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Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies

Journal of Perinatology volume 41, pages 502–511 (2021)Cite this article

Subjects

Abstract

Objective

To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia.

Methods

We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, “usual care” arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18–22 months adjusted for severity of HIE, center, and RCT.

Results

Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR: 1.65, 0.86–3.14) and death was 26% vs. 12% (adjusted OR: 2.04, 0.92–4.53), respectively.

Conclusions

PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.

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Acknowledgements

The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Induced Hypothermia trial, Optimizing Cooling trial, and Late Hypothermia trial through cooperative agreements. While NICHD staff did have input into the study design, conduct, analysis, and paper drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. One behalf of the NRN, Drs. AD (DCC Principal Investigator) and Breda Munoz, Ph.D. (DCC Statistician) had full access to all of the data in the study, and with the NRN Center Principal Investigators, take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chairs: Richard A. Polin, M.D., Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011 to present); Michael S. Caplan, M.D., University of Chicago, Pritzker School of Medicine (2006–2011); Alan H. Jobe, M.D. Ph.D., University of Cincinnati (2003–2006). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904)—William Oh, M.D.; Betty R. Vohr, M.D.; Angelita M. Hensman, Ph.D. RNC-NIC; Barbara Alksninis, RNC PNP; Joseph Bliss, M.D. Ph.D.; Carmena Bishop; Robert T. Burke, M.D. MPH; William Cashore, M.D.; Melinda Caskey, M.D.; Nicholas Guerina, M.D. Ph.D.; Hussnain Mirza, M.D.; Katharine Johnson, M.D.; Mary Lenore Keszler, M.D.; Andrea M. Knoll; Theresa M. Leach, MEd CAES; Martha R. Leonard, BA BS; Emilee Little, RN BSN; Elizabeth C. McGowan, M.D.; Ross Sommers, M.D.; Birju A. Shah, M.D. MPH; Bonnie E. Stephens, M.D.; Suzy Ventura; Elisa Vieira, RN BSN; Victoria E. Watson, MS CAS. Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80)—Anna Maria Hibbs, M.D.; Avroy A. Fanaroff, M.D.; Deanne E. Wilson-Costello, M.D.; Nancy S. Newman, RN; Beau Batton, M.D.; Monika Bhola, M.D.; Juliann M. Di Fiore, BSEE; Harriet G. Friedman, MA; Bonnie S. Siner, RN; Elizabeth Smart, MS; Eileen K. Stork, M.D.; Gulgun Yalcinkaya, M.D.; Arlene Zadell, RN. Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284)—William E. Truog, M.D.; Eugenia K. Pallotto, M.D. MSCE; Howard W. Kilbride M.D.; Cheri Gauldin, RN BS CCRC; Anne Holmes RN MSN MBA-HCM CCRC; Kathy Johnson RN, CCRC; Allison Knutson, BSN RNC-NIC. Cincinnati Children’s Hospital Medical Center, University of Cincinnati Medical Center, and Good Samaritan Hospital (U10 HD27853, M01 RR8084, UL1 TR77)—Brenda B. Poindexter, M.D. MS; Kurt Schibler, M.D.; Edward F. Donovan, M.D.; Suhas G. Kallapur, M.D.; Kimberly Yolton, Ph.D.; Cathy Grisby, BSN CCRC; Barbara Alexander, RN; Estelle E. Fischer, MHSA MBA; Teresa L. Gratton, PA; Jody Hessling, MSN RN; Lenora Jackson, CRC; Jennifer Jennings, RN BSN; Kristin Kirker, CRC; Stephanie Merhar, M.D. MS; Holly L. Mincey, MS RN BSN; Greg Muthig, BA; Jean J. Steichen, M.D.; Sandra Wuertz, RN BSN CLC. Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, M01 RR30, UL1 TR1117)—C. Michael Cotten, M.D. MHS; Ronald N. Goldberg, M.D.; Kimberley A. Fisher, Ph.D. FNP-BC IBCLC; Joanne Finkle, RN JD; Ricki F. Goldstein, M.D.; Kathryn E. Gustafson, Ph.D.; William F. Malcolm, M.D.; Patricia L. Ashley, M.D. Ph.D.; Kathy J. Auten, MSHS; Sandra Grimes, RN BSN; Melody B. Lohmeyer, RN MSN; Matthew M. Laughon, M.D. MPH; Carl L. Bose, M.D.; Janice Bernhardt, MS RN; Cindy Clark, RN; Diane D. Warner, M.D. MPH; Janice Wereszcsak, CPNP; Sofia Aliaga, M.D., MPH. Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39, UL1 TR454)—David P. Carlton, M.D.; Barbara J. Stoll, M.D.; Lucky Jain, M.D.; Ellen C. Hale, RN BS CCRC; Yvonne Loggins, RN; Diane I. Bottcher, MSN RN; Shannon E. G. Hamrick, M.D.; Colleen Mackie, BS RT; Maureen Mulligan LaRossa, RN; Ira Adams-Chapman, M.D.; Lynn C. Wineski, RN MS; Sheena L. Carter, Ph.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development—Rosemary D. Higgins, M.D.; Linda L. Wright, M.D.; Stephanie Wilson Archer, MA; Elizabeth M. McClure, MEd. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children at Indiana University Health, and Eskenazi Health (U10 HD27856, M01 RR750, UL1 TR6)—Gregory M. Sokol, M.D.; Brenda B. Poindexter, M.D. MS; James A. Lemons, M.D.; Heidi M. Harmon, M.D. MS; Lu-Ann Papile, M.D.; Diana D. Appel, RN BSN; Jessica Bissey, PsyD HSPP; Lon G. Bohnke, MS; Ann B. Cook, MS; Anna M. Dusick, M.D. (deceased); Susan Gunn, NNP-BC CCRC; Dianne E. Herron, RN CCRC; Abbey C. Hines, PsyD; Darlene Kardatzke, M.D. (deceased); Carolyn Lytle, M.D. MPH; Lucy C. Miller, RN BSN CCRC; Heike M. Minnich, PsyD HSPP; Leslie Richard, RN; Lucy C. Smiley, CCRC; Leslie Dawn Wilson, BSN CCRC. McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital (U10 HD21373, M01 RR2588)—Jon E. Tyson, M.D. MPH; Kathleen A. Kennedy, M.D. MPH; Amir M. Khan, M.D.; Esther G. Akpa, RN BSN; Julie Arldt-McAlister, MSN APRN; Pamela J. Bradt, M.D. MPH; Katrina Burson, RN BSN; Allison G. Dempsey, Ph.D.; Andrea F. Duncan, M.D. MSClinRes; Patricia W. Evans, M.D.; Claudia I. Franco, RNC MSN; Carmen Garcia, RN BSN; Margarita Jimenez, M.D. MPH; Janice John, CPNP; Patrick M. Jones, M.D. MA; M. Layne Lillie, RN BSN; Anna E. Lis, RN BSN; Karen Martin, RN; Sara C. Martin, RN BSN; Georgia E. McDavid, RN; Brenda H. Morris, M.D.; Patricia Ann Orekoya, RN BSN; Claudia Pedroza, Ph.D.; Patti L. Pierce Tate, RCP; Shawna Rodgers, RN, BSN; Saba Khan Siddiki, M.D.; Daniel K. Sperry, RN; Sharon L. Wright, MT (ASCP). Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center (U10 HD68278)—Pablo J. Sánchez, M.D.; Leif D. Nelin, M.D.; Nehal A. Parihk, DO MS; Sudarshan R. Jadcherla, M.D.; Patricia Luzader, RN; Roopali Bapat, M.D.; Thomas Bartman, M.D.; Elizabeth Bonachea, M.D.; Louis G. Chicoine, M.D.; Bronte Clifford; Erin Ferns; Christine A. Fortney, Ph.D. RN; Jennifer Fuller, MS RNC; Ish Gulati, M.D.; Julie Gutentag, BSN; Krista Haines, M.D.; Brandon Hart, M.D.; Michael Hokenson, M.D.; Marissa E. Jones, RN MBA; Sarah McGregor, BSN RNC; Marliese Dion Nist, BSN; Elizabeth Ann Rodgers, BSN; Ruth Seabrook, M.D.; Tiffany Sharp; Edward G. Shepherd, M.D.; Jonathan Slaughter, M.D., MPH; Jodi A. Ulloa, MSN APRN NNP-BC; Jon Wispe, M.D.; Tara Wolfe, BSN; L. Yossef, M.D.; Nahla Zaghoul, M.D. RTI International (U10 HD36790)—Dennis Wallace, Ph.D.; Marie G. Gantz, Ph.D.; Kristin M. Zaterka-Baxter, RN BSN CCRP; Margaret M. Crawford, BS CCRP; Jenna Gabrio, MPH CCRP; Betty K. Hastings; Scott A. McDonald, BS; Jamie E. Newman, Ph.D. MPH; Jeanette O’Donnell Auman, BS; Carolyn M. Petrie Huitema, MS CCRP; James W. Pickett II, BS; W. Kenneth Poole, Ph.D. (deceased); Annie M. VonLehmden, BS. Stanford University and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70, UL1 TR93)—David K. Stevenson, M.D.; Valerie Y. Chock, M.D. MS Epi; Susan R. Hintz, M.D. MS Epi; M. Bethany Ball, BS CCRC; Elizabeth F. Bruno, Ph.D.; Alexis S. Davis, M.D. MS Epi; Maria Elena DeAnda, Ph.D.; Anne M. DeBattista, RN PNP Ph.D.; Lynne C. Huffman, M.D.; Casey E. Krueger, Ph.D.; Melinda S. Proud, RCP; Nicholas H. St. John, Ph.D.; Hali E. Weiss, M.D. Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54)—Ivan D. Frantz III, M.D.; Elisabeth C. McGowan, M.D.; John M. Fiascone, M.D.; Brenda L. MacKinnon, RNC; Ana Brussa, MS OTR/L; Anne Furey, MPH; Juliette C. Madan, M.D. MS; Ellen Nylen, RN BSN; Cecelia Sibley, PT MHA. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32)—Waldemar A. Carlo, M.D.; Myriam Peralta-Carcelen, M.D. MPH; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Vivien A. Phillips, RN BSN; Richard V. Rector, Ph.D.; Sally Whitley, MA OTR-L FAOTA. University of California—Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270)—Uday Devaskar, M.D.; Meena Garg, M.D.; Isabell B. Purdy, Ph.D. CPNP; Teresa Chanlaw, MPH; Rachel Geller, RN BSN. University of California—San Diego Medical Center and Sharp Mary Birch Hospital for Women & Newborns (U10 HD40461)—Neil D. Finer, M.D.; Maynard R. Rasmussen, M.D.; Paul R. Wozniak, M.D.; Wade Rich, BSHS RRT; Kathy Arnell, RNC; Renee Bridge, RN; Clarence Demetrio, RN; Martha G. Fuller, RN MSN; Christopher Henderson, AS CRTT; David Kaegi, M.D. University of Iowa and Mercy Medical Center (U10 HD53109, UL1 TR442)—Edward F. Bell, M.D.; Tarah T. Colaizy, M.D. MPH; Karen J. Johnson, RN BSN; Diane L. Eastman, RN CPNP MA; Michael J. Acarregui, M.D. MBA; Jane E. Brumbaugh, M.D.; Jacky R. Walker, RN; Claire A. Goeke, RN; Jonathan M. Klein, M.D.; Nancy J. Krutzfield, RN MA; Jeffrey L. Segar, M.D.; John M. Dagle, M.D. Ph.D.; Julie B. Lindower, M.D. MPH; Steven J. McElroy, M.D.; Glenda K. Rabe, M.D. MME; Robert D. Roghair, M.D.; Lauritz R. Meyer, M.D.; Dan L. Ellsbury, M.D.; Donia B. Bass, RNC-NIC; Cary R. Murphy, M.D.; Vipinchandra Bhavsar, MB BS. University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587)—Shahnaz Duara, M.D.; Charles R. Bauer, M.D.; Ruth Everett-Thomas, RN MSN. University of New Mexico Health Sciences Center (U10 HD53089, UL1 TR41)—Kristi L. Watterberg, M.D.; Robin K. Ohls, M.D.; Conra Backstrom Lacy, RN; Sandra Sundquist Beauman, MSN RNC; Sandra Brown, BSN; Erika Fernandez, M.D.; Andrea Freeman