Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g

Jane E Brumbaugh; Nellie I Hansen; Edward F Bell; Amaanti Sridhar; Waldemar A Carlo; Susan R Hintz; Betty R Vohr; Tarah T Colaizy; Andrea F Duncan; Myra H Wyckoff; Michelle L Baack; Matthew A Rysavy; Sara B DeMauro; Barbara J Stoll; Abhik Das; Rosemary D Higgins

doi:10.1001/jamapediatrics.2019.0180

. 2019 Mar 25;173(5):434–445. doi: 10.1001/jamapediatrics.2019.0180

Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g

Jane E Brumbaugh ¹, Nellie I Hansen ², Edward F Bell ^3,^✉, Amaanti Sridhar ², Waldemar A Carlo ⁴, Susan R Hintz ⁵, Betty R Vohr ⁶, Tarah T Colaizy ³, Andrea F Duncan ⁷, Myra H Wyckoff ⁸, Michelle L Baack ⁹, Matthew A Rysavy ³, Sara B DeMauro ¹⁰, Barbara J Stoll ⁷, Abhik Das ¹¹, Rosemary D Higgins ¹², for the National Institute of Child Health and Human Development Neonatal Research Network

¹Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota

²Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina

³Department of Pediatrics, University of Iowa, Iowa City

⁴Department of Pediatrics, University of Alabama at Birmingham

⁵Department of Pediatrics, Stanford University, Palo Alto, California

⁶Department of Pediatrics, Brown University, Providence, Rhode Island

⁷Department of Pediatrics, University of Texas Health Science Center at Houston

⁸Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas

⁹Children’s Health Research Center, Sanford Research, Sioux Falls, South Dakota

¹⁰Department of Pediatrics, University of Pennsylvania, Philadelphia

¹¹Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland

¹²Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland

Group Information: Members of the National Institute of Child Health and Human Development Neonatal Research Network appear at the end of the article.

Accepted for Publication: December 28, 2018.

^✉

Corresponding Author: Edward F. Bell, MD, Department of Pediatrics, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242 (edward-bell@uiowa.edu).

Published Online: March 25, 2019. doi:10.1001/jamapediatrics.2019.0180

Author Contributions: Mss Hansen and Sridhar had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.

Study concept and design: Brumbaugh, Bell, Carlo, Colaizy, Higgins.

Acquisition, analysis, or interpretation of data: Brumbaugh, Hansen, Bell, Sridhar, Carlo, Hintz, Vohr, Duncan, Wyckoff, Baack, Rysavy, DeMauro, Stoll, Das.

Drafting of the manuscript: Brumbaugh, Bell, Sridhar.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hansen, Sridhar, Das.

Obtained funding: Bell, Carlo.

Administrative, technical, or material support: Hintz, Duncan, Wyckoff, Baack, Higgins.

Study supervision: Brumbaugh, Bell, Wyckoff, Higgins.

Conflict of Interest Disclosures: Mss Hansen and Sridhar have received grants from the National Institute of Child Health and Human Development to their institution. Drs Bell, Duncan, and Das have received grants from the National Institutes of Health. Dr Carlo serves on the Mednax board of directors. Dr Vohr has received grants from the National Institute of Child Health and Human Development Neonatal Research Network and Health Resources and Services Administration as well as royalties from UpToDate. Dr Baack has received grants and salary support from the National Institute of Child Health and Human Development. No other disclosures were reported.

Funding/Support: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network generic database and follow-up studies through cooperative agreements.

Role of the Funder/Sponsor: Dr Higgins, a National Institute of Child Health and Human Development employee, had input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Data collected at participating sites of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study.

