follow-up care of high-risk infants · risk factors for preterm (

Follow-up Care of High-Risk Infants

ABSTRACT. A workshop on the follow-up care ofhigh-risk infants sponsored by the National Institute ofChild Health and Human Development, National Insti-tute of Neurologic Disorders and Stroke, and the Centersfor Disease Control and Prevention was held June 19-20,2002. There are currently no standardized guidelines forprovision of follow-up services for high-risk infants intertiary care centers despite the requirement for fol-low-up clinic experience in the 97 approved neonatalfellowship training programs in the United States andthe increasing number of centers participating in multi-center networks. As the total number of survivors at riskfor neurodevelopmental morbidities increases, manyclinical research questions have surfaced that can only beanswered by long-term follow-up studies. There is in-creasing awareness of the importance of long-term out-come in randomized, controlled trials, because perinatalinterventions may dramatically alter later growth anddevelopment. There is also an increased recognition ofthe potential disconnect between perinatal outcomes andlong-term outcomes. The administration of oxygen andpostnatal steroids are prime examples of interventionsthat may have immediate positive effects but negativelong-term effects. In addition, multicenter studies haveidentified significant center differences in the manage-ment and developmental outcome of high-risk infants.These findings led to the recognition of the need toimprove standardization and comparability of methodol-ogy and data collection within and among centers andnetworks as a first step toward research to improve thelong-term neurodevelopmental outcome of high-risk in-fants. The workshop participants met to define optimalmethods to assess the outcome of high-risk infants, iden-tify gaps in knowledge about the neurodevelopmentaloutcome of high-risk infants, and prioritize research ef-forts in response to these gaps. Pediatrics 2004;114:1377–1397.

ABBREVIATIONS. NICHD, National Institute of Child Healthand Development; NICU, neonatal intensive care unit; RCT, ran-domized, controlled trial; ELBW, extremely low birth weight;VLBW, very low birth weight; CNS, central nervous system; MRI,magnetic resonance imaging; PVL, periventricular leukomalacia;NEC, necrotizing enterocolitis; SES, socioeconomic status; MDI,Mental Development Index; PDI, Psychomotor DevelopmentalIndex; BSID-II, Bayley Scales of Infants Development-II; GMFCS,Gross Motor Function Classification System; ADHD, attention-deficit/hyperactivity disorder; NEPSY, Neuropsychological Test;BINS, Bayley Infant Neurodevelopmental Screener; LRO, Lan-guage Receptive Organization; LEO, Language Expressive Orga-nization; CPT, Continuous Performance Test; CAT/CLAMS, Cog-nitive Adaptive Test/Clinical Linguistic and Auditory MilestoneScale; TOVO, Test of Variables of Attention; CBCL, Child BehaviorCheck List; QOL, quality of life; CHQ, Child Health Question-naire; HRQL, health-related quality of life.

BACKGROUND

Advances in perinatal intensive care have beenassociated with improved survival of high-risk neonates but have not resulted in de-

creased morbidity. Small sample sizes, heterogeneityof cohorts and methodology, diversity of perinatalclinical practice, and the high cost of randomized,controlled trials (RCTs) and follow-up care have allcontributed to the lack of rigorous data on the se-quelae of preterm delivery and the therapies used toimprove the long-term outcome of high-risk infants.In response to this need, a workshop on follow-upcare of high-risk infants sponsored by the NationalInstitute of Child Health and Development (NICHD)and the National Institute of Neurologic Diseasesand Stroke was held in Bethesda, Maryland, on June19 and 20, 2002. The goal of the workshop was todefine optimal methods to assess the outcome ofhigh-risk infants, identify gaps in knowledge aboutthe neurodevelopmental outcome of high-risk in-fants, and prioritize research efforts in response tothese gaps.