Duncan, M.D.; Janell Fuller, M.D.; Jean R. Lowe, Ph.D. University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244)—Barbara Schmidt, M.D. MSc; Haresh Kirpalani, MB MSc; Sara B. DeMauro, M.D. MSCE; Kevin C. Dysart, M.D.; Soraya Abbasi, M.D.; Aasma S. Chaudhary, BS RRT; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Judy C. Bernbaum, M.D.; Marsha Gerdes, Ph.D.; Hallam Hurt, M.D. University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (U10 HD68263, UL1 TR42)—Carl D’Angio, M.D.; Ronnie Guillet, M.D. Ph.D.; Dale L. Phelps, M.D.; Nirupama Laroia, M.D.; Gary J. Myers, M.D.; Osman Farooq, M.D.; Stephanie Guilford, BS; Rosemary L. Jensen; Diane Hust, MS RN CS; Linda J. Reubens, RN CCRC; Ann Marie Scorsone, MS CCRC; Karen Wynn, NNP RN; Kelley Yost, Ph.D.; Anne Marie Reynolds, M.D. MPH; Michelle E. Hartley-McAndrew, M.D.; Michael G. Sacilowski, MAT; Holly I.M. Wadkins, MA; Ashley Williams, MS Ed; Joan Merzbach, LMSW; Patrick Conway, MS; Melissa Bowman, MSN; William Zorn, Ph.D.; Julie Babish Johnson, MSW; Emily Kushner, MA; Cait Fallone, MA; Kyle Binion, BS; Constance Orme; Satyan Lakshminrusimha, M.D. University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Myra H. Wyckoff, M.D.; Luc P. Brion, M.D.; Merle Ipson, M.D.; Walid A. Salhab, M.D.; Pablo J. Sánchez, M.D.; Sue Broyles, M.D.; P. Jeannette Burchfield, RN BSN; Lina F. Chalak, M.D. MSCS; Lijun Chen, Ph.D. RN; Janet S. Morgan, RN; Diana M. Vasil, MSN BSN RNC-NIC; Sally S. Adams, MS RN CPNP; Catherine Twell Boatman, MS CIMI; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, MS MA PA-C PsyD; Jackie F. Hickman, RN; Lizette E. Lee, RN; Melissa H. Leps, RN; Linda A. Madden, BSN RN CPNP; Susie Madison, RN; Nancy A. Miller, RN; Emma Ramon, RNC-NIC RN BSN. University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124)—Bradley A. Yoder, M.D.; Roger G. Faix, M.D.; Karen A. Osborne, RN BSN CCRC; Cynthia Spencer, RNC; R. Edison Steele, RN; Mike Steffen, Ph.D.; Karena Strong, RN BSN; Kimberlee Weaver-Lewis, RN BSN; Shawna Baker, RN; Sarah Winter, M.D.; Karie Bird, RN BSN; Jill Burnett, RNC BSN. Wake Forest Baptist Medical Center, Brenner Children’s Hospital, and Forsyth Medical Center (U10 HD40498, M01 RR7122)—T. Michael O’Shea, M.D. MPH; Robert G. Dillard, M.D.; Lisa K. Washburn, M.D.; Nancy J. Peters, RN CCRP. Wayne State University, University of Michigan, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385)—Athina Pappas, M.D.; Beena G. Sood, M.D. MS; Rebecca Bara, RN BSN; Monika Bajaj, M.D.; Kirsten Childs, RN BSN; Lilia C. De Jesus, M.D.; Laura A. Goldston, MA; Mary E. Johnson, RN BSN; Yvette R. Johnson, M.D. MPH; Deborah Kennedy, RN BSN; Geraldine Muran, RN BSN; Bogdan Panaitescu, M.D.; Jeannette E. Prentice, M.D.; Laura Sumner, RN BSN; Kathleen Weingarden, RN BSN; Eunice Hinz Woldt, RN MSN; Melissa February, M.D.; John Barks, M.D.; Mary Christensen, RT; Stephanie A. Wiggins, MS; Martha Carlson, M.D.; Diane F. White, RRT CCRP. Yale-New Haven Children’s Hospital (U10 HD27871, UL1 TR142)—Richard A. Ehrenkranz, M.D. (deceased); Matthew Bizzarro, M.D.; Monica Konstantino, RN BSN; Nancy Close, Ph.D.; Patricia Gettner, RN; JoAnn Poulsen, RN; Elaine Romano, MSN; Janet Taft, RN BSN.