Group Information: The following investigators, in addition to those listed in the byline, participated in this study: Neonatal Research Network Steering Committee: Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, New York, New York (2011-present); and Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine, Chicago, Illinois (2006-2011); Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island (grant UG1 HD27904): Abbot R. Laptook, MD; Martin Keszler, MD; Angelita M. Hensman, MS, RNC-NIC; Barbara Alksninis, RNC, PNP; Carmena Bishop; Robert T. Burke, MD, MPH; Melinda Caskey, MD; Laurie Hoffman, MD; Katharine Johnson, MD; Mary Lenore Keszler, MD; Teresa M. Leach, MEd, CAES; Elisabeth C. McGowan, MD; Bonnie E. Stephens, MD; Kristin Basso, MaT, RN; Elisa Vieira, BSN, RN; Emily Little, BSN, RN; Lucille St. Pierre, BS; and Victoria E. Watson, MS, CAS; Case Western Reserve University, Rainbow Babies, and Children’s Hospital (grant UG1 HD21364): Michele C. Walsh, MD, MS; Anna Maria Hibbs, MD, MSCE; Nancy S. Newman, RN; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; Monika Bhola, MD; and Gulgun Yalcinkaya, MD; Children’s Mercy Hospital (grant UG1 HD68284): William E. Truog, MD; Eugenia K. Pallotto, MD, MSCE; Howard W. Kilbride, MD; Cheri Gauldin, RN, BS, CCRC; Anne Holmes, RN, MSN, MBA-HCM, CCRC; Kathy Johnson, RN, CCRC; Allison Scott, RNC-NIC, BSN, CCRC; Prabhu S. Parimi, MD; and Lisa Gaetano, RN, MSN; Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (grants UG1 HD27853 and UL1 TR77): Brenda B. Poindexter, MD, MS; Kurt Schibler, MD; Suhas G. Kallapur, MD; Kimberly Yolton, PhD; Barbara Alexander, RN; Teresa L. Gratton, PA; Cathy Grisby, BSN, CCRC; Kristin Kirker, CRC; Lenora D. Jackson, CRC; Jean J. Steichen, MD; and Sandra Wuertz, RN, BSN, CLC; Duke University School of Medicine, University Hospital, University of North Carolina, Duke Regional Hospital, and WakeMed Health and Hospitals (grants UG1 HD40492 and UL1 TR1117): C. Michael Cotten, MD, MHS; Ronald N. Goldberg, MD; Ricki F. Goldstein, MD; William F. Malcolm, MD; Patricia L. Ashley, MD, PhD; Joanne Finkle, RN, JD; Kimberley A. Fisher, PhD, FNP-BC, IBCLC; Sandra Grimes, RN, BSN; Kathryn E. Gustafson, PhD; Melody B. Lohmeyer, RN, MSN; Matthew M. Laughon, MD, MPH; Carl L. Bose, MD; Janice Bernhardt, MS, RN; Gennie Bose, RN; Janice Wereszczak, CPNP-AC/PC; Stephen D. Kicklighter, MD; and Ginger Rhodes-Ryan, ARNP, MSN, NNP-BC; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (grants UG1 HD27851 and UL1 TR454): David P. Carlton, MD; Ira Adams-Chapman, MD; Ellen C. Hale, RN, BS, CCRC; Yvonne Loggins, RN; Diane Bottcher, RN; Sheena L. Carter, PhD; Salathiel Kendrick-Allwood, MD; Maureen Mulligan LaRossa, RN; Colleen Mackie, RRT; Irma Seabrook, RRT; Gloria Smikle, PNP, MSN; and Lynn Wineski, NNP; Eunice Kennedy Shriver National Institute of Child Health and Human Development: Stephanie Wilson Archer, MA. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (grants UG1 HD27856 and UL1 TR6): Gregory M. Sokol, MD; Brenda B. Poindexter, MD, MS; Anna M. Dusick, MD (deceased); Faithe Hamer, BS; Dianne E. Herron, RN; Abbey C. Hines, PsyD; Carolyn Lytle, MD, MPH; Lucy C. Miller, RN, BSN, CCRC; Heike M. Minnich, PsyD, HSPP; Lu Ann Papile, MD; Leslie Richard, RN; Lucy Smiley, CCRC; and Leslie Dawn Wilson, BSN, CCRC; McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Memorial Hermann Southwest Hospital (grant UG1 HD21373): Kathleen A. Kennedy, MD, MPH; Jon E. Tyson, MD, MPH; Julie Arldt-McAlister, RN, BSN; Katrina Burson, RN, BSN; Allison G. Dempsey, PhD; Elizabeth Eason, MD; Patricia W. Evans, MD; Carmen Garcia, RN, CCRP; Charles Green, PhD; Donna Hall, RN; Beverly Harris, RN, BSN; Margarita Jiminez, MD, MPH; Janice John, CPNP; Patrick M. Jones, MD, MA; M. Layne Lillie, RN, BSN; Karen Martin, RN; Sara C. Martin, RN, BSN; Georgia E. McDavid, RN; Shawna Rodgers, RN, BSN; Saba Khan Siddiki, MD; Daniel Sperry, RN; Emily K. Stephens, RN, BSN; Patti L. Pierce Tate, RCP; and Sharon L. Wright, MT (ASCP); Nationwide Children’s Hospital and the Ohio State University Medical Center (grant UG1 HD68278): Pablo J. Sánchez, MD; Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Christine A. Fortney, PhD, RN; Gail E. Besner, MD; and Nehal A. Parikh, MD; RTI International (grant UG1 HD36790): Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Jenna Gabrio, MPH; Jamie E. Newman, PhD, MPH; Carolyn M. Petrie Huitema, MS; W. Kenneth Poole, PhD (deceased); and Kristin M. Zaterka-Baxter, RN, BSN; Tufts Medical Center (grant U10 HD53119): Ivan D. Frantz III, MD; John M. Fiascone, MD; Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN, BSN; and Paige T. Church, MD; Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (grants UG1 HD27880 and UL1 TR93): Krisa P. Van Meurs, MD; David K. Stevenson, MD; Marian M. Adams, MD; M. Bethany Ball, BS, CCRC; Barbara Bentley, PhD; Elizabeth Bruno, PhD; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN, PNP; Lynne C. Huffman, MD; Magdy Ismael, MD, MPH; Jean G. Kohn, MD, MPH; Casey Krueger, PhD; Andrew Palmquist, RN; Melinda S. Proud, RCP; Nicholas H. St. John, PhD; and Hali Weiss, MD; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (grant UG1 HD34216): Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD, MPH; Kathleen G. Nelson, MD; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Monica V. Collins, RN, BSN, MaEd; Shirley S. Cosby, RN, BSN; Kristen C. Johnston, MSN, CRNP; Mary Beth Moses, PT, MS, PCS; Cryshelle S. Patterson, PhD; Vivien A. Phillips, RN, BSN; Julie Preskitt, MSOT, MPH; Richard V. Rector, PhD; and 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 (grant UG1 HD68270): Uday Devaskar, MD; Meena Garg, MD; Isabell B. Purdy, PhD, CPNP; Teresa Chanlaw, MPH; and Rachel Geller, RN, BSN; University of Iowa and Mercy Medical Center (grants UG1 HD53109 and UL1 TR442): John A. Widness, MD; Michael J. Acarregui, MD, MBA; Dan L. Ellsbury, MD; Karen J. Johnson, RN, BSN; Jacky R. Walker, RN; Claire A. Goeke, RN; Diane L. Eastman, RN, CPNP, MA; Donia B. Campbell, RNC-NIC; and Tracy L. Tud, RN; University of New Mexico Health Sciences Center (grants UG1 HD53089 and UL1 TR41): Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Sandra Brown, BSN; Janell Fuller, MD; Carol Hartenberger, BSN, MPH; Jean R. Lowe, PhD; Rebecca A. Thomson, RN, BSN; Sandra Sundquist Beauman, MSN, RNC-NIC; Mary Hanson, RN, BSN; and Elizabeth Kuan RN, BSN; University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (UG1 HD68244): Barbara Schmidt, MD, MSc; Haresh Kirpalani, MB, MSc; Aasma S. Chaudhary, BS, RRT; Soraya Abbasi, MD; Toni Mancini, RN, BSN, CCRC; Dara M. Cucinotta, RN; Judy C. Bernbaum, MD; Marsha Gerdes, PhD; Hallam Hurt, MD; and Jonathan Snyder, BSN, RN. University of Rochester Medical Center, Golisano Children’s Hospital, and the University at Buffalo Women’s and Children’s Hospital of Buffalo (grants UG1 HD68263 and UL1 TR42): Carl T. D’Angio, MD; Dale L. Phelps, MD; Ronnie Guillet, MD, PhD; Gary J. Myers, MD; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD; Linda J. Reubens, RN, CCRC; Erica Burnell, RN; Ann Marie Scorsone, MS, CCRC; Kyle Binion, BS; Constance Orme, BA; Holly I. M. Wadkins, MA; Michael G. Sacilowski, MAT, CCRC; Rosemary L. Jensen; Joan Merzbach, LMSW; William Zorn, PhD; Osman Farooq, MD; Dee Maffett, RN; Ashley Williams, MSEd; Julianne Hunn, BS; Stephanie Guilford, BS; Kelley Yost, PhD; Mary Rowan, RN; Diane Prinzing, AAS; Karen Wynn, RN; and Melissa Bowman, RN, NP; University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children’s Medical Center Dallas (grant UG1 HD40689): Luc P. Brion, MD; Pablo J. Sánchez, MD; Roy J. Heyne, MD; Diana M. Vasil, MSN, BSN, RNC-NIC; Sally S. Adams, MS, RN, CPNP; Lijun Chen, RN, PhD; Maria M. De Leon, RN, BSN; Francis Eubanks, RN, BSN; Alicia Guzman; Elizabeth T. Heyne, MS, MA, PA-C, PsyD; Lizette E. Lee, RN; Melissa H. Leps, RN; Linda A. Madden, BSN, RN, CPNP; Nancy A. Miller, RN; Janet S. Morgan, RN; Lara Pavageau, MD; Pollieanna Sepulveda, RN; and Cathy Twell Boatman, MS, CIMI; University of Utah University Hospital, Intermountain Medical Center, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Medical Center (grants UG1 HD87226 and UL1 RR25764): Bradley A. Yoder, MD; Mariana Baserga, MD, MSCI; Roger G. Faix, MD; Stephen D. Minton, MD; Mark J. Sheffield, MD; Carrie A. Rau, RN, BSN, CCRC; Sarah Winter, MD; Karen A. Osborne, RN, BSN, CCRC; Cynthia Spencer, RNC; Kimberlee Weaver-Lewis, RN, MS; Shawna Baker, RN; Jill Burnett, RNC; Mike Steffen, PhD; Manndi C. Loertscher, BS, CCRP; Kathryn D. Woodbury, RN, BSN; Brixen A. Reich, RNC, BSN, CCRC; Susan T. Schaefer, RRT, RN, BSN; Laura Cole-Bledsoe, RN; Jennifer O. Elmont, RN, ASN; D. Melody Parry, RN, BSN; Trisha Marchant, RN; Susan Christensen, RNC, BSN; Earl Maxson, BSN; and Brandy Davis, RN; Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (grant UG1 HD21385): Seetha Shankaran, MD; Beena G. Sood, MD, MS; Athina Pappas, MD; Girija Natarajan, MD; Sanjay Chawla, MD; Monika Bajaj, MD; Rebecca Bara, RN, BSN; Kirsten Childs, RN, BSN; Bogdan Panaitescu, MD; Mary E. Johnson, RN, BSN; Laura A. Goldston, MA; Stephanie A. Wiggins, MS; Mary K. Christensen, BA, RRT; Martha Carlson, MD; and John Barks, MD; and Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (grants U10 HD27871 and UL1 TR142): Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Christine G. Butler, MD; Patricia Cervone, RN; Sheila Greisman, RN; Monica Konstantino, RN, BSN; JoAnn Poulsen, RN; Janet Taft, RN, BSN; Joanne Williams, RN, BSN; and Elaine Romano, MSN.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: We are indebted to our medical and nursing colleagues as well as the infants and their parents who agreed to take part in this study.

^✉

Corresponding author.

PMCID: PMC6503635 PMID: 30907941

Key Points

Question

What are the mortality and morbidity risks for infants with a birth weight less than 400 g?

Findings

In this cohort study of 205 inborn, preterm infants with a birth weight less than 400 g and a gestational age of 22 to 26 weeks, 26 liveborn infants (12.7% of liveborn infants; 25.7% of those actively treated at birth) survived to discharge. Among the 19 infants in the 2008 to 2015 birth cohort who completed follow-up evaluation (10% of liveborn infants; 21% of actively treated infants), 14 (74%) had neurodevelopmental impairment.

Meaning

Infants with a birth weight less than 400 g are at risk of significant, but not universal, morbidity and mortality.

This cohort study characterizes the outcomes of liveborn infants with a birth weight less than 400 g and a gestational age of 22 to 26 weeks.

Abstract

Importance

Birth weight (BW) is an important predictor of mortality and morbidity. At extremely early gestational ages (GAs), BW may influence decisions regarding initiation of resuscitation.

Objective

To characterize outcomes of liveborn infants with a BW less than 400 g.

Design, Setting, and Participants

This retrospective multicenter cohort study analyzed extremely preterm infants born between January 2008 and December 2016 within the National Institute of Child Health and Human Development Neonatal Research Network. Infants with a BW less than 400 g and a GA of 22 to 26 weeks were included. Active treatment was defined as the provision of any potentially lifesaving intervention after birth. Survival was analyzed for the entire cohort; neurodevelopmental impairment (NDI) was examined for those born between January 2008 and December 2015 (birth years with outcomes available for analysis). Neurodevelopmental impairment at 18 to 26 months’ corrected age (CA) was defined as a Bayley Scales of Infant and Toddler Development, Third Edition, cognitive composite score less than 85, a motor composite score less than 85, moderate or severe cerebral palsy, gross motor function classification system score of 2 or greater, bilateral blindness, and/or hearing impairment. Data were analyzed from September 2017 to October 2018.

Exposures

Birth weight less than 400 g.

Main Outcomes and Measures

The primary outcome was survival to discharge among infants who received active treatment. Analysis of follow-up data was limited to infants born from 2008 to 2015 to ensure children had reached assessment age. Within this cohort, neurodevelopmental outcomes were assessed for infants who survived to 18 to 26 months’ CA and returned for a comprehensive visit.

Results

Of the 205 included infants, 121 (59.0%) were female, 133 (64.9%) were singletons, and 178 (86.8%) were small for gestational age. Almost half (101 of 205 [49.3%]) received active treatment at birth. A total of 26 of 205 infants (12.7%; 95% CI, 8.5-18.9) overall survived to discharge, and 26 of 101 actively treated infants (25.7%; 95% CI, 17.6-35.4) survived to discharge. Within the subset of infants with a BW less than 400 g and a GA of 22 to 23 weeks, 6 of 36 actively treated infants (17%; 95% CI, 6-33) survived to discharge. Among infants born between 2008 and 2015, 23 of 90 actively treated infants (26%; 95% CI, 17-36) survived to discharge. Two infants died after discharge, and 2 were lost to follow-up. Thus, 19 of 90 actively treated infants (21%; 95% CI, 13-31) were evaluated at 18 to 26 months’ CA. Moderate or severe NDI occurred in 14 of 19 infants (74%).

