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Figure.
Flow Diagram of Study Participants
Flow Diagram of Study Participants

Included and excluded infants. Three additional infants were excluded owing to missing data, including 1 missing data for blood in ventricle within 28 days and 2 missing data for periventricular leukomalacia.

Table 1.  
Timing and Laterality of Ultrasonographic Ventriculomegaly Findings
Timing and Laterality of Ultrasonographic Ventriculomegaly Findings
Table 2.  
Maternal and Neonatal Characteristics of Patients Followed up vs Patients Lost to Follow-up
Maternal and Neonatal Characteristics of Patients Followed up vs Patients Lost to Follow-up
Table 3.  
Participant Demographics
Participant Demographics
Table 4.  
Neurodevelopmental Outcomes by Cranial Ultrasonographic Findingsa
Neurodevelopmental Outcomes by Cranial Ultrasonographic Findingsa
1.
Woodward  LJ, Clark  CA, Bora  S, Inder  TE.  Neonatal white matter abnormalities an important predictor of neurocognitive outcome for very preterm children.  PLoS One. 2012;7(12):e51879.PubMedGoogle ScholarCrossref
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Miller  SP, Ferriero  DM, Leonard  C,  et al.  Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome.  J Pediatr. 2005;147(5):609-616.PubMedGoogle ScholarCrossref
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Inder  TE, Wells  SJ, Mogridge  NB, Spencer  C, Volpe  JJ.  Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study.  J Pediatr. 2003;143(2):171-179.PubMedGoogle ScholarCrossref
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Payne  AH, Hintz  SR, Hibbs  AM,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage.  JAMA Pediatr. 2013;167(5):451-459.PubMedGoogle ScholarCrossref
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O’Shea  TM, Allred  EN, Kuban  KC,  et al; ELGAN Study Investigators.  Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants.  J Child Neurol. 2012;27(1):22-29.PubMedGoogle ScholarCrossref
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Stoll  BJ, Hansen  NI, Bell  EF,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.  Pediatrics. 2010;126(3):443-456.PubMedGoogle ScholarCrossref
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Shankaran  S, Langer  JC, Kazzi  SN, Laptook  AR, Walsh  M; National Institute of Child Health and Human Development Neonatal Research Network.  Cumulative index of exposure to hypocarbia and hyperoxia as risk factors for periventricular leukomalacia in low birth weight infants.  Pediatrics. 2006;118(4):1654-1659.PubMedGoogle ScholarCrossref
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Hamrick  SE, Miller  SP, Leonard  C,  et al.  Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia.  J Pediatr. 2004;145(5):593-599.PubMedGoogle ScholarCrossref
9.
Fox  LM, Choo  P, Rogerson  SR,  et al.  The relationship between ventricular size at 1 month and outcome at 2 years in infants less than 30 weeks’ gestation.  Arch Dis Child Fetal Neonatal Ed. 2014;99(3):F209-F214.PubMedGoogle ScholarCrossref
10.
Maunu  J, Lehtonen  L, Lapinleimu  H,  et al; PIPARI Study Group.  Ventricular dilatation in relation to outcome at 2 years of age in very preterm infants: a prospective Finnish cohort study.  Dev Med Child Neurol. 2011;53(1):48-54.PubMedGoogle ScholarCrossref
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O’Shea  TM, Allred  EN, Dammann  O,  et al; ELGAN study Investigators.  The ELGAN study of the brain and related disorders in extremely low gestational age newborns.  Early Hum Dev. 2009;85(11):719-725.PubMedGoogle ScholarCrossref
12.
Brouwer  MJ, de Vries  LS, Groenendaal  F,  et al.  New reference values for the neonatal cerebral ventricles.  Radiology. 2012;262(1):224-233.PubMedGoogle ScholarCrossref
13.
Hintz  SR, Slovis  T, Bulas  D,  et al; NICHD Neonatal Research Network.  Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants.  J Pediatr. 2007;150(6):592-596, 596.e1-596.e5.PubMedGoogle ScholarCrossref
14.
Ment  LR, Bada  HS, Barnes  P,  et al.  Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.  Neurology. 2002;58(12):1726-1738.PubMedGoogle ScholarCrossref
15.
Wyldes  M, Watkinson  M.  Isolated mild fetal ventriculomegaly.  Arch Dis Child Fetal Neonatal Ed. 2004;89(1):F9-F13.PubMedGoogle ScholarCrossref
16.
Cardoza  JD, Goldstein  RB, Filly  RA.  Exclusion of fetal ventriculomegaly with a single measurement: the width of the lateral ventricular atrium.  Radiology. 1988;169(3):711-714.PubMedGoogle ScholarCrossref
17.
Stoll  BJ, Hansen  NI, Bell  EF,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.  JAMA. 2015;314(10):1039-1051.PubMedGoogle ScholarCrossref
18.
Newman  JE, Bann  CM, Vohr  BR, Dusick  AM, Higgins  RD; Follow-Up Study Group of Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Improving the Neonatal Research Network annual certification for neurologic examination of the 18-22 month child.  J Pediatr. 2012;161(6):1041-1046.PubMedGoogle ScholarCrossref
19.
O’Shea  TM, Shah  B, Allred  EN,  et al; ELGAN Study Investigators.  Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants.  Brain Behav Immun. 2013;29:104-112.PubMedGoogle ScholarCrossref
20.
Vohr  BR, Stephens  BE, Higgins  RD,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes.  J Pediatr. 2012;161(2):222-8.e3.PubMedGoogle ScholarCrossref
21.
Bayley  N.  Bayley Scales of Infant Development. 3rd ed. San Antonio, TX: The Psychological Corporation; 2006.
22.
Briggs-Gowan  MJCA.  Brief Infant-Toddler Social and Emotional Assessment (BITSEA) Manual, version 2. New Haven, CT: Yale University; 2002.
23.
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.PubMedGoogle ScholarCrossref
24.
Spittle  AJ, Ferretti  C, Anderson  PJ,  et al.  Improving the outcome of infants born at <30 weeks’ gestation—a randomized controlled trial of preventative care at home.  BMC Pediatr. 2009;9(73).PubMedGoogle Scholar
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Pocock  SJ, Smith  M, Baghurst  P.  Environmental lead and children’s intelligence: a systematic review of the epidemiological evidence.  BMJ. 1994;309(6963):1189-1197.PubMedGoogle ScholarCrossref
26.
McLendon  D, Check  J, Carteaux  P,  et al.  Implementation of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants.  Pediatrics. 2003;111(4 Pt 2):e497-e503.PubMedGoogle Scholar
27.
Ment  LR, Vohr  B, Allan  W,  et al.  The etiology and outcome of cerebral ventriculomegaly at term in very low birth weight preterm infants.  Pediatrics. 1999;104(2 Pt 1):243-248.PubMedGoogle ScholarCrossref
28.
Krishnamoorthy  KS, Kuban  KC, O’Shea  TM, Westra  SJ, Allred  EN, Leviton  A; ELGAN Study Co-investigators.  Early cranial ultrasound lesions predict microcephaly at age 2 years in preterm infants.  J Child Neurol. 2011;26(2):188-194.PubMedGoogle ScholarCrossref
29.
Kuban  KC, Allred  EN, O’Shea  TM,  et al; ELGAN study investigators.  Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children born at extremely low gestational age.  J Child Neurol. 2009;24(1):63-72.PubMedGoogle ScholarCrossref
30.
O’Shea  TM, Kuban  KC, Allred  EN,  et al; Extremely Low Gestational Age Newborns Study Investigators.  Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children.  Pediatrics. 2008;122(3):e662-e669.PubMedGoogle ScholarCrossref
31.
Murphy  BP, Inder  TE, Rooks  V,  et al.  Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome.  Arch Dis Child Fetal Neonatal Ed. 2002;87(1):F37-F41.PubMedGoogle ScholarCrossref
32.
Adams-Chapman  I, Hansen  NI, Stoll  BJ, Higgins  R; NICHD Research Network.  Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion.  Pediatrics. 2008;121(5):e1167-e1177.PubMedGoogle ScholarCrossref
33.
Brouwer  AJ, Groenendaal  F, Han  KS, de Vries  LS.  Treatment of neonatal progressive ventricular dilatation: a single-centre experience.  J Matern Fetal Neonatal Med. 2015;28(suppl 1):2273-2279.PubMedGoogle ScholarCrossref
34.
Pappas  A, Kendrick  DE, Shankaran  S,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates.  JAMA Pediatr. 2014;168(2):137-147.PubMedGoogle ScholarCrossref
35.
Hintz  SR, Barnes  PD, Bulas  D,  et al; SUPPORT Study Group of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Neuroimaging and neurodevelopmental outcome in extremely preterm infants.  Pediatrics. 2015;135(1):e32-e42.PubMedGoogle ScholarCrossref
36.
Inder  TE, Anderson  NJ, Spencer  C, Wells  S, Volpe  JJ.  White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term.  AJNR Am J Neuroradiol. 2003;24(5):805-809.PubMedGoogle Scholar
37.
Maalouf  EF, Duggan  PJ, Counsell  SJ,  et al.  Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants.  Pediatrics. 2001;107(4):719-727.PubMedGoogle ScholarCrossref
38.
Miller  SP, Cozzio  CC, Goldstein  RB,  et al.  Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography findings.  AJNR Am J Neuroradiol. 2003;24(8):1661-1669.PubMedGoogle Scholar
Original Investigation
January 2018