There are currently no standardized guidelines forprovision of follow-up services for high-risk infantsin tertiary care centers despite the requirement forfollow-up clinic experience in the 97 approved neo-natal fellowship training programs in the UnitedStates and the increasing number of centers partici-pating in multicenter networks. As the total numberof survivors at risk for neurodevelopmental morbid-ities increases, many clinical research questions havesurfaced that can only be answered by long-termfollow-up studies. There is increasing awareness ofthe importance of long-term outcome in RCTs, be-cause perinatal interventions may dramatically alterlater growth and development. There is also an in-creased recognition of the potential disconnect be-tween perinatal outcomes and long-term outcomes.The administration of oxygen and postnatal steroidsare prime examples of interventions that may haveimmediate positive effects but negative long-termeffects.1–4 In addition, multicenter studies have iden-tified significant center differences in the manage-ment and developmental outcome of high-risk in-fants.5–8 These findings led to the recognition of theneed to improve standardization and comparabilityof methodology and data collection within andamong centers and networks as a first step towardresearch to improve the long-term neurodevelop-mental outcome of high-risk infants.

OBJECTIVES OF THE WORKSHOP

1. To discuss the benefits of neonatal follow-up pro-grams for nurseries providing neonatal intensivecare unit (NICU) care.

Accepted for publication Aug 2, 2004.doi:10.1542/peds.2004-0866PEDIATRICS (ISSN 0031 4005). Published in the public domain by theAmerican Academy of Pediatrics.

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2. To define who should be followed and what char-acteristics of premature infants and term infantsare associated with an increased risk for neurode-velopmental morbidity.

3. To define the (1) the optimal ages of follow-upassessment and (2) the optimal assessment mea-sures and to minimize barriers to assessmentcaused by motor, vision, or hearing impairments.

4. To discuss approaches to selection of controls andmaintaining follow-up.

5. To describe alternative, less costly methods andapproaches to assessment for the community phy-sician.

6. Describe the challenges encountered in multi-center networks.

7A. To identify gaps in knowledge about assessmentof neurodevelopmental outcome among high-risk infants and the mechanisms contributing tothese outcomes.

7B. To further advance areas of investigation.8. To propose future research questions.

OBJECTIVE 1: DETERMINE THE BENEFITS OFNEONATAL FOLLOW-UP PROGRAMS AT

PERINATAL CENTERSThe 2 primary areas of responsibility for neonatal

follow-up programs are surveillance and research.

SurveillanceThe first step in surveillance is to establish a mech-

anism to systematically monitor the care of high-riskinfants during their initial hospitalization as well astheir general health and neurodevelopmental out-comes after discharge from the NICU. Surveillance isnecessary for NICUs to (1) audit NICU interventions,(2) monitor important quality indicators for the indi-vidual NICU, (3) summarize information about cen-ter outcomes for a specific condition (eg, chroniclung disease), and (4) summarize annual outcomedata to be used to influence policy and as a basis forpublic health programs designed to improve out-comes. Outcomes of interest may include rates ofgrowth failure, cerebral palsy, mental retardation, ordevelopmental delay; hearing impairments, visionimpairments, or autism; need for technologic sup-port such as home oxygen, ventilators, tracheosto-mies, or gastrostomies; and educational resourcesneeded. Information about center outcomes forspecific conditions and specific gestational ages alsoallows staff caring for high-risk infants to counselparents with regard to prognosis.9 Providing com-prehensive feedback of each evaluation to the familyand the primary provider with appropriate counsel-ing and referrals supports the concept of an effectivemedical home for NICU graduates.

ResearchFollow-up results of populations enrolled in RCTs

and well-designed cohort studies are needed to eval-uate the long-term impact of interventions designedto improve the outcome of high-risk populations andidentify previously unknown safety problems.

OBJECTIVE 2: DETERMINE WHO NEEDS TO BEFOLLOWED AND WHAT THE IMPORTANT RISK

CATEGORIES AREIdentified risk factors for adverse neurodevelop-

mental outcome in preterm and term infants identi-fied in studies to date are listed in Table 1. Infantsshould receive follow-up assessments based on theseverity of the perinatal problems, the interventionsreceived in the NICU, the demographic risk factorsof the infants’ families, the outcome profile of thecohort in the individual NICU, and the NICU’s re-sources. At a minimum, the follow-up cohort shouldinclude extremely low birth weight (ELBW) infants�1000 g birth weight and/or �28 weeks’ gestationand term infants with hypoxic ischemic encephalop-athy or severe hyperbilirubinemia requiring ex-change transfusion. In addition, it is recommendedthat all children, especially those cared for in aNICU, have the benefit of periodic preventive assess-ments by their primary care physicians within thecontext of a medical home. The guidelines estab-lished for the periodicity schedule developed by theCommittee on Practice and Ambulatory Medicine10