Conclusions and Relevance

Infants born with a BW less than 400 g are at high risk of mortality and significant morbidity. Although 21% of infants survived to 18 to 26 months’ CA with active treatment, NDI was common among survivors.

Introduction

Systematic assessment of survival and neurodevelopmental outcomes for the smallest extremely preterm infants is needed to inform decisions surrounding initiation of active treatment. The deaths of infants once classified as fetal deaths may now be classified as neonatal deaths.¹ Little is known about outcomes of infants with birth weights (BWs) below traditional cutoffs for viability.

Early analyses reported poor survival for infants born with a BW less than 500 g.^2,3 Reports published since 2010 present improved short-term survival.^4,5,6,7,8,9 In Germany, Rieger-Fackeldey et al⁴ found that 60% of liveborn infants with a BW of 500 g or less actively treated at birth survived to discharge. Keir et al⁵ reported that 54% of infants with a BW of 500 g or less survived to discharge with active treatment in an Australian center; 43% had no or mild disability at 12 months’ corrected age (CA). Pedley et al⁶ found 64% survival to discharge for infants with a BW less than 500 g in a United Kingdom tertiary care unit. The California Perinatal Quality Care Collaborative recorded 21% survival for infants with a BW of 300-500 g.⁷ In British Columbia, Canada, Bashir et al⁸ reported 55% survival to discharge for infants admitted to intensive care with a BW less than 500 g; 27% had no impairment at 4 years. Nagara et al⁹ found 80% survival with a BW less than 500 g in a Japanese case series; 5 of 7 infants (71%) had no or mild developmental disability at 3 years. Although these reports include a few infants with a BW less than 400 g, the sparse details provided do not permit any conclusions about the smallest survivors. Since 2000, case reports of surviving infants with a BW less than 400 g have been compiled in the Tiniest Babies Registry, a web-based registry (https://webapps1.healthcare.uiowa.edu/tiniestbabies/).¹⁰ The registry has facilitated reporting of the smallest survivors, confirmed the survival advantage of females, and demonstrated the prevalence of small-for-gestational-age (SGA) infants among survivors.

The current study aims to expand understanding of outcomes for the smallest infants by examining outcomes after active treatment using a multicenter cohort. The present work has the potential to inform counseling and perinatal practice for expectant mothers and preterm infants by reporting in-hospital and 2-year outcomes of a cohort of extremely preterm infants with a BW less than 400 g.

Methods

This study is a retrospective analysis of a cohort of extremely preterm infants born at 21 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) from January 2008 to December 2016. Infants with a BW less than 400 g, a gestational age (GA) of 22 to 26 weeks, and no major birth defects were included. Gestational age was determined by obstetrical estimate. If obstetrical dating was unavailable, GA estimation was based on newborn examination. Detailed maternal and neonatal data were collected prospectively until infants were discharged, transferred, or died. For infants remaining hospitalized at 120 days, limited additional data were collected after 120 days.

The institutional review boards at the 21 centers approved participation in the registry and the follow-up study. Eighteen centers granted waivers of consent for the registry, and 6 centers granted waivers of consent for the follow-up study. Written informed consent was obtained from one or both parents or a guardian at all but 1 of the remaining centers; written or verbal consent was obtained from a parent at this site.

Birth Hospitalization Data

Collected maternal information appears in Table 1. Infants with a BW less than the 10th percentile for GA based on standards reported by Alexander et al¹¹ were considered SGA. Short-term morbidities and interventions were recorded for infants surviving more than 12 hours. Morbidities recorded included sepsis, meningitis, pneumothorax, pulmonary hemorrhage, pulmonary interstitial emphysema, intracranial hemorrhage (ICH), white matter injury (WMI), retinopathy of prematurity, possible hearing loss, and necrotizing enterocolitis. Sepsis was defined as positive findings on blood culture and therapy (5 or more days or, in the case of death, intent to treat), and meningitis, positive findings on cerebrospinal fluid culture and therapy (7 or more days or, in the case of death, intent to treat). Intracranial hemorrhage was determined for infants who had cranial sonography performed within 28 days of birth, with findings classified by Papile criteria.¹² Grades 3 and 4 were considered severe ICH. White matter injury was defined as periventricular leukomalacia, porencephalic cyst, posthemorrhagic cyst, and/or cystic encephalomalacia on cranial sonography, magnetic resonance imaging, or computed tomography. Possible hearing loss was determined by a failed auditory brain stem response test in either ear. Necrotizing enterocolitis was defined as modified Bell stage of IIA or worse.¹³ Beginning April 1, 2011, data were collected on prenatal diagnoses influencing decisions to limit care and postnatal discussions with parents regarding decisions to limit, withdraw, or not escalate care for infants.

Table 1. Maternal and Neonatal Characteristics for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016.

Characteristic	No./Total No. (%)			P Value^b
Characteristic	All Infants (N = 205)	Infants Who Received Active Treatment (n = 101)^a	Infants Who Did Not Receive Active Treatment (n = 104)^a	P Value^b
Maternal Characteristics
Age, y				.67
<18	2/205 (1.0)	2/101 (2.0)	0
18-25	72/205 (35.1)	37/101 (36.6)	35/104 (33.7)
26-30	61/205 (29.8)	21/101 (20.8)	40/104 (38.5)
31-35	37/205 (18.0)	23/101 (22.8)	14/104 (13.5)
>35	33/205 (16.1)	18/101 (17.8)	15/104 (14.4)
Education				.38
Less than high school	21/123 (17.1)	15/70 (21)	6/53 (11)
High school degree	36/123 (29.3)	20/70 (29)	16/53 (30)
Partial college/trade/technical	33/123 (26.8)	16/70 (23)	17/53 (32)
College degree or higher	33/123 (26.8)	19/70 (27)	14/53 (26)
Insurance status				.002
Public insurance/Medicaid	106/200 (53.0)	58/97 (60)	48/103 (46.6)
Private	83/200 (41.5)	39/97 (40)	44/103 (42.7)
Self-pay/uninsured	10/200 (5.0)	0	10/103 (9.7)
Other	1/200 (0.5)	0	1/103 (1.0)
Race/ethnicity				.61
Non-Hispanic white	80/200 (40.0)	40/99 (40)	40/101 (39.6)
Non-Hispanic black	72/200 (36.0)	39/99 (39)	33/101 (32.7)
Non-Hispanic other	13/200 (6.5)	5/99 (5)	8/101 (7.9)
Hispanic or Latino	35/200 (17.5)	15/99 (15)	20/101 (19.8)
Prenatal care^c	201/204 (98.5)	100/100 (100)	101/104 (97.1)	.25
Diabetes with insulin use	6/204 (2.9)	3/100 (3)	3/104 (2.9)	>.99
Hypertension	89/204 (43.6)	57/100 (57)	32/104 (30.8)	<.001
Antenatal steroids	119/205 (58.0)	94/101 (93.1)	25/104 (24.0)	<.001
Maternal antibiotics^d	104/203 (51.2)	60/99 (61)	44/104 (42.3)	.01
Magnesium sulfate^e	77/125 (61.6)	54/66 (82)	23/59 (39)	<.001
Multiple gestation	72/205 (35.1)	34/101 (33.7)	38/104 (36.5)	.77
Rupture of membranes	69/200 (34.5)	27/100 (27)	42/100 (42)	.04
>18 h	29/200 (14.5)	9/100 (9)	20/100 (20)	.04
>24 h	22/196 (11.2)	7/99 (7)	15/97 (15)	.07
Fetal heart rate monitoring^f	16/19 (84)	11/11 (100)	5/8 (63)	.06
Cesarean delivery	80/204 (39.2)	72/101 (71.3)	8/103 (7.8)	<.001
Neonatal Characteristics
Inborn	205/205 (100)	101/101 (100)	104/104 (100)	NA
Male	84/205 (41.0)	41/101 (40.6)	43/104 (41.3)	>.99
Gestational age, wk				<.001
22	80/205 (39.0)	12/101 (11.9)	68/104 (65.4)
23	49/205 (23.9)	24/101 (23.8)	25/104 (24.0)
24	35/205 (17.1)	28/101 (27.7)	7/104 (6.7)
25	24/205 (11.7)	21/101 (20.8)	3/104 (2.9)
26	17/205 (8.3)	16/101 (15.8)	1/104 (1.0)
Birth weight, g				.004
<300	19/205 (9.3)	2/101 (2.0)	17/104 (16.3)
300-350	47/205 (22.9)	25/101 (24.8)	22/104 (21.2)
351-375	62/205 (30.2)	27/101 (26.7)	35/104 (33.7)
376-399	77/205 (37.6)	47/101 (46.5)	30/104 (28.8)
Small for gestational age	178/205 (86.8)	95/101 (94.1)	83/104 (79.8)	.003
5-min Apgar score <5	143/194 (73.7)	50/100 (50)	93/94 (99)	<.001

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Abbreviation: NA, not applicable.