Neurodevelopmental and Behavioral Outcomes in Extremely Premature Neonates With Ventriculomegaly in the Absence of Periventricular-Intraventricular Hemorrhage

Author Affiliations
  • 1Department of Pediatrics, Wayne State University, Detroit, Michigan
  • 2Emory University School of Medicine, Department of Pediatrics, Children’s Healthcare of Atlanta, Atlanta, Georgia
  • 3Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
  • 4Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center, Houston
  • 5Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, Rhode Island
  • 6Division of Neonatology, University of Alabama, Birmingham
  • 7Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
  • 8Department of Pediatrics, University of Michigan, Ann Arbor
  • 9Department of Pediatrics, University of Iowa, Iowa City
  • 10Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
  • 11Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
  • 12Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
  • 13Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland
  • 14Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
JAMA Pediatr. 2018;172(1):32-42. doi:10.1001/jamapediatrics.2017.3545
Key Points

Question  What is the significance of nonhemorrhagic ventriculomegaly detected on cranial ultrasonography prior to 36 weeks’ postmenstrual age in extremely preterm neonates?

Findings  This observational cohort study of 4193 neonates born at less than 27 weeks’ gestational age found that those with nonhemorrhagic ventriculomegaly had higher odds of neurodevelopmental impairment, poor cognitive outcome, moderate to severe cerebral palsy, and death or neurodevelopmental impairment at 18 to 22 months’ corrected age compared with neonates with normal cranial ultrasonograms. Behavioral outcomes did not differ.

