catts, Aimee Cunningham, Sara B. DeMauro, Megan A. Dhawan, Mary Catherine Gambacorta, Sarvin Ghavam, Toni Mancini, Karen M. Puopolo, Jonathan M. Snyder, Elizabeth Boylin, Ronnie Guillet, Rachel Jones, Jennifer Kachelmeyer, Alison Kent, Kimberly G. McKee, Melissa Moreland, Ann Marie Scorsone, David Leblond, Amanda Lewis, Kimberly L. McMillian, Brae McVoy, Jeanette O’Donnell Auman, Carolyn M. Petrie Huitema, Kristin M. Zaterka-Baxter, Megan Broadbent, Chelsey Elenkiwich, Megan M. Henning, Laurie A. Richards, Sarah Van Muyden, Marian M. Adams, Dona Bahmani, M. Bethany Ball, Valerie Y. Chock, Alexis S. Davis, Beth A. Earhart, Lynne C. Huffman, Karen K. Morris, Melinda S. Proud, Barbara P. Recine, Elizabeth N. Reichert, Lilia Rutkowska, David K. Stevenson, Heather L. Taylor, Hali E. Weiss, R. Jordan Williams, Janice Bernhardt, Carl L. Bose, Gennie Bose, Matthew Maxwell Laughon, Jennifer Talbert, John D. Wright, Conra Backstrom Lacy, Elizabeth Kuan, Mary Ruffner Hanson, Sandra Sundquist Beauman, Lisa M. Bell, Dawn Bentley, Susan Christensen, Laura Cole Bledsoe, Kathleen Coleman, Brandy Davis, Rachyl M. Davis, Jennifer O. Elmont, Roger G. Faix, Barbara L. Francom, Erick B. Gerday, Diana Grant, Susan E. Johnson, Jamie Jordan, Manndi C. Loertscher, Trisha Marchant, Hena G. Mickelsen, Stephen D. Minton, D. Melody Parry, Brandy J. Petersen, Carrie A. Rau, Brixen A. Reich, Blake Scullin, Mark J. Sheffield, Susie Solosth Moody, Katherine Tice, Kimberlee Weaver-Lewis, Kathryn D. Woodbury, Bradley A. Yoder, Alexandra Bentley, Laura Edwards, Stephen D. Kicklighter, Ginger Rhodes-Ryan, Donna White
Journal: JAMA (2025)

Hospitalization of moderately preterm infants may be prolonged while waiting for apnea of prematurity to resolve after discontinuing caffeine. To evaluate whether extending caffeine treatment reduces the duration of hospitalization. From February 2019 to December 2022, this randomized clinical trial in 29 US hospitals enrolled infants born at 29 to 33 weeks' gestation who at 33 to 35 weeks' postmenstrual age were receiving caffeine treatment with plans to discontinue it plus receiving full feeds (≥120 mL/kg/d). Follow-up was completed on March 20, 2023. Infants were randomized to oral caffeine citrate (10 mg/kg/d) or placebo until 28 days after discharge. The primary outcome was days to discharge after randomization. Secondary outcomes included days to physiological maturity (apnea free for 5 consecutive days, receiving full oral feeds, and out of the incubator for at least 48 hours), postmenstrual age at discharge, all-cause hospital readmissions, all-cause sick and emergency department visits, safety outcomes, and death. A total of 827 infants (median gestational age, 31 weeks; 414 female [51%]) were randomized (416, caffeine; 411, placebo) out of the 878 planned before reaching the prespecified futility threshold. Days of hospitalization after randomization did not differ between groups (18.0 days [IQR, 10 to 30 days] for caffeine vs 16.5 [IQR, 10 to 27 days] for placebo; adjusted median difference, 0 days [95% CI, -1.7 to 1.7 days]), nor did days to physiological maturity differ (14.0 vs 15.0 days, adjusted median difference, -1 day [95% CI, -2.4 to 0.4 days]). Infants receiving caffeine were apnea free sooner (6.0 vs 10.0 days; adjusted median difference, -2.7 days [95% CI, -3.4 to -2.0 days ]) but had similar days to full oral feeding (7.5 vs 6.0 days, adjusted median difference, 0 days [95% CI, -0.1 to 0.1]). Rates of readmissions and sick visits did not differ between groups. There was no statistically significant difference in adverse events between the 2 groups. In moderately preterm infants, continuation of caffeine treatment compared with placebo did not shorten hospitalization. ClinicalTrials.gov Identifier: NCT03340727.