^{^a}

Active treatment was defined as intubation, surfactant therapy, respiratory support, chest compressions, epinephrine, volume resuscitation, blood pressure support, or parenteral nutrition administration.

^{^b}

P values by the χ² test (ordinal variables) or Fisher exact test (nominal and dichotomous variables).

^{^c}

Prenatal care was considered to be given if there was evidence of at least 1 prenatal visit (2008-2015) or evidence of limited or adequate prenatal healthcare (2016).

^{^d}

Maternal antibiotics were recorded if given within 72 hours prior to birth.

^{^e}

Data collection on the administration of magnesium sulfate prior to delivery began on April 1, 2011.

^{^f}

Data collection on electronic fetal heart rate monitoring within 12 hours prior to delivery began on January 1, 2016.

Follow-up for Infants Born From 2008 to 2015

Surviving infants were eligible for comprehensive follow-up at 18 to 22 months’ CA (births before July 2012) or 22 to 26 months’ CA (births in or after July 2012). Follow-up outcomes were reported for infants born from 2008 to 2015, the subset reaching the assessment age by the time of this analysis. Assessment included an interview with the primary caretaker to review medical history. Growth was assessed with weight-for-age, length-for-age, and head circumference–for-age measures using the World Health Organization Child Growth Standards.^14,15 Vision and hearing status were determined by caretaker report, testing after initial discharge (when available), and examination at follow-up. Ophthalmology and audiology assessment were not standardized, as they were guided by retinal vasculature maturity and newborn hearing screening results, respectively, prior to discharge. Vision impairment was defined as wearing or being prescribed corrective lenses, eye abnormality, or blindness. Blindness was defined as a corrected visual acuity less than 20/200 bilaterally. Hearing impairment was defined as permanent hearing loss that did not permit the child to understand the examiner’s directions and communicate, with or without amplification, based on observation and history.

A neurological examination and the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III),¹⁶ were administered by certified examiners. An abnormal neurological examination included any abnormality in tone, reflexes, or movement, with or without cerebral palsy (CP). Cerebral palsy severity was defined as mild (level 1 or lower), moderate (level 2 or 3), or severe (level 4 or 5) using the gross motor function classification system (GMFCS).¹⁷ Neurodevelopmental impairment (NDI) was defined as a Bayley-III cognitive composite score less than 85, a Bayley-III motor composite score less than 85, moderate or severe CP, GMFCS level 2 or greater, blindness (bilateral), or hearing loss (bilateral) with no functional hearing. Neurodevelopmental impairment was subdivided into moderate and severe. Moderate NDI was defined as a cognitive composite score of 70 to 84, a motor composite score of 70 to 84, or GMFCS level 2 or 3. Severe NDI was defined as a cognitive composite score less than 70, a motor composite score less than 70, GMFCS level 4 or 5, bilateral blindness, or bilateral hearing loss with no functional hearing. Among infants with severe NDI, profound impairment was defined as a cognitive composite score of 54 or less, a motor composite score of 46 or less, or GMFCS level 5.

Outcomes

The primary outcome was survival to discharge home or 1 year (if still hospitalized) among infants who received active treatment. We defined active treatment at birth using a modification of the definition by Rysavy et al,¹⁸ which included any of the following: endotracheal intubation, surfactant therapy, continuous positive airway pressure, bag-and-mask ventilation or mechanical ventilation, chest compressions, epinephrine, volume resuscitation, blood pressure support, or parenteral nutrition. Secondary outcomes included survival to discharge among all infants and NDI.

Statistical Analysis

Maternal and neonatal characteristics were compared between infants who did and did not receive active treatment, with statistical significance for unadjusted comparisons determined by χ² or Fisher exact test. A logistic regression model that used generalized estimating equations to account for potential correlation of response (provision of active treatment) within study centers was used to assess characteristics that differed between infants who did and did not receive active treatment while adjusting for other characteristics. Characteristics included in the model were available for the entire study period and were compared using univariate analysis (ie, public insurance, maternal hypertension, antenatal steroids, maternal antibiotic use, rupture of membranes for more than 18 hours, cesarean delivery, GA, and BW). Interventions and outcomes were summarized with descriptive statistics for all infants and for the subset who received active treatment. Clopper-Pearson exact confidence intervals were calculated for the primary outcome, survival to status, and death before discharge proportions. Age at death was determined for infants who died after 12 hours using descriptive statistics to provide the median and quartiles. Time to death was estimated using the Kaplan-Meier method, with maximum censored survival time of 1 year.

Statistical significance was set at a P value less than .05, and all P values were 2-tailed. Analyses were performed using SAS version 9.4 (SAS Institute).

Results

Study Population

Between January 1, 2008, and December 31, 2016, 9786 infants were born at 22 to 26 weeks’ GA at NRN centers. Of these, 220 infants (2.2%) had a BW less than 400 g. After excluding infants with major birth defects, 205 infants were studied (Figure). Of the 205 infants, 129 infants (62.9%) were born at 22 to 23 weeks’ GA, 35 (17.1%) at 24 weeks’ GA, 24 (11.7%) at 25 weeks’ GA, and 17 (8.3%) at 26 weeks’ GA (Table 1). Altogether, 101 of 205 infants (49.3%) received active treatment at birth. Provision of active treatment ranged from 10% to 100% among centers. The proportion of infants who received active treatment increased with advancing GA (12 of 80 [15%] at 22 weeks’ GA; 24 of 49 [49%] at 23 weeks’ GA; 28 of 35 [80%] at 24 weeks’ GA; 21 of 24 [88%] at 25 weeks’ GA; 16 of 17 [94%] at 26 weeks’ GA; P < .001). Infants who received active treatment were more likely to have been exposed to antenatal steroids (93.1% vs 24.0%; P < .001) and antenatal antibiotics (60.6% vs 42.3%; P = .01) than infants who did not receive active treatment. A total of 53 of 80 infants born at 22 weeks’ GA (66%) were SGA, while all infants born at 23 to 26 weeks’ GA were SGA. In a multivariable model, receipt of antenatal steroids, cesarean delivery, and higher BW remained associated with provision of active treatment.

Figure. — BW indicates birth weight; GA, gestational age; NRN, Neonatal Research Network.

Survival and Mortality

Overall, 26 of 205 infants (12.7%; 95% CI, 8.5-18.0) survived to discharge (n = 25) or remained hospitalized at 1 year (n = 1) (Table 2). All 26 infants who survived received active treatment at birth. Thus, 26 of 101 infants who received active treatment (25.7%; 95% CI, 17.6-35.4) survived. Survival ranged from 0% to 63% among centers. With active treatment, survival increased with advancing GA, from 16.7% (95% CI, 6.4-32.8) at 22 to 23 weeks’ GA to 32.4% (95% CI, 18.0-49.8) at 25 to 26 weeks’ GA (P < .001). The smallest surviving infant weighed 330 g at birth. All 104 infants who did not receive active treatment died, nearly all within 12 hours of birth (103 of 104 [99.0%]). The median (interquartile range [IQR]) time to death among actively treated infants who died was 5 (1-192) days. The leading causes of death were immaturity, respiratory distress syndrome, and severe ICH. The median (IQR) length of hospitalization for infants who received active treatment and survived to discharge was 156 (138-189) days.

Table 2. Survival, Mortality, and Resuscitation Decisions for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016.

Variable	No./Total No. (%)
	All Infants, GA					Infants Who Received Active Treatment, GA^a
	22-23 wk	24 wk	25 wk	26 wk	All	22-23 wk	24 wk	25 wk	26 wk	All
All Births
No.	129	35	24	17	205	36	28	21	16	101
Survived to status^b	6/129 (4.7)	8/35 (23)	7/24 (29)	5/17 (29)	26/205 (12.7)	6/36 (17)	8/28 (29)	7/21 (33)	5/16 (31)	26/101 (25.7)
All deaths	123/129 (95.3)	27/35 (77)	17/24 (71)	12/17 (71)	179/205 (87.3)	30/36 (83)	20/28 (71)	14/21 (67)	11/16 (69)	75/101 (74.3)
Death within 12 h	107/129 (82.9)	17/35 (49)	7/24 (29)	3/17 (18)	134/205 (65.4)	15/36 (42)	10/28 (36)	4/21 (19)	2/16 (13)	31/101 (30.7)
Survived >12 h	22/129 (17.1)	18/35 (51)	17/24 (71)	14/17 (82)	71/205 (34.6)	21/36 (58)	18/28 (64)	17/21 (81)	14/16 (88)	70/101 (69.3)
Death before discharge	16/22 (73)	10/18 (56)	10/17 (59)	9/14 (64)	45/71 (63)	15/21 (71)	10/18 (56)	10/17 (59)	9/14 (64)	44/70 (63)
Age at death, median (IQR), d	8 (3-10)	4.5 (3-7)	6 (4-10)	13 (4-77)	5 (3-10)	9 (3-10)	4.5 (3-7)	6 (4-10)	13 (4-77)	6 (3-10.5)
All Births On or After April 1, 2011
No.	77	18	18	13	126	26	13	15	13	67
Survived to status^b	6/77 (8)	3/18 (17)	4/18 (22)	4/13 (31)	17/126 (13.5)	6/26 (23)	3/13 (23)	4/15 (27)	4/13 (31)	17/67 (25)
Prenatal diagnosis associated with decision to limit intensive care^c	3/77 (4)	2/18 (11)	1/18 (6)	0	6/126 (4.8)	0	1/13 (8)	0	0	1/67 (1)
All deaths	71/77 (92)	15/18 (83)	14/18 (78)	9/13 (69)	109/126 (86.5)	20/26 (77)	10/13 (77)	11/15 (73)	9/13 (69)	50/67 (75)
Death within 12 h	61/77 (79)	9/18 (50)	4/18 (22)	2/13 (15)	76/126 (60.3)	10/26 (38)	4/13 (31)	1/15 (7)	2/13 (15)	17/67 (25)
Treatments limited or withdrawn	24/61 (39)	4/9 (44)	0	2/2 (100)	30/76 (39)	8/10 (80)	2/4 (50)	0	2/2 (100)	12/17 (71)
Survived >12 h	16/77 (21)	9/18 (50)	14/18 (78)	11/13 (85)	50/126 (39.7)	16/26 (62)	9/13 (69)	14/15 (93)	11/13 (85)	50/67 (75)
Discussion to limit or withdraw support^d	5/16 (31)	7/9 (78)	7/14 (50)	4/11 (36)	23/50 (46)	5/16 (31)	7/9 (78)	7/14 (50)	4/11 (36)	23/50 (46)
Treatments limited or withdrawn^e	4/16 (25)	6/9 (67)	7/14 (50)	3/11 (27)	20/50 (40)	4/16 (25)	6/9 (67)	7/14 (50)	3/11 (27)	20/50 (40)
Death before discharge	10/16 (63)	6/9 (67)	10/14 (71)	7/11 (64)	33/50 (66)	10/16 (63)	6/9 (67)	10/14 (71)	7/11 (64)	33/50 (66)
Age at death, median (IQR), d	5 (3-10)	4 (2-5)	6 (4-10)	46 (4-108)	5 (3-10)	5 (3-10)	4 (2-5)	6 (4-10)	46 (4-108)	5 (3-10)