Meaning  Nonhemorrhagic ventriculomegaly is a marker of brain injury and might be associated with early neurodevelopmental risk among extremely preterm neonates.

Abstract

Importance  Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood.

Objective  To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age.

Design, Setting, and Participants  This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017.

Main Outcomes and Measures  The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes.

Results  Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ.

Conclusions and Relevance  Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Introduction

Magnetic resonance imaging studies1-3 have reported an association between ventriculomegaly accompanied by white matter loss and neurocognitive and developmental outcomes among preterm neonates. The association between cranial ultrasonography measures of cerebral ventriculomegaly and long-term outcomes among extremely preterm (EP) neonates without prior or concurrent hemorrhage remains unclear, despite an established role for cranial ultrasonography to detect important pathologic lesions, such as periventricular-intraventricular hemorrhage (PIVH)4,5 and cystic periventricular leukomalacia.6-8 One small single-center study of 44 infants born prior to 30 weeks’ gestational age reported an association between ventriculomegaly at age 1 month and delayed motor and language development at 2 years.9 Another prospective single-center study of very low-gestational-age neonates reported poor neurodevelopmental outcomes among neonates with ventriculomegaly and other brain lesions, but not among those with ventriculomegaly alone.10

Compared with the poor interrater agreement for echodense lesions suggestive of white matter injury, there is an overall better agreement in assessment of ventriculomegaly.9,11-13 In the United States, guidance for the timing and definitions for the classification of preterm cranial ultrasonographic findings, including ventriculomegaly, have been established by the quality standards subcommittee of the American Academy of Neurology and the practice committee of the Child Neurology Society since 2002.14 Similar to prenatal ultrasonographic guidelines, these guidelines define significant ventricular enlargement as a ventricular measurement of 1 cm or larger.14,15 The atrial diameter of the fetal lateral ventricles is constant from 14 to 38 weeks’ gestation, with a mean (SD) of 7.6 (0.6) mm.15,16

We sought to explore the association between nonhemorrhagic ventriculomegaly in neonates and neurodevelopmental and behavioral outcomes at age 18 to 22 months. The objectives of this observational cohort study were to (1) characterize the frequency of nonhemorrhagic ventriculomegaly on cranial ultrasonograms performed during the neonatal intensive care unit stay of neonates born before 27 weeks’ gestational age, (2) explore short-term morbidities, especially systemic inflammation, associated with ventriculomegaly and neonatal brain injury, and (3) characterize the neurodevelopmental and behavioral outcomes of neonates with nonhemorrhagic ventriculomegaly compared with neonates with normal cranial ultrasonograms in a contemporary multicenter cohort within the 16 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN). We hypothesized that EP neonates with evidence of nonhemorrhagic ventriculomegaly would be at increased odds of neurodevelopmental impairment (NDI), cerebral palsy, gross motor functional limitations, and poor behavioral outcomes at 18 to 22 months’ corrected age compared with EP neonates who had had normal cranial ultrasonographic findings. We also hypothesized that a greater proportion of EP neonates would have ventriculomegaly reported on late cranial ultrasonographic findings (closest to 36 weeks’ postmenstrual age) compared with cranial ultrasonograms performed within 28 days of birth.

Methods

This study was a retrospective analysis of prospectively collected data from the Eunice Kennedy Shriver NICHD NRN’s generic database17 and follow-up studies.18 Institutional review board approval was obtained at each participating NRN center, and informed consent was obtained from the parent(s) or legal guardian as specified by each participating center.

As part of the generic database registry, the Eunice Kennedy Shriver NICHD NRN prospectively collects maternal and neonatal data from birth until patient death, hospital discharge, transfer, or 120 days postdelivery. In-hospital outcomes include mortality (ie, death before 12 hours or death before hospital discharge), early-onset sepsis, late-onset sepsis, bronchopulmonary dysplasia, PIVH, ventriculomegaly, cystic periventricular leukomalacia, necrotizing enterocolitis (NEC), retinopathy of prematurity at stage 3 or greater, and inflammation-initiating illnesses, among others.6 Inflammation-initiating illness is defined as any 1 or more of the following: mechanical ventilation at the neonatal age of 2 weeks, culture-proven sepsis or meningitis, and surgical NEC or intestinal perforation.19

Our research team identified infants who were born between July 1, 2006, and June 30, 2011, at any of the 16 centers participating in the Eunice Kennedy Shriver NICHD NRN, at a gestational age of 26 weeks and 6 days or less, with a birth weight greater than 401 g, and with ultrasonographic results and outcome data available. Neonates who died prior to 12 hours of age were excluded, because many of these neonates were not resuscitated and ultrasonographic data were often missing.

Cranial Ultrasonographic Data

Routine cranial ultrasonograms were performed on infants per existing standards of care; ultrasonography was not specified by the study protocol. Ultrasonographical guidelines established by the quality standards subcommittee of the American Academy of Neurology and the practice committee of the Child Neurology Society14 serve as minimum requirements at NRN centers.

Cranial imaging findings were reported by local site radiologists for sonograms performed within 28 days of birth and 36 weeks’ postmenstrual age (or closest to 36 weeks’ postmenstrual age). If multiple scans were performed, the scan closest to 7 days within the 36 weeks’ postmenstrual age date was used. The date of the cranial ultrasonogram with the most severe findings, along with the specific findings, location, and laterality of the ultrasonogram, were included in the data set of the present study. For neonates with multiple scans prior to 28 days, the most severe findings were identified, and the earliest scan that showed these findings was used.