in consultation with national committees and sec-tions of the American Academy of Pediatrics includeregular basic assessments of growth, sensory func-tion, behavior, and neurodevelopment. Infants withsuspect findings and families with parenting chal-lenges should be referred for additional, more com-prehensive evaluation to their follow-up program,child development center, and additional commu-nity resources as needed. Moreover, follow-up carein a follow-up program or by the primary care pro-vider should include counseling and support forfamilies and communication among all participantsin the medical home. Evaluation of the family shouldinclude information on adequacy of parenting skills,use of drugs, alcohol, and/or cigarettes, parent phys-ical and mental health status, and adequacy of fi-nances and health insurance. Referrals need to befacilitated by the medical home, as needed, withinput from the family. Early-intervention parentgroups, NICU parent groups, Family Voices, andcommunity mental health services may be beneficial.

Risk Factors for Preterm (<32 Weeks or Very Low BirthWeight, <1500 g) Infants

The developing brain of the premature infant isextremely vulnerable to injury. The long-term conse-quences of such injury include motor deficits com-monly referred to as cerebral palsy (a nonprogressiveinjury of the central nervous system (CNS) charac-terized by abnormal control of movement and pos-ture) as well as cognitive and behavioral prob-lems.11–19 The risk for neurodevelopmental deficitsincreases with decreasing gestational age, resultingin relatively high risk of cerebral palsy, develop-mental delay, hearing and vision impairment, andsubnormal academic achievement among ELBW in-fants.4,8,11 These performance deficits are thoughtto be related to the increased biological vulnerabilityto injury of the basal ganglia, hippocampus, andperiventricular white matter in premature in-

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fants.20–23 Risk for cerebral palsy and neurodevelop-mental disabilities can be predicted in part fromspecific abnormalities on neonatal cranial ultrasoundor magnetic resonance imaging (MRI); however, cog-nitive and behavioral problems may occur in theabsence of identified neonatal neuroimaging abnor-malities.13

Factors That May Affect Outcome: Biological FactorsPeriventricular-intraventricular hemorrhage is the

most common CNS lesion in the premature infant,which in its mildest form is confined to the germinalmatrix and in more severe cases is complicated bybleeding into the adjacent ventricular system and/orwhite matter. Long-term neurodevelopmental defi-cits are strongly linked to these severe lesions.16,17

Approximately 26% of infants with birth weightsbetween 501 and 750 g and 12% of infants with birthweights between 751 and 1000 g develop the moresevere forms of CNS hemorrhage.18

Periventricular white matter injury (or periven-tricular leukomalacia [PVL]) may be identified oncranial ultrasound or MRI by the appearance of cys-tic lesions.12 Cystic PVL is invariably associated withsignificant motor and cognitive deficits. Nonprogres-sive ventriculomegaly, secondary to loss of cortical

mass, is also associated with increased risk of neu-rodevelopmental deficit.20 Linear hyperechogenicitywithin the thalamo-striatal ganglia of premature in-fants also has been associated with lower mental anddevelopmental behavioral scores.21

Severe preterm delivery, male gender, sepsis, men-ingitis, necrotizing enterocolitis (NEC) requiring sur-gery, chronic lung disease/prolonged ventilation, se-vere growth restriction (�10th percentile for age andgestational age), and posthemorrhagic hydrocepha-lus have been identified as risk factors for adverseneurodevelopmental outcome in neonatal follow-updatabases.18,19 Additional risk factors identified in-clude multiple birth, medical complications in theNICU, and congenital abnormalities requiring med-ical or surgical intervention. Finally, research sug-gests that environmental stress in the NICU may bean important risk factor. For example, experimentalevidence from animal models implicates environ-mental stress in the genesis of hippocampal inju-ry.22–24

Therapeutic InterventionsPerinatal interventions may affect neurodevelop-

mental outcome. For example, a large RCT and manylarge observational studies have documented that a

TABLE 1. Defined Risk Categories in the Term and Preterm Infant

Infants Preterm Term

Biologic risk VLBW infants �1500 g birth weight Encephalopathy persisting at dischargeELBW infants �1000 g birth weight Other neurologic problems/meningitisInfants with cranial ultrasound abnormalities

including PVL-intraventricular hemorrhage,linear hyperechogenicity,

Complex medical problems

Other neurologic problems (seizures,hydrocephalus)