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Abbreviations: GA, gestational age; IQR, interquartile range.

^{^a}

^{^b}

Survived to status includes all infants who were discharged home directly from the birth hospital (n = 20), discharged home after transfer to another hospital (n = 5), or remained in the hospital at 1 year (n = 1).

^{^c}

Data collection on prenatal diagnoses associated with a decision to withdraw or limit intensive care either prenatally or postnatally began on April 1, 2011.

^{^d}

Data collection of documented discussion with parents to limit, withdraw, or not escalate care for infants who survived more than 12 hours after birth began on April 1, 2011.

^{^e}

Data collection on treatments limited or withdrawn with the intent to limit care for infants who survived more than 12 hours after birth began on April 1, 2011, and included any of the following: intubation/ventilation, nutrition/hydration, and/or medication.

Beginning in April 2011, additional data were collected on decisions to limit intensive care. Six of 126 infants (4.8%) born in April 2011 or later had a prenatal diagnosis that influenced the decision to limit intensive care, 1 of whom received active treatment at birth. The diagnoses cited were extremely low GA, intrauterine growth restriction, twin-to-twin transfusion, and discordant twins. Fifty of 126 infants (39.7%) survived more than 12 hours. There was documentation of discussion with parents to limit, withdraw, or not escalate care postnatally in 23 of these 50 infants (46%); treatments were withdrawn with the intent to limit care in 20 of 50 infants (40%).

Interventions and Morbidities During Hospitalization

Among the 71 infants who survived more than 12 hours, 68 of 70 (97%) received surfactant and 59 of 69 (86%) were treated with high-frequency ventilation (Table 3). Because of the frequency and timing of deaths at 22 to 23 weeks’ GA, the median duration on supplemental oxygen appeared shorter at younger GA. Pulmonary interventions included inhaled nitric oxide in 27 of 71 infants (38%) and steroids for bronchopulmonary dysplasia in 19 of 69 infants (28%). Necrotizing enterocolitis occurred in 7 of 71 infants (10%). Severe ICH affected 12 of 63 infants (19%), while WMI affected 2 of 62 infants (3%). An ophthalmologic examination was performed in 29 of 71 infants (41%). Nine of 29 examined infants (31%) underwent treatment for retinopathy of prematurity. Eighteen of 20 survivors (90%) were discharged with supplemental oxygen, and 12 (60%) were discharged with pulmonary medications.

Table 3. Interventions and In-Hospital Morbidities of Infants With Birth Weight Less Than 400 g Surviving More Than 12 Hours Born From 2008 to 2016.

Variable	Infants Who Received Active Treatment, No./Total No. (%)^a
Variable	22-23 wk GA	24 wk GA	25 wk GA	26 wk GA	All
Pulmonary Interventions
Surfactant	20/21 (95)	18/18 (100)	16/17 (94)	14/14 (100)	68/70 (97)
Steroids for bronchopulmonary dysplasia	2/21 (10)	7/18 (39)	4/16 (25)	6/13 (46)	19/68 (28)
Inhaled nitric oxide	10/21 (48)	6/18 (33)	2/17 (12)	9/14 (64)	27/70 (39)
High-frequency ventilator	18/21 (86)	15/18 (83)	13/16 (81)	13/14 (93)	59/69 (86)
Duration, median (IQR), d	7 (3-34)	11 (3-37)	7 (3-11)	27 (5-31)	7 (3-31)
Conventional ventilator	15/21 (71)	13/18 (72)	15/16 (94)	12/14 (86)	55/69 (80)
Duration, median (IQR), d	7 (3-9)	5 (4-37)	20.5 (2-50)	12.5 (1-55)	8.5 (2-29)
Nasal IMV	5/21 (24)	4/18 (22)	6/16 (38)	7/14 (50)	22/69 (32)
Duration, median (IQR), d	15 (14-18)	15.5 (10.5-20)	3.5 (1-13)	7 (5-18)	11 (5-18)
CPAP	9/21 (43)	8/18 (44)	10/17 (59)	12/14 (86)	39/70 (56)
Duration, median (IQR), d	27.5 (15-31)	16 (8-27)	8.5 (2-28)	12 (4-25)	16 (7-30)
Supplemental oxygen	20/21 (95)	18/18 (100)	16/16 (100)	14/14 (100)	68/69 (99)
Duration, median (IQR), d	9.5 (5-119)	9 (4-119)	35 (5.5-117)	92.5 (5-120)	13 (5-119)
Early Clinical Outcomes
Pulmonary
Pneumothorax	1/21 (5)	3/18 (17)	2/17 (12)	0	6/70 (9)
Pulmonary interstitial emphysema^b	3/16 (19)	0	5/14 (36)	3/11 (27)	11/50 (22)
Pulmonary hemorrhage	5/21 (24)	2/18 (11)	4/17 (24)	3/14 (21)	14/70 (20)
Discharged home from birth hospital	4/21 (19)	6/18 (33)	7/17 (41)	3/14 (21)	20/70 (29)
Discharged on oxygen	4/4 (100)	4/6 (67)	7/7 (100)	3/3 (100)	18/20 (90)
Discharged on pulmonary medication	4/4 (100)	3/6 (50)	4/7 (57)	1/3 (33)	12/20 (60)
Infectious disease
Early onset sepsis or meningitis	1/20 (5)	0	0	0	1/69 (1)
Survived >3 d	15/21 (71)	15/18 (83)	15/17 (88)	12/14 (86)	57/70 (81)
Late onset sepsis or meningitis	5/15 (33)	5/15 (33)	4/15 (27)	3/12 (25)	17/57 (30)
Neurosensory
Cranial imaging studies performed	18/21 (86)	16/18 (89)	17/17 (100)	12/14 (86)	63/70 (90)
ICH	9/18 (50)	6/16 (38)	8/17 (47)	1/12 (8)	24/63 (38)
Severe ICH (grade 3 or 4)	6/18 (33)	0	5/17 (29)	1/12 (8)	12/63 (19)
White matter injury	1/17 (6)	1/16 (6)	0	0	2/62 (3)
Possible hearing loss	2/5 (40)	1/7 (14)	0	1/4 (25)	4/21 (19)
ROP examination performed	6/21 (29)	8/18 (44)	7/17 (41)	8/14 (57)	29/70 (41)
ROP, any stage	6/6 (100)	8/8 (100)	6/7 (86)	6/8 (75)	26/29 (90)
ROP, stage 3 or higher	2/6 (33)	7/8 (88)	4/7 (57)	4/8 (50)	17/29 (59)
Intervention for ROP	1/6 (17)	4/8 (50)	3/7 (43)	1/8 (13)	9/29 (31)
Miscellaneous
Necrotizing enterocolitis	1/21 (5)	3/18 (17)	1/17 (6)	2/14 (14)	7/70 (10)
Major surgery^c	5/21 (24)	3/18 (17)	3/17 (18)	1/14 (7)	12/70 (17)

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Abbreviations: CPAP, continuous positive airway pressure; GA, gestational age; ICH, intracranial hemorrhage; IQR, interquartile range; IMV, intermittent mandatory ventilation; ROP, retinopathy of prematurity.

^{^a}

^{^b}

Data collection of pulmonary interstitial emphysema began on April 1, 2011.

^{^c}

Major surgery included patent ductus arteriosus ligation, surgery for necrotizing endocolitis, gastrointestinal tract surgery resulting in short gut, and/or any other major surgeries reported.