The following lesions were defined: blood or echodensity in the germinal matrix or subependymal area, blood or echodensity in the ventricle, ventricular size enlarged with concurrent or prior blood in the ventricles, ventricular size enlarged without concurrent or prior blood in the ventricles, blood echodensity in the parenchyma, cerebellar hemorrhage, and cystic areas in the parenchyma (cystic periventricular leukomalacia and porencephalic cyst). Nonhemorrhagic ventriculomegaly was defined as enlarged ventricular size without concurrent or prior blood in the ventricles detected on cranial sonogram. Periventricular leukomalacia was defined as cystic areas in the white matter around the ventricles (most commonly dorsal and lateral to the external angle of the lateral ventricle). These echolucencies could be single or multiple, unilateral or bilateral, diffuse or focal, and could vary in size.

Follow-up at Corrected Age 18 to 22 Months

Neonatal data collected during the initial hospitalization of EP infants were linked to follow-up data from the Eunice Kennedy Shriver NICHD NRN follow-up study18 at 18 to 22 months (corrected age). In this study,18 surviving infants underwent formal neurodevelopmental testing and behavioral screenings performed by certified examiners who were blinded to neonatal clinical variables (including ultrasonographic findings); all investigators were certified and trained for reliability.18,20 Psychometric testing was performed using the Bayley Scales of Infant and Toddler Development III (Bayley III),21 which includes cognitive, language, and motor subscales and is standardized to a mean (SD) of 100 (15), and thus a score of less than 70 represents 2 SD or more below the mean. Children who are so developmentally delayed that they cannot be assessed are assigned scores of 54 for severe cognitive delay and 46 for severe language or motor delay. Behavioral screening was performed using the Brief Infant-Toddler Social and Emotional Assessment administered to the primary caregiver in the form of a structured interview.22 The Brief Infant-Toddler Social and Emotional Assessment is a nationally standardized, normative value–referenced behavioral screening instrument that can be used to determine whether diagnostic assessment or referral for socioemotional and behavioral problems may be indicated. Total problem scores can be compared with specific percentile rankings of normative populations; lower percentile rankings (25% or less) are associated with higher problem scores. Specific items address externalizing, internalizing, and dysregulation problems, as well as behaviors or deficits often seen in autism spectrum disorders.

Cerebral palsy is defined as a nonprogressive central nervous system disorder with abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture that interferes with age-appropriate activities.20 Disabling cerebral palsy is classified based on a modified Gross Motor Function Classification System score of level 2 or greater.23 Hearing impairment is defined as permanent hearing loss that does not permit the child to understand or communicate despite amplification. Visual impairment is defined as corrected visual acuity less than 20/200 in both eyes. Neurodevelopmental impairment is defined by 1 or more of the following: a Bayley III cognitive score less than 70, disabling cerebral palsy, a Gross Motor Function Classification System score of level 2 or greater, blindness, or hearing impairment. The primary outcome was composite NDI. Secondary outcome measures included cerebral palsy; gross motor functional limitation; Bayley III cognitive, language, and motor subscores; behavioral scores according to the Brief Infant-Toddler Social and Emotional Assessment; risk of death or NDI combined as a single unit of statistical analysis; and death.

Statistical Analysis

Data analysis was completed from August 2013 to August 2017. For the statistical analysis, continuous variables were described using mean (SD) or median (interquartile range). Categorical variables were described using frequency and percentage. Unadjusted comparisons of maternal demographics, neonatal baseline characteristics, neurodevelopmental outcomes, and behavioral outcomes between the ventriculomegaly group and the normal cranial ultrasonogram group were made using χ2 tests or Fisher exact tests for categorical data and Wilcoxon 2-sample tests (as an approximation for the t test) for continuous data. Logistic regression modeling was used to evaluate the association between nonhemorrhagic ventriculomegaly and adverse outcomes while controlling for center differences (defined as differences in health care populations, facilities, and clinical practices in the centers at which data were collected) as a random effect and for other potentially confounding variables (estimated gestational age, sex, antenatal steroids, maternal educational attainment of less than a high school diploma, late-onset sepsis, physiologic BPD, NEC, and retinopathy of prematurity) as fixed effects. Linear regression was used in a similar manner for continuous outcomes. The NRN center was included in all models as a random effect to control for potential differences in clinical management and interpretation of cranial ultrasonography at different health care centers.

Results

Among the Eunice Kennedy Shriver NICHD NRN centers, 4193 EP neonates younger than 27 weeks’ gestational age and more than 401 g birth weight survived longer than 12 hours and had a cranial ultrasonogram available within or after 28 days of life (Figure). Of these, 3045 had normal cranial ultrasonographic findings (72.6%); 775 neonates had PIVH identified within 28 days of life (18.5%), 73 had findings of isolated cystic periventricular leukomalacia without ventriculomegaly (1.74%), and 300 neonates had nonhemorrhagic ventriculomegaly (7.15%). Nineteen participants (n = 19 of 300; 6.3%) with ventriculomegaly were lost to follow-up. Among neonates with nonhemorrhagic ventriculomegaly who were followed up to 18 to 22 months (corrected age), most had bilateral ventriculomegaly (n = 209 of 281; 74%) and half developed ventricular enlargement after 28 days of life (n = 147 of 281; 52%) (Table 1). Thirty-nine participants had both nonhemorrhagic ventriculomegaly and cystic periventricular leukomalacia. Analyzing the data with and without these participants did not alter the results (eTables 1 and 2 in the Supplement). None of the neonates with nonhemorrhagic ventriculomegaly required ventricular drainage.