Funding

Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD21364, U10 HD21373, U10 HD21397, U10 HD21385, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 20HD40689, U10 HD53089, U10 HD53109, U10 HD53124, U10 HD53119, U10 HD68244, U10 HD68263, U10 HD68270, U10 HD68278, U10 HD6828) and from the National Institutes of Health (M01 RR44, M01 RR30, M01 RR32, M01 RR39, M01 RR54, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR2588, M01 RR7122, M01 RR8084, M01 RR16587, UL1 TR6, UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR142, UL1 TR442, UL1 TR454, UL1 TR1117).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Wayne State University, Detroit, MI, USA

    Prashant Agarwal, Seetha Shankaran, Girija Natarajan & Sanjay Chawla

  2. Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, RI, USA

    Abbot R. Laptook & Martin Keszler

  3. Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Triangle, NC, USA

    Dhuly Chowdhury

  4. Department of Pediatrics, University of Buffalo Women’s and Children’s Hospital of Buffalo, Buffalo, NY, USA

    Satyan Lakshminrusimha

  5. University of California at Davis, Sacramento, CA, USA

    Satyan Lakshminrusimha

  6. Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, CA, USA

    Sonia Lomeli Bonifacio & Krisa P. Van Meurs

  7. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Roy J. Heyne

  8. Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL, USA

    Namasivayam Ambalavanan

  9. Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, OH, USA

    Michele C. Walsh

  10. Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, MD, USA

    Abhik Das

Authors
  1. Prashant Agarwal
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  2. Seetha Shankaran
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  3. Abbot R. Laptook
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  4. Dhuly Chowdhury
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  5. Satyan Lakshminrusimha
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  6. Sonia Lomeli Bonifacio
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  7. Girija Natarajan
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  8. Sanjay Chawla
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  9. Martin Keszler
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  10. Roy J. Heyne
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  11. Namasivayam Ambalavanan
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  12. Michele C. Walsh
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  13. Abhik Das
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  14. Krisa P. Van Meurs
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for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network

Corresponding author

Correspondence to Prashant Agarwal.

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Members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network are listed in Supplementary Information.

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Agarwal, P., Shankaran, S., Laptook, A.R. et al. Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies. J Perinatol 41, 502–511 (2021). https://doi.org/10.1038/s41372-020-00905-7

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  • DOI: https://doi.org/10.1038/s41372-020-00905-7

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