Small for gestation

NEC Twin-twin transfusionChronic lung disease Complex congenital anomaliesComplex medical problems Birth defectsSmall for gestation Metabolic disordersHigher-order multiples Sepsis, meningitis, nosocomial infectionsTwin-twin transfusion Hyperbilirubinemia requiring exchangeComplex congenital anomalies Failure to grow in the NICURecurrent apnea and bradycardia MultiparityHyperbilirubinemia requiring exchange Abnormal neurologic exam at dischargeFailure to grow in the NICUSepsis, meningitis, nosocomial infectionsMultiparityAbnormal neurologic exam at discharge

Interventions Resuscitation ResuscitationPostnatal steroids Postnatal steroidsHigh-frequency ventilation High-frequency ventilationProlonged ventilation �7 days Prolonged ventilation �7 daysTotal parenteral nutrition Total parenteral nutritionProlonged oxygen requirements Prolonged oxygen requirementsNutritional therapies Nutritional therapiesOther medications Other medicationsSurgical interventions for NEC, patent ductus

arteriosus, shuntSurgical intervention for NEC, shunt

Extracorporeal membrane oxygenationSocial/environmental Low maternal education, teen mother Low maternal education, teen mother

Low SES: Hollingshead,32 Hauser33 Low SES: Hollingshead,32 Hauser33

Single marital status Single marital statusMinority status Minority statusNo insurance or Medicaid insurance No insurance or Medicaid insuranceLow income Low incomeDrugs/alcohol, smoking, substance abuse Drugs/alcohol, smoking, substance abuseNo prenatal care No prenatal careEnvironmental stress Environmental stress

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single course of antenatal glucocorticoid therapy ma-tures the fetus and improves survival, skin integrity,and renal function and decreases periventricular/intraventricular hemorrhage.25–27 In contrast, pro-longed postnatal steroid therapy to prevent or ame-liorate chronic lung disease seems to be associatedwith negative CNS outcomes.19,28–30 Prolonged expo-sure to glucocorticoids in the animal model is asso-ciated with reductions in regional cerebral bloodflow, specifically to hippocampus, with concomitanthistologic changes, significant reduction in hip-pocampal volume, down-regulation of myelin basicprotein and proteolipid protein in white matter, de-layed myelination of optic axons, hyperactivity of thehypothalamic-pituitary-adrenal axis, and alterationsin dopamine receptor responses.31

Family/Environmental CharacteristicsThe social and/or environmental characteristics of

families32–35 become increasingly important as thechild matures. Assessment of socioeconomic status(SES) in an individual or family unit is an indirectrather than direct measure of the social environmentof the family. Mother-child interaction is a moreproximal factor and is more predictive of earlieroutcome �2 years, whereas SES is a status or distalfactor and is more predictive of later outcome.36 In areview of social class and developmental outcomesin 37 studies conducted in 2000,33 low social class, asdetermined by several different means, was associ-ated with poorer growth, greater academic difficul-ties including reading and spelling problems, lowerIQ, poorer language skills, poorer fine motor skills,more aggression and externalizing behavior, moredepression and other psychiatric disorders, poorersibling relationships, and poorer social development.However, social class did not consistently predictsymbolic play in infants or Bayley Mental Develop-ment Index (MDI)37 and Psychomotor Developmen-tal Index (PDI) scores up to 2 years. Although indi-cators of social class are effective predictors for anumber of developmental outcomes, it must be rec-ognized that effects are mediated by the child char-acteristics, family characteristics, and external sup-ports.

The most common single measures used to assessSES are family income, educational level, and occu-pation. The easiest information to obtain is maternaleducational level, but it may be only weakly relatedto the current status of the family. Although incomemay be more closely related to the family’s currentSES status, many respondents are uncomfortableabout disclosing their income or uncertain about theactual amount. To overcome these problems, re-search protocols typically ask for income category,which is easier for the respondent but poses statisti-cal challenges because categories are not continuousvariables. The most common composite measure ofSES is the Hollingshead32 Index of Social Prestