Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g | Neonatology | JAMA Pediatrics | JAMA Network
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Figure.  Participant Flow Diagram
Participant Flow Diagram

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

Table 1.  Maternal and Neonatal Characteristics for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016
Maternal and Neonatal Characteristics for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016
Table 2.  Survival, Mortality, and Resuscitation Decisions for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016
Survival, Mortality, and Resuscitation Decisions for Infants With Birth Weight Less Than 400 g Born From 2008 to 2016
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
Interventions and In-Hospital Morbidities of Infants With Birth Weight Less Than 400 g Surviving More Than 12 Hours Born From 2008 to 2016
Table 4.  Long-term Outcomes of Children With Birth Weight Less Than 400 g Born From 2008 to 2015
Long-term Outcomes of Children With Birth Weight Less Than 400 g Born From 2008 to 2015
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-yPubMedGoogle ScholarCrossref
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.113.6.1559PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.12414PubMedGoogle ScholarCrossref
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-2014-306576.110Google ScholarCrossref
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.2014.233PubMedGoogle ScholarCrossref
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-0037-1603462PubMedGoogle ScholarCrossref
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.2017.09.005PubMedGoogle ScholarCrossref
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.2010-1855PubMedGoogle ScholarCrossref
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-XPubMedGoogle ScholarCrossref
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)80282-0PubMedGoogle ScholarCrossref
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)34975-6PubMedGoogle ScholarCrossref
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.
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.
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:10.1177/0734282906297199Google ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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/NEJMoa1410689PubMedGoogle ScholarCrossref
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.PubMedGoogle 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.2012-2471PubMedGoogle ScholarCrossref
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-2011-301359PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.2012-2857PubMedGoogle ScholarCrossref
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.2017.200PubMedGoogle ScholarCrossref
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.23843PubMedGoogle ScholarCrossref
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.2010-1534PubMedGoogle ScholarCrossref
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.2017-1881PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
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.13993PubMedGoogle ScholarCrossref
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.0000000000000243PubMedGoogle ScholarCrossref
Original Investigation
March 25, 2019

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

Author Affiliations
  • 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
JAMA Pediatr. 2019;173(5):434-445. doi:10.1001/jamapediatrics.2019.0180
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.

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.4-9 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; Quiz Ref ID43% 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, Quiz Ref IDand 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.

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.

Survival and Mortality

Quiz Ref IDOverall, 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.

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.

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). Quiz Ref IDOngoing 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.

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.21-23 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.25-27 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.

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Article Information

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.

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-yPubMedGoogle ScholarCrossref
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.113.6.1559PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.12414PubMedGoogle ScholarCrossref
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-2014-306576.110Google ScholarCrossref
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.2014.233PubMedGoogle ScholarCrossref
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-0037-1603462PubMedGoogle ScholarCrossref
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.2017.09.005PubMedGoogle ScholarCrossref
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.2010-1855PubMedGoogle ScholarCrossref
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-XPubMedGoogle ScholarCrossref
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)80282-0PubMedGoogle ScholarCrossref
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)34975-6PubMedGoogle ScholarCrossref
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.
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.
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:10.1177/0734282906297199Google ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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/NEJMoa1410689PubMedGoogle ScholarCrossref
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.PubMedGoogle 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.2012-2471PubMedGoogle ScholarCrossref
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-2011-301359PubMedGoogle ScholarCrossref
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.xPubMedGoogle ScholarCrossref
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.2012-2857PubMedGoogle ScholarCrossref
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.2017.200PubMedGoogle ScholarCrossref
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.23843PubMedGoogle ScholarCrossref
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.2010-1534PubMedGoogle ScholarCrossref
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.2017-1881PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
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.13993PubMedGoogle ScholarCrossref
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.0000000000000243PubMedGoogle ScholarCrossref
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