Follow-up for Infants Born From 2008 to 2015

Among 184 infants born from 2008 to 2015, 90 (48.9%) were actively treated, and 23 of 90 (26%; 95% CI, 16.9-35.8) survived to discharge or 1 year. Two infants (9%) died after discharge, and 2 (9%) were lost to follow-up with unknown survival status at 18 to 26 months’ CA (Figure). Thus, 19 of 184 infants overall (10.3%; 95% CI, 6.3-15.7) and 19 of 90 actively treated infants (21%; 95% CI, 13-31) were known to have survived to 18 to 26 months’ CA, and all 19 completed the follow-up evaluation. Most were rehospitalized after their initial discharge home (12 of 19 [63%]) (Table 4). Ongoing medical needs, as reflected by use of medical equipment, were present in 8 of 19 infants (42%). Hearing impairment occurred in 1 infant (5%) and vision impairment in 5 infants (26%). The median (IQR) weight-for-age z score was −1.4 (−2.2 to 0.2), and the median (IQR) length-for-age z score was −2.0 (−2.8 to −1.2). Five of 19 infants (26%) had no or mild NDI. Moderate NDI occurred in 5 of 19 infants (26%) and severe NDI in 9 (47%). Of the children with severe NDI, 1 child met criteria for profound impairment. Two children had mild CP; 1 had severe CP. The median (IQR) Bayley-III cognitive, language, and motor composite scores were 75.0 (60.0-85.0), 79.0 (71.0-86.0), and 77.5 (52.0-88.0), respectively. One child was not tested with the Bayley-III battery but met criteria for severe NDI owing to hearing impairment. Most children (14 of 19 [74%]) had multiple morbidities at 18 to 26 months’ CA.

Table 4. Long-term Outcomes of Children With Birth Weight Less Than 400 g Born From 2008 to 2015.

Variable	No./Total No. (%)
All Births
No.	184
Active treatment at birth	90/184 (48.9)
Death
Before initial discharge	161/184 (87.5)
After initial discharge	2/23 (9)
Lost to follow-up	2/23 (9)
Evaluated at 18-26 mo Corrected Age
No.	19
Weight^a
No.	19
Median (IQR), kg	9.6 (8.6 to 11.6)
Weight-for-age z score, median (IQR)	−1.4 (−2.2 to 0.2)
Length^b
No.	19
Median (IQR), cm	79.4 (76.0 to 82.6)
Length-for-age z score, median (IQR)	−2.0 (−2.8 to −1.2)
Head circumference^c
No.	19
Median (IQR), cm	45.5 (44.5 to 47.0)
Head circumference–for-age z score, median (IQR)	−1.4 (−2.0 to −0.1)
Growth problems^d	12/19 (63)
Rehospitalization since initial discharge	12/19 (63)
No. of rehospitalizations
0	7/19 (37)
1	4/19 (21)
2	5/19 (26)
3	1/19 (5)
4	2/19 (11)
Seizure disorder	0
Medical equipment needed	8/19 (42)
Feeding problems^e	9/16 (56)
Pulmonary problems	7/19 (37)
Vision impairment	5/19 (26)
Blindness	0
Hearing impairment	1/19 (5)
Hearing aids/cochlear implants	0
Autism spectrum disorder, diagnosed or suspected^f	0
Abnormal neurological examination^g	11/19 (58)
Any cerebral palsy	3/19 (16)
Mild cerebral palsy	2/19 (11)
Moderate cerebral palsy	0
Severe cerebral palsy	1/19 (5)
Cognitive composite score^h
No.	18
Median (IQR)	75 (60 to 85)
<85	11/18 (61)
<70	6/18 (33)
Language composite score^h
No.	17
Median (IQR)	79 (71 to 86)
<85	11/17 (65)
<70	4/17 (24)
Motor composite score^h
No.	18
Median (IQR)	77.5 (52 to 88)
<85	12/18 (67)
<70	7/18 (39)
Neurodevelopmental impairmentⁱ	14/19 (74)
Moderate	5/19 (26)
Severe or profound	9/19 (47)
No. of morbidities^j
0	1/19 (5)
1	4/19 (21)
2	4/19 (21)
3 or more	10/19 (53)

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Abbreviation: IQR, interquartile range.

^{^a}

Weight-for-age z scores were determined based on World Health Organization Child Health Standards. Weight and weight-for-age z scores are set to missing for infants with z scores <−6 or >5.¹⁴

^{^b}

Length-for-age z scores were determined based on World Health Organization Child Health Standards. Length and length-for-age z scores are set to missing for infants with z scores <−6 or >6.¹⁴

^{^c}

Head circumference–for-age z scores were determined based on World Health Organization Child Health Standards. Head circumference and head circumference–for-age z scores are set to missing for infants with z scores <−5 or >5.¹⁵

^{^d}

Growth problems were defined as a z score of –2 or worse for weight-for-age, length-for-age, or head circumference–for-age based on the World Health Organization Child Health Standards.^14,15

^{^e}

Data collection on feeding problems began on April 1, 2011, and included any of the following: resists/refuses some/all food by mouth, difficulty with swallowing food, and/or documented aspiration.

^{^f}

Data collection on suspected or diagnosed autism spectrum disorder began on April 1, 2011. Data were obtained from primary caretaker report and from the medical record.

^{^g}

Abnormal neurological examination includes abnormal in the absence of cerebral palsy and abnormal with cerebral palsy.

^{^h}

Cognitive, language, and motor composite scores were based on the Bayley Scales of Infant and Toddler Development, Third Edition.¹⁶

^ⁱ

Neurodevelopmental impairment was defined as any of the following: cognitive composite score <85, motor composite score <85, moderate or severe cerebral palsy, gross motor function level ≥2, blindness, or hearing impairment. Moderate neurodevelopmental impairment was defined as any of the following: cognitive composite score of 70 to 84, motor composite score of 70 to 84, moderate cerebral palsy, or gross motor function level 2 or 3. Severe neurodevelopmental impairment was defined as any of the following: cognitive composite score <70, motor composite score <70, severe cerebral palsy, gross motor function level 4 or 5, blindness, or hearing impairment.

^{^j}

Morbidities included were growth problems, pulmonary problems, sensory impairment (vision or hearing), cognitive problems (cognitive composite score <85), and motor problems (motor composite score <85).

Discussion

In this multicenter cohort of extremely preterm infants with a BW less than 400 g and a GA of 22 to 26 weeks, approximately half received active treatment at birth. With active treatment, 25.7% survived to discharge, with survivors spanning the GA range of 22 to 26 weeks. No infant survived without active treatment. Discussions with parents about limiting intensive care were more common postnatally than prenatally. This may be explained in part by the circumstances of unanticipated preterm birth and lack of opportunity to counsel prenatally. For those infants who survived more than 12 hours and underwent brain imaging, severe ICH was found in 19% and WMI in 3%. Five of 19 infants evaluated as toddlers (26%) were not significantly impaired (Bayley-III cognitive and motor composite scores of 85 or greater, no or mild CP, functional vision, and functional hearing).

In the 1980s, nearly 100% mortality was presumed for infants with a BW less than 500 g.¹⁹ This assumption is no longer accurate. One reason the United States infant mortality rate is higher than other developed nations is the inclusion of infants with a BW less than 500 g in mortality statistics.²⁰ In Europe, there is variability in interventions offered and in reporting of fetal and neonatal deaths at a GA less than 24 weeks and a BW less than 500 g.^21,22,23 The United States is not exempt from variability. Between-hospital variation in provision of active treatment at birth accounted for 78% of the variation in survival at 22 to 23 weeks’ GA across the National Institute of Child Health and Human Development NRN.¹⁸

This study provides detailed information about interventions and outcomes for a subset of the highest-risk preterm population whose long-term outcomes remain unclear. Others have reported outcomes of similar cohorts. Neonatal Research Network Japan reported 12% to 20% unimpaired survival at 3 years following birth at 22 to 23 weeks’ gestation in a cohort that included infants with a BW less than 400 g.²⁴ As of December 2018, The Tiniest Babies Registry contained data on 207 infant survivors with a BW of 252 to 399 g and a GA of 21 to 34 weeks.

Most of our cohort was supported with surfactant and high-frequency ventilation. Many received controversial therapies, including inhaled nitric oxide and systemic postnatal corticosteroids.^25,26,27 Most infants surviving to discharge or 1 year continued to receive pulmonary therapies, including supplemental oxygen, bronchodilators, and/or diuretics. Ongoing respiratory therapies in the home environment can be anticipated for the smallest infants who survive to discharge.

In our cohort, SGA infants were more common among those who received active treatment at birth. This is because appropriately grown infants with birth weights less than 400 g are of a GA less than 22 weeks. Antenatal and postnatal growth trajectories are relevant to long-term outcomes. Ray et al²⁸ reported that the relative risk of neonatal death was more than twice as high for preterm infants with a BW lower than the fifth percentile compared with preterm infants with a BW at the fifth percentile or higher. Beyond mortality, SGA status may be associated with poorer neurosensory outcomes. Within another NRN cohort, SGA status was significantly associated with death or NDI at 18 to 22 months’ CA.²⁹ In the Stockholm Birth Cohort, children who were SGA scored lower on verbal, numerical, and spatial assessments at 13 years.³⁰ This is relevant since most of our survivors were SGA.