Outcome data were available for 3008 of the 3345 neonates with either normal cranial sonograms or ventriculomegaly (90%). Maternal and neonatal characteristics among those who were successfully followed up were compared with those who were lost to follow-up (Table 2). Neonates lost to follow-up were more likely than neonates assessed at follow-up to be singleton, be in a higher gestational age and birthweight strata, have higher umbilical cord pH, and have been exposed to chorioamnionitis. Other baseline characteristics did not differ.

Table 3 presents maternal and neonatal demographic data for the study participants. Compared with participants with normal cranial ultrasonograms, those with ventriculomegaly had lower gestational age, were male, died prior to discharge, and had neonatal morbidities commonly associated with systemic inflammation: respiratory distress syndrome treated with the administration of surfactant, late-onset sepsis, meningitis, BPD, NEC, stage 3 retinopathy of prematurity, and inflammation-initiating illnesses (P < .05; all data supporting comparisons are detailed in Table 3).

Outcomes at 18 to 22 Months’ Corrected Age

Outcomes of neonates with normal cranial ultrasonographic findings were compared with outcomes of those with ventriculomegaly (Table 4) at the corrected age of 18 to 22 months. Models were adjusted for the following covariates: nonhemorrhagic ventriculomegaly, gestational age, sex, use of antenatal steroids, maternal educational attainment less than high school diploma, late-onset sepsis, physiologic BPD, NEC, and retinopathy of prematurity, as well as by Eunice Kennedy Shriver NICHD NRN center (as a random effect). Neonates with ventriculomegaly had higher odds of NDI (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate to severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), and death or NDI (OR, 2.17; 95% CI, 1.62-2.91) compared with premature neonates with normal cranial ultrasonograms; however, they did not have higher odds of death alone (OR, 1.09; 95% CI, 0.76-1.57). Median cognitive composite scores, language scores, and motor scores were 6 to 7 points lower (SD, −0.40 to 0.47) among neonates with nonhemorrhagic ventriculomegaly compared with neonates with normal cranial ultrasonographic findings; this is a clinically meaningful result.24,25 Behavioral outcomes assessed with the Brief Infant-Toddler Social and Emotional Assessment were not associated with ventriculomegaly, although rates of behavioral problems were higher than those typically reported for normally developing children.22

Discussion

Nonhemorrhagic ventriculomegaly is an important but underrecognized neuroimaging finding that predicts early childhood neurodevelopmental risk. Despite an association in magnetic resonant imaging studies1-3 with poor neurodevelopmental outcomes data on nonhemorrhagic ventriculomegaly remain sparse, to our knowledge.6,9 Although identification is potentially easy, these findings are not routinely collected by clinicians and researchers in many quality-improvement collaboratives focused on very low-birth-weight infants.26

Several of our findings are worthy of comment. First, nonhemorrhagic ventriculomegaly was observed in 7% of participants, typically bilateral, and often identified after multiple cranial ultrasonograms had been completed. Second, compared with neonates with normal cranial ultrasonographic findings, neonates with nonhemorrhagic ventriculomegaly had a 2-fold to 3-fold higher odds of NDI, cognitive impairment, moderate to severe cerebral palsy, and death or NDI, but not death alone. Finally, there was no association between nonhemorrhagic ventriculomegaly and parent-reported behavioral outcomes, although behavioral problems were more common in children with ventriculomegaly than in term population norms per parental reports.22

Most studies on the association between ventriculomegaly detected by cranial ultrasonography and outcomes among preterm neonates include lesions with prior or concurrent PIVH. Ment and colleagues27 were among the first to study the cause and outcome of cerebral ventriculomegaly in very low-birth-weight neonates. This pioneering work found a strong association between ventriculomegaly at term-equivalent age and 2 short-term neonatal morbidities: high-grade PIVH and BPD. Long-term outcomes were assessed prospectively at the corrected age of 4.5 years; ventriculomegaly was associated with both motor and cognitive impairment and was the most important predictor of IQ less than 70.

Further work by the ELGAN group11 also investigated the association between unspecified ventriculomegaly (with and without hemorrhage) and short-term and long-term morbidities among neonates born prior to 28 weeks’ gestation. These investigators showed that 12% of neonates had moderate or severe ventriculomegaly on assessment by cranial ultrasonography at up to 3 time points: between days 1 and 4, days 5 to 14, and days 15 through the 40th postconceptional week. Moderate to severe ventriculomegaly was identified with the use of templates for evaluating ventricular size. Ultrasonograms were reviewed by at least 2 study ultrasonographic technicians, who were blinded to clinical data; a third, tie-breaking technician addressed discrepancies between the 2 independent assessments.

Ventriculomegaly was associated with an increased risk of microcephaly28 and cerebral palsy29 at age 2 years, with cerebral palsy affecting 44% of children with ventriculomegaly.29 Compared with children without cranial ultrasonographic abnormalities, those with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis and 11 times more likely to have significant gross motor delay (ie, Gross Motor Function Classification System scores of 2 or more). Ventriculomegaly was also associated with an increased risk of developmental delay, including a 4-fold increase in the risk of psychomotor impairment and a 3-fold increase in the risk of mental impairment as measured by the Bayley Scales of Infant Development II.30

Other investigators have reported on the natural history of posthemorrhagic ventricular dilation; the severity of PIVH has been found to be a major predictor of adverse outcomes.31-33 Neonates with ventriculomegaly or posthemorrhagic hydrocephalus had worse neurodevelopmental outcomes at 18 to 22 months’ corrected age than those who had hemorrhage without persistent ventricular enlargement.32

Similar to prior work, the present study reports poor neurodevelopmental outcomes among EP neonates with ventriculomegaly. However, our focus was on ventriculomegaly without concomitant or preceding hemorrhage. Our data suggest that the accumulation of inflammatory diagnoses might affect the likelihood of ventriculomegaly progression in an infant younger than 28 days to 36 weeks old and thus impact the brain development and subsequent neurodevelopmental trajectory of that infant. In the future, we hope to investigate the pathogenesis and timing of progressive ventriculomegaly in greater detail with serial ventricular measurements. The recent publication of new ultrasonographic reference values might facilitate more consistent identification of ventriculomegaly and facilitate further study.12

Important strengths of our work included the large sample size, which permitted assessment of a variety of neurodevelopmental outcomes of interest; the assimilation of a multicenter cohort (which might have increased the generalizability of the results); the prospective data collection; and the carefully designed and detailed follow-up assessments. Follow-up assessments were performed by blinded examiners who were certified for reliability on an annual basis.

Limitations

The early end point of neurodevelopmental follow-up is a limitation deserving mention. Given the progressive trajectories of many neurocognitive and behavioral skills, longer follow-up of development as the child grows is essential for accurate appraisal of neurobehavioral functioning.

Second, we admit that an obvious limitation of our work is the potential use of differing strategies by individual site radiologists in the interpretation of cranial ultrasonograms. Center differences in cranial ultrasonography technique might result in failures to identify milder ventriculomegaly or mild hemorrhage. Thus, the exclusion of mild PIVH prior to the development of ventriculomegaly might not be possible.

Third, specific ventricular measurements were not recorded in the NRN generic database. Given the fairly constant size of the fetal lateral ventricles from 14 to 38 weeks’ gestation,16 however, a clinical diagnosis of nonhemorrhagic ventriculomegaly remains an important and readily identifiable neuroimaging finding.

As our intent was to capture significant brain injury, the approach of the present study to ultrasonography may predict severe adverse outcomes without overidentifying brain injuries that are amenable to adaptive mechanisms of the developing brain. As a result, the generalizability of our results may also be broader for the practicing neonatologist because this approach uses clinically available data.

An additional limitation was that the precise timing of onset of ventriculomegaly was not reported. Cranial ultrasonogram findings were recorded for sonograms performed in 2 time periods: within 28 days of birth and at 36 weeks’ postmenstrual age (or the date closest to that point).

Finally, a disproportionate number of participants with exposure to maternal chorioamnionitis were lost to follow-up. Chorioamnionitis is associated with subsequent development of ventriculomegaly and poor outcomes,34 so we might have underestimated the effect of ventriculomegaly on our participants.

Conclusions

Though less sensitive than magnetic resonance imaging in detecting white and gray matter loss,35-38 the bedside capability for cranial ultrasonography to identify clinically significant brain lesions in a timely and cost-effective manner make it an important neuroimaging technique for screening large numbers of critically ill neonates. Nonhemorrhagic ventriculomegaly is associated with early childhood developmental risk. Despite the greater emphasis on long-term outcomes of neonates with PIVH in the neonatal literature, nonhemorrhagic ventriculomegaly on sonogram is associated with worse outcomes. In a contemporaneous cohort of EP neonates born at NRN centers, severe PIVH was associated with an approximately 1.7-fold higher odds of NDI4; the present study shows nearly 3-fold higher odds of NDI among neonates with ventriculomegaly. This work provides important data to consider when evaluating the need for advanced neuroimaging, parental counseling, and referral to early intervention and support services. Further study is needed to assess more stringent definitions of ventriculomegaly,12 the specific brain areas that are most compromised (eg, white matter, association tracts, basal ganglia, or cortex), the progression and timing of ventriculomegaly, the intervening factors, and prospective neuroprotective strategies that might ameliorate systemic inflammation and ventriculomegaly.

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Article Information

Corresponding Author: Athina Pappas, MD, St. John Hospital and Medical Center, NICU, 22101 Moross Rd, Detroit, MI 48236 (apappas@med.wayne.edu).

Accepted for Publication: August 10, 2017.

Published Online: November 27, 2017. doi:10.1001/jamapediatrics.2017.3545

Author Contributions: Mr McDonald and Dr Das 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: Pappas, Adams-Chapman, Shankaran, Hintz, Higgins.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pappas.

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

Statistical analysis: McDonald, Das.

Obtained funding: as below.

Administrative, technical, or material support: Stoll, Carlo, Higgins.

Study supervision: Pappas, Shankaran, Hintz, Carlson, Wyckoff, Das, Higgins.

Conflict of Interest Disclosures: None reported.

Funding/Support: The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources (via General Clinical Research Center, or GCRC, grants), and the National Center for Advancing Translational Sciences (NCATS) provided grant support for generic database and follow-up studies of the Neonatal Research Network through cooperative agreements to the following institutions: Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island (NICHD grant U10 HD27904); Case Western Reserve University and Rainbow Babies and Children's Hospital (U10 HD21364, GCRC grant M01 RR80), Children's Mercy Hospital (U10 HD68284), Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, GCRC grant M01 RR8084); Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, M01 RR30, NCATS grant UL1 TR83); Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39, UL1 TR454); Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750, UL1 TR6); Nationwide Children’s Hospital and the Ohio State University Medical Center (U10 HD68278); RTI International (U10 HD36790); Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital (U10 HD27880, M01 RR70, UL1 TR93); Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54); University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32); University of California, Los Angeles, Mattel Children's Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270); University of California, San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461); University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59); University of Miami, Holtz Children's Hospital (U10 HD21397, M01 RR16587); University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997, UL1 TR41); University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children's Hospital of Philadelphia (U10 HD68244); University of Rochester Medical Center, Golisano Children's Hospital, the University of Buffalo Women's, and Children's Hospital of Buffalo (U10 HD68263, U10 HD40521, UL1 RR24160, M01 RR44, UL1 TR42); University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373); University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children's Medical Center Dallas (U10 HD40689, M01 RR633); University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children's Medical Center (U10 HD53124, M01 RR64, UL1 TR105); Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122); Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385); and Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 RR24139, M01 RR125, UL1 TR142).