Strengths and Limitations

The strengths of this study include the ability to identify a number of infants with a BW less than 400 g from across the United States. The NRN registry and follow-up evaluation enable reporting of both in-hospital and 2-year outcomes. We report outcomes from several large US centers providing neonatal tertiary care. While our results are not population based, guidelines recommend that extremely preterm births only take place at such hospitals.³¹

Our study has limitations. The sample was limited to live births and does not account for stillbirths meeting the GA and BW criteria. Standardized criteria were not applied to determine whether active treatment should be provided at birth or to guide discussions to limit, withdraw, or not escalate intensive care. There were potential unmeasured patient and clinician factors affecting decision making related to active treatment at birth. Discussions regarding limiting intensive care may have occurred but may not have been documented. An additional limitation is the age at follow-up. Two-year follow-up hinders the ability to evaluate executive function and academic achievement, areas where children born extremely preterm, including those with no or mild impairment at 2 years, may have difficulty. Children may be identified as having autism spectrum disorder beyond this age. Vision and hearing impairment included observation-based findings, as ophthalmology and audiology follow-up assessments after discharge were individualized. Given the small number of survivors with follow-up to toddlerhood, outcomes may not be generalizable.

Conclusions

We provide updated information about the care and outcomes of extremely preterm infants born weighing less than 400 g. As practice is evolving in the active management of the most premature infants, the results may inform counseling and perinatal practice for those who care for expectant mothers and the smallest extremely preterm infants. Infants with a BW less than 400 g are at risk of significant morbidity and mortality, yet with active treatment, survival to discharge and to 18 to 26 months’ CA are possible. Informed conversations regarding goals of care are warranted, given the significant but not universal morbidity and mortality.

References

1.Ehrenthal DB, Wingate MS, Kirby RS. Variation by state in outcomes classification for deliveries less than 500 g in the United States. Matern Child Health J. 2011;15(1):42-48. doi: 10.1007/s10995-010-0566-y [DOI] [PubMed] [Google Scholar]
2.Lucey JF, Rowan CA, Shiono P, et al. . Fetal infants: the fate of 4172 infants with birth weights of 401 to 500 grams—the Vermont Oxford Network experience (1996-2000). Pediatrics. 2004;113(6):1559-1566. doi: 10.1542/peds.113.6.1559 [DOI] [PubMed] [Google Scholar]
3.Hsieh WS, Jeng SF, Hung YL, Chen PC, Chou HC, Tsao PN. Outcome and hospital cost for infants weighing less than 500 grams: a tertiary centre experience in Taiwan. J Paediatr Child Health. 2007;43(9):627-631. doi: 10.1111/j.1440-1754.2007.01137.x [DOI] [PubMed] [Google Scholar]
4.Rieger-Fackeldey E, Blank C, Dinger J, Steinmacher J, Bode H, Schulze A. Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years. Acta Paediatr. 2010;99(9):1350-1355. doi: 10.1111/j.1651-2227.2010.01762.x [DOI] [PubMed] [Google Scholar]
5.Keir A, McPhee A, Wilkinson D. Beyond the borderline: outcomes for inborn infants born at ≤500 grams. J Paediatr Child Health. 2014;50(2):146-152. doi: 10.1111/jpc.12414 [DOI] [PubMed] [Google Scholar]
6.Pedley ML, Brown K, Scorrer TJ, Chowdhury O. Outcome of infants with birth weight less than 500 grams in a tertiary neonatal unit. Arch Dis Child Fetal Neonatal Ed. 2014;99(suppl 1):A38. doi: 10.1136/archdischild-2014-306576.110 [DOI] [Google Scholar]
7.Griffin IJ, Lee HC, Profit J, Tancedi DJ. The smallest of the small: short-term outcomes of profoundly growth restricted and profoundly low birth weight preterm infants. J Perinatol. 2015;35(7):503-510. doi: 10.1038/jp.2014.233 [DOI] [PubMed] [Google Scholar]
8.Bashir RA, Thomas JP, MacKay M, et al. . Survival, short-term, and long-term morbidities of neonates with birth weight < 500 g. Am J Perinatol. 2017;34(13):1333-1339. doi: 10.1055/s-0037-1603462 [DOI] [PubMed] [Google Scholar]
9.Nagara S, Kouwaki M, Togawa T, Sugiura T, Okada M, Koyama N. Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g. Pediatr Neonatol. 2018;59(3):274-280. doi: 10.1016/j.pedneo.2017.09.005 [DOI] [PubMed] [Google Scholar]
10.Bell EF, Zumbach DK. The tiniest babies: a registry of survivors with birth weight less than 400 grams. Pediatrics. 2011;127(1):58-61. doi: 10.1542/peds.2010-1855 [DOI] [PubMed] [Google Scholar]
11.Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87(2):163-168. doi: 10.1016/0029-7844(95)00386-X [DOI] [PubMed] [Google Scholar]
12.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]
13.Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179-201. doi: 10.1016/S0031-3955(16)34975-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.WHO Multicentre Growth Reference Study Group WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development. Geneva, Switzerland: World Health Organization; 2006. [Google Scholar]
15.WHO Multicentre Growth Reference Study Group WHO Child Growth Standards: Head Circumference-for-Age, Arm Circumference-for-Age, Triceps Skinfold-for-Age and Subscapular Skinfold-for-Age: Methods and Development. Geneva, Switzerland: World Health Organization; 2007. [Google Scholar]
16.Albers CA, Grieve AJ. Test review: Bayley, N (2006): Bayley Scales of Infant and Toddler Development—third edition: San Antonio, TX: Harcourt Assessment. J Psychoeduc Assess. 2007;25(2):180-190. doi: 10.1177/0734282906297199 [DOI] [Google Scholar]
17.Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214-223. doi: 10.1111/j.1469-8749.1997.tb07414.x [DOI] [PubMed] [Google Scholar]
18.Rysavy MA, Li L, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med. 2015;372(19):1801-1811. doi: 10.1056/NEJMoa1410689 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Wilson AL, Fenton LJ, Munson DP. State reporting of live births of newborns weighing less than 500 grams: impact on neonatal mortality rates. Pediatrics. 1986;78(5):850-854. [PubMed] [Google Scholar]
20.Lau C, Ambalavanan N, Chakraborty H, Wingate MS, Carlo WA. Extremely low birth weight and infant mortality rates in the United States. Pediatrics. 2013;131(5):855-860. doi: 10.1542/peds.2012-2471 [DOI] [PubMed] [Google Scholar]
21.Zeitlin J, Mohangoo A, Delnord M European Perinatal Health Report: health and care of pregnant women and babies in Europe in 2010. Euro-Peristat Network; 2013:137-143. https://www.europeristat.com/images/doc/EPHR2010_w_disclaimer.pdf. Accessed February 18, 2019.
22.Smith L, Draper ES, Manktelow BN, Pritchard C, Field DJ. Comparing regional infant death rates: the influence of preterm births <24 weeks of gestation. Arch Dis Child Fetal Neonatal Ed. 2013;98(2):F103-F107. doi: 10.1136/fetalneonatal-2011-301359 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Kollée LA, Cuttini M, Delmas D, et al. ; MOSAIC Research group . Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study. BJOG. 2009;116(11):1481-1491. doi: 10.1111/j.1471-0528.2009.02235.x [DOI] [PubMed] [Google Scholar]
24.Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M; Neonatal Research Network, Japan . Outcomes of infants born at 22 and 23 weeks’ gestation. Pediatrics. 2013;132(1):62-71. doi: 10.1542/peds.2012-2857 [DOI] [PubMed] [Google Scholar]
25.Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ. Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr Res. 2017;82(6):901-914. doi: 10.1038/pr.2017.200 [DOI] [PubMed] [Google Scholar]
26.Dani C, Corsini I, Cangemi J, Vangi V, Pratesi S. Nitric oxide for the treatment of preterm infants with severe RDS and pulmonary hypertension. Pediatr Pulmonol. 2017;52(11):1461-1468. doi: 10.1002/ppul.23843 [DOI] [PubMed] [Google Scholar]
27.Watterberg KL; Committee on Fetus and Newborn . Policy statement: postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(4):800-808. doi: 10.1542/peds.2010-1534 [DOI] [PubMed] [Google Scholar]
28.Ray JG, Park AL, Fell DB. Mortality in infants affected by preterm birth and severe small-for-gestational age birth weight. Pediatrics. 2017;140(6):e20171881. doi: 10.1542/peds.2017-1881 [DOI] [PubMed] [Google Scholar]
29.De Jesus LC, Pappas A, Shankaran S, et al. ; Eunice Kennedy Shriver National Institute of Health and Human Development Neonatal Research Network . Outcomes of small for gestational age infants born at <27 weeks’ gestation. J Pediatr. 2013;163(1):55-60.e1, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Yu B, Garcy AM. A longitudinal study of cognitive and educational outcomes of those born small for gestational age. Acta Paediatr. 2018;107(1):86-94. doi: 10.1111/apa.13993 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Raju TN, Mercer BM, Burchfield DJ, Joseph GF Jr. Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(5):1083-1096. doi: 10.1097/AOG.0000000000000243 [DOI] [PubMed] [Google Scholar]

[poi190004r1] 1.Ehrenthal DB, Wingate MS, Kirby RS. Variation by state in outcomes classification for deliveries less than 500 g in the United States. Matern Child Health J. 2011;15(1):42-48. doi: 10.1007/s10995-010-0566-y [DOI] [PubMed] [Google Scholar]

[poi190004r2] 2.Lucey JF, Rowan CA, Shiono P, et al. . Fetal infants: the fate of 4172 infants with birth weights of 401 to 500 grams—the Vermont Oxford Network experience (1996-2000). Pediatrics. 2004;113(6):1559-1566. doi: 10.1542/peds.113.6.1559 [DOI] [PubMed] [Google Scholar]

[poi190004r3] 3.Hsieh WS, Jeng SF, Hung YL, Chen PC, Chou HC, Tsao PN. Outcome and hospital cost for infants weighing less than 500 grams: a tertiary centre experience in Taiwan. J Paediatr Child Health. 2007;43(9):627-631. doi: 10.1111/j.1440-1754.2007.01137.x [DOI] [PubMed] [Google Scholar]

[poi190004r4] 4.Rieger-Fackeldey E, Blank C, Dinger J, Steinmacher J, Bode H, Schulze A. Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years. Acta Paediatr. 2010;99(9):1350-1355. doi: 10.1111/j.1651-2227.2010.01762.x [DOI] [PubMed] [Google Scholar]

[poi190004r5] 5.Keir A, McPhee A, Wilkinson D. Beyond the borderline: outcomes for inborn infants born at ≤500 grams. J Paediatr Child Health. 2014;50(2):146-152. doi: 10.1111/jpc.12414 [DOI] [PubMed] [Google Scholar]

[poi190004r6] 6.Pedley ML, Brown K, Scorrer TJ, Chowdhury O. Outcome of infants with birth weight less than 500 grams in a tertiary neonatal unit. Arch Dis Child Fetal Neonatal Ed. 2014;99(suppl 1):A38. doi: 10.1136/archdischild-2014-306576.110 [DOI] [Google Scholar]

[poi190004r7] 7.Griffin IJ, Lee HC, Profit J, Tancedi DJ. The smallest of the small: short-term outcomes of profoundly growth restricted and profoundly low birth weight preterm infants. J Perinatol. 2015;35(7):503-510. doi: 10.1038/jp.2014.233 [DOI] [PubMed] [Google Scholar]

[poi190004r8] 8.Bashir RA, Thomas JP, MacKay M, et al. . Survival, short-term, and long-term morbidities of neonates with birth weight < 500 g. Am J Perinatol. 2017;34(13):1333-1339. doi: 10.1055/s-0037-1603462 [DOI] [PubMed] [Google Scholar]

[poi190004r9] 9.Nagara S, Kouwaki M, Togawa T, Sugiura T, Okada M, Koyama N. Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g. Pediatr Neonatol. 2018;59(3):274-280. doi: 10.1016/j.pedneo.2017.09.005 [DOI] [PubMed] [Google Scholar]

[poi190004r10] 10.Bell EF, Zumbach DK. The tiniest babies: a registry of survivors with birth weight less than 400 grams. Pediatrics. 2011;127(1):58-61. doi: 10.1542/peds.2010-1855 [DOI] [PubMed] [Google Scholar]

[poi190004r11] 11.Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87(2):163-168. doi: 10.1016/0029-7844(95)00386-X [DOI] [PubMed] [Google Scholar]

[poi190004r12] 12.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]

[poi190004r13] 13.Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179-201. doi: 10.1016/S0031-3955(16)34975-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi190004r14] 14.WHO Multicentre Growth Reference Study Group WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development. Geneva, Switzerland: World Health Organization; 2006. [Google Scholar]

[poi190004r15] 15.WHO Multicentre Growth Reference Study Group WHO Child Growth Standards: Head Circumference-for-Age, Arm Circumference-for-Age, Triceps Skinfold-for-Age and Subscapular Skinfold-for-Age: Methods and Development. Geneva, Switzerland: World Health Organization; 2007. [Google Scholar]

[poi190004r16] 16.Albers CA, Grieve AJ. Test review: Bayley, N (2006): Bayley Scales of Infant and Toddler Development—third edition: San Antonio, TX: Harcourt Assessment. J Psychoeduc Assess. 2007;25(2):180-190. doi: 10.1177/0734282906297199 [DOI] [Google Scholar]

[poi190004r17] 17.Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214-223. doi: 10.1111/j.1469-8749.1997.tb07414.x [DOI] [PubMed] [Google Scholar]

[poi190004r18] 18.Rysavy MA, Li L, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med. 2015;372(19):1801-1811. doi: 10.1056/NEJMoa1410689 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi190004r19] 19.Wilson AL, Fenton LJ, Munson DP. State reporting of live births of newborns weighing less than 500 grams: impact on neonatal mortality rates. Pediatrics. 1986;78(5):850-854. [PubMed] [Google Scholar]

[poi190004r20] 20.Lau C, Ambalavanan N, Chakraborty H, Wingate MS, Carlo WA. Extremely low birth weight and infant mortality rates in the United States. Pediatrics. 2013;131(5):855-860. doi: 10.1542/peds.2012-2471 [DOI] [PubMed] [Google Scholar]

[poi190004r21] 21.Zeitlin J, Mohangoo A, Delnord M European Perinatal Health Report: health and care of pregnant women and babies in Europe in 2010. Euro-Peristat Network; 2013:137-143. https://www.europeristat.com/images/doc/EPHR2010_w_disclaimer.pdf. Accessed February 18, 2019.

[poi190004r22] 22.Smith L, Draper ES, Manktelow BN, Pritchard C, Field DJ. Comparing regional infant death rates: the influence of preterm births <24 weeks of gestation. Arch Dis Child Fetal Neonatal Ed. 2013;98(2):F103-F107. doi: 10.1136/fetalneonatal-2011-301359 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi190004r23] 23.Kollée LA, Cuttini M, Delmas D, et al. ; MOSAIC Research group . Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study. BJOG. 2009;116(11):1481-1491. doi: 10.1111/j.1471-0528.2009.02235.x [DOI] [PubMed] [Google Scholar]

[poi190004r24] 24.Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M; Neonatal Research Network, Japan . Outcomes of infants born at 22 and 23 weeks’ gestation. Pediatrics. 2013;132(1):62-71. doi: 10.1542/peds.2012-2857 [DOI] [PubMed] [Google Scholar]

[poi190004r25] 25.Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ. Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr Res. 2017;82(6):901-914. doi: 10.1038/pr.2017.200 [DOI] [PubMed] [Google Scholar]

[poi190004r26] 26.Dani C, Corsini I, Cangemi J, Vangi V, Pratesi S. Nitric oxide for the treatment of preterm infants with severe RDS and pulmonary hypertension. Pediatr Pulmonol. 2017;52(11):1461-1468. doi: 10.1002/ppul.23843 [DOI] [PubMed] [Google Scholar]

[poi190004r27] 27.Watterberg KL; Committee on Fetus and Newborn . Policy statement: postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(4):800-808. doi: 10.1542/peds.2010-1534 [DOI] [PubMed] [Google Scholar]

[poi190004r28] 28.Ray JG, Park AL, Fell DB. Mortality in infants affected by preterm birth and severe small-for-gestational age birth weight. Pediatrics. 2017;140(6):e20171881. doi: 10.1542/peds.2017-1881 [DOI] [PubMed] [Google Scholar]

[poi190004r29] 29.De Jesus LC, Pappas A, Shankaran S, et al. ; Eunice Kennedy Shriver National Institute of Health and Human Development Neonatal Research Network . Outcomes of small for gestational age infants born at <27 weeks’ gestation. J Pediatr. 2013;163(1):55-60.e1, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi190004r30] 30.Yu B, Garcy AM. A longitudinal study of cognitive and educational outcomes of those born small for gestational age. Acta Paediatr. 2018;107(1):86-94. doi: 10.1111/apa.13993 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi190004r31] 31.Raju TN, Mercer BM, Burchfield DJ, Joseph GF Jr. Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(5):1083-1096. doi: 10.1097/AOG.0000000000000243 [DOI] [PubMed] [Google Scholar]

PERMALINK

Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g

Jane E Brumbaugh, MD

Nellie I Hansen, MPH

Edward F Bell, MD

Amaanti Sridhar, MS

Waldemar A Carlo, MD

Susan R Hintz, MD, MS

Betty R Vohr, MD

Tarah T Colaizy, MD, MPH

Andrea F Duncan, MD, MS

Myra H Wyckoff, MD

Michelle L Baack, MD

Matthew A Rysavy, MD, PhD

Sara B DeMauro, MD, MSCE

Barbara J Stoll, MD

Abhik Das, PhD

Rosemary D Higgins, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Birth Hospitalization Data

Table 1. Maternal and Neonatal Characteristics for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016.

Follow-up for Infants Born From 2008 to 2015

Outcomes

Statistical Analysis

Results

Study Population

Figure. Participant Flow Diagram.

Survival and Mortality

Table 2. Survival, Mortality, and Resuscitation Decisions for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016.

Interventions and Morbidities During Hospitalization

Table 3. Interventions and In-Hospital Morbidities of Infants With Birth Weight Less Than 400 g Surviving More Than 12 Hours Born From 2008 to 2016.

Follow-up for Infants Born From 2008 to 2015

Table 4. Long-term Outcomes of Children With Birth Weight Less Than 400 g Born From 2008 to 2015.

Discussion

Strengths and Limitations

Conclusions

References

ACTIONS

PERMALINK

RESOURCES

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