Role of the Funder/Sponsor: While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. The funders had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

Group Information: The following investigators, in addition to those listed as authors, participated in this study: Neonatal Research Network Steering Committee Chairs: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006-2011); Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011-present). Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island: Martin Keszler, MD; William Oh, MD; Betty R. Vohr, MD; Angelita M. Hensman, MS, RNC-NIC; Kristin M. Basso, BSN, MaT; Barbara Alksninis, PNP; Robert Burke, MD; Melinda Caskey, MD; Andrea Halbrook; Katharine Johnson, MD; Mary Lenore Keszler, MD; Theresa M. Leach, MEd, CAES; Bonnie E. Stephens, MD; Suzy Ventura; Victoria E. Watson, MS, CAS. Case Western Reserve University Rainbow Babies and Children's Hospital: Avroy A. Fanaroff, MD; Anna Marie Hibbs, MD; Deanne E. Wilson-Costello, MD; Nancy S. Newman, BA, RN; Allison F. Payne, MD; Bonnie S. Siner, RN; Monika Bhola, MD; Gulgun Yalcinkaya, MD; Harriet G. Friedman, MA. Children's Mercy Hospital: William E. Truog, MD; Eugenia K. Pallotto, MD, MSCE; Howard W. Kilbride, MD; Cheri Gauldin, RN, MSN CCRC; Anne Holmes RN, MSN, MBA-HCM, CCRC; Kathy Johnson RN, CCRC. Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital: Kurt Schibler, MD; Edward F. Donovan, MD; Cathy Grisby, BSN CCRC; Barbara Alexander, RN; Kate Bridges, MD; Estelle E. Fischer, MHSA MBA; Teresa L. Gratton, PA; Holly L. Mincey, RN BSN; Greg Muthig, BS; Jody Hessling, RN; Teresa L. Gratton, PA; Lenora D. Jackson, CRC; Kristin Kirker, CRC; Kimberly Yolton, PhD. Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital: Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Ricki F. Goldstein, MD; Kathryn E. Gustafson, PhD; Joanne Finkle, RN JD; Patricia L. Ashley, MD PhD; William F. Malcolm, MD; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD FNP-BC IBCLC; Katherine A. Foy, RN; Sandra Grimes, RN BSN; Melody B. Lohmeyer, RN MSN; Matthew M. Laughon, MD, MPH; Carl L. Bose, MD; Janice Bernhardt, MS, RN; Gennie Bose, RN; Janice K. Wereszczak, CPNP-AC/PC. Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown: David P. Carlton, MD; Ellen C. Hale, RN, BS, CCRC; Yvonne C. Loggins, RN, BSN; Maureen Mulligan LaRossa, RN; Sheena L. Carter, PhD. Eunice Kennedy Shriver National Institute of Child Health and Human Development: Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services: Gregory M. Sokol, MD; Brenda B. Poindexter, MD, MS; Anna M. Dusick, MD (deceased); Lu-Ann Papile, MD; Dianne E. Herron, RN; Lucy C. Miller, RN, BSN, CCRC; Carolyn Lytle, MD, MPH; Ann B. Cook, MS; Heike M. Minnich, PsyD, HSPP; Abbey C. Hines, PsyD; Leslie Dawn Wilson, BSN, CCRC; Faithe Hamer, BS. Nationwide Children’s Hospital and the Ohio State University Medical Center: Pablo J. Sánchez, MD; Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Keith Owen Yeates, PhD; Patricia Luzader, RN; Christine A. Fortney, PhD, RN; Gail E. Besner; Nehal A. Parikh, MD. RTI International: Dennis Wallace, PhD; W. Kenneth Poole, PhD (deceased); Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS, CCRP; Marie G. Gantz, PhD; Jamie E. Newman, PhD; Carolyn M. Petrie Huitema, MS, CCRP; Kristin M. Zaterka-Baxter, RN, BSN, CCRP. Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital: David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Marian M. Adams, MD; Barbara Bentley, PhD; Elizabeth Bruno, PhD; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN, PNP; Lynne C. Huffman, MD; Jean G. Kohn, MD, MPH; Casey E. Krueger, PhD; Andrew W. Palmquist, RN; Melinda S. Proud, RCP; Brian Tang, MD; Hali E.Weiss, MD. Tufts Medical Center, Floating Hospital for Children: Ivan D. Frantz III, MD; John M. Fiascone, MD; Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Ana K. Brussa, MS,OTR/L; Anne Furey, MPH; Ellen Nylen, RN, BSN; Cecelia E Sibley PT, MHA. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama: Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD, MPH; Monica V. Collins, RN, BSN, MaEd; Shirley S. Cosby, RN, BSN; Vivien A. Phillips RN; Fred J. Biasini, PhD; Kristy Domnanovich, PhD; Kristen C. Johnston, MSN, CRNP; Carin Kiser, MD; Sara Kryzwanski, MS; Kathleen G. Nelson, MD; Cryshelle S. Patterson, PhD; Richard V. Rector, PhD; Leslie Rodrigues, PhD; Sarah Ryan, PhD; Leigh Ann Smith, CRNP; Amanda D. Soong, MD; 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: Uday Devaskar, MD; Meena Garg, MD; Isabell B. Purdy, PhD, CPNP; Teresa Chanlaw, MPH; Rachel Geller, RN, BSN. University of California, San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns: Neil N. Finer, MD; David Kaegi, MD; Maynard R. Rasmussen, MD; Yvonne E. Vaucher, MD, MPH; Kathy Arnell, RNC; Clarence Demetrio, RN; Martha G. Fuller, RN, MSN; Chris Henderson, RCP, CRTT; Wade Rich, BSHS, RRT; Radmila West, PhD. University of Iowa and Mercy Medical Center: Edward F. Bell, MD; Dan L. Ellsbury, MD; John A. Widness, MD; Tarah T. Colaizy, MD, MPH; Michael J. Acarregui, MD; Karen J. Johnson, RN, BSN; Donia B. Campbell, RNC-NC; Diane L. Eastman, RN, CPNP, MA; Jacky R. Walker, RN. University of Miami and Holtz Children's Hospital: Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN; Sylvia Fajardo-Hiriart, MD; Arielle Rigaud, MD; Maria Calejo, MS; Silvia M. Frade Eguaras, MA; Michelle Harwood Berkowits, PhD; Andrea Garcia, MS; Helina Pierre, BA; Alexandra Stoerger, BA. University of New Mexico Health Sciences Center: Kristi L. Watterberg, MD; Robin K. Ohls, MD; Andrea H. Duncan, MD; Janell F. Fuller, MD; Conra Backstrom Lacy, RN; Sandra Brown, BSN; Carol Hartenberger, BSN MPH; Jean R. Lowe, PhD; Rebecca A. Montman, BSN, RNC. University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children's Hospital of Philadelphia: Barbara Schmidt, MD, MSc; Haresh Kirpalani, MB, MSc; Sara B. DeMauro, MD, MSCE; 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. University of Rochester Medical Center, Golisano Children's Hospital, the University of Buffalo Women's, and Children's Hospital of Buffalo: Carl T. D’Angio, MD; Dale L. Phelps, MD; Ronnie Guillet, MD, PhD; Gary J. Myers, MD; Linda J. Reubens, RN, CCRC; Erica Burnell, RN; Diane Hust, MS, RN, CS; Julie Babish Johnson, MSW; Julianne Hunn, BS; Rosemary L. Jensen; Emily Kushner, MA; Deanna Maffett, RN; Joan Merzbach, LMSW; Holly I.M. Wadkins; Kelley Yost, PhD; Lauren Zwetsch, RN, MS, PNP; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD, MPH; Farooq Osman, MD; Ashley Williams, MSEd; Karen Wynn, RN. University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District: Kathleen A. Kennedy, MD, MPH; Jon E. Tyson, MD, MPH; Georgia E. McDavid, RN; Nora I. Alaniz, BS; Katrina Burson, RN, BSN; Patricia W. Evans, MD; Charles Green, PhD; Beverly Foley Harris, RN, BSN; Margarita Jiminez, MD, MPH; Anna E. Lis, RN, BSN; Sarah Martin, RN, BSN; Brenda H. Morris, MD; M. Layne Poundstone, RN, BSN; Peggy Robichaux, RN, BSN; Saba Siddiki, MD; Maegan C. Simmons, RN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT(ASCP). University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children's Medical Center Dallas: Pablo J. Sánchez, MD; Luc P. Brion, MD; Roy J. Heyne, MD; Walid A. Salhab, MD; Charles R. Rosenfeld, MD; Diana M. Vasil, RNC-NIC; Sally S. Adams, MS, RN CPNP; Lijun Chen, PhD, RN; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, MS, MA, PA-C PsyD; Melissa H. Leps, RN; Linda A. Madden, RN, CPNP; Nancy A. Miller, RN; Janet S. Morgan, RN; Lizette E. Torres, RN; Catherine Twell Boatman, MS, CIMI. University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children's Medical Center: Roger G. Faix, MD; Bradley A. Yoder, MD; Anna Bodnar, MD; Karen A. Osborne, RN, BSN, CCRC; Shawna Baker, RN; Karie Bird, RN BSN; Jill Burnett, RNC BSN; Laura Cole, RN; Jennifer J. Jensen, RN, BSN; Cynthia Spencer, RNC; Michael Steffen, MS, CPM; Kimberlee Weaver-Lewis, RN, BSN; Sarah Winter, MD; Karen Zanetti, RN. Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital: T. Michael O’Shea, MD, MPH; Robert G. Dillard, MD; Lisa K. Washburn, MD; Barbara G. Jackson, RN, BSN; Nancy Peters, RN; Korinne Chiu, MA; Deborah Evans Allred, MA, LPA; Donald J. Goldstein, PhD; Raquel Halfond, MA; Carroll Peterson, MA; Ellen L. Waldrep, MS; Cherrie D. Welch, MD MPH; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD. Wayne State University and Hutzel Women’s Hospital and Children’s Hospital of Michigan: John Barks, MD; Rebecca Bara, RN, BSN; Angela Argento; PhD; Laura A. Goldston, MA; Mary Johnson, RN, BSN; Mary Christensen, RT; Stephanie Wiggins, MS. Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital: 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; Elaine Romano, MSN.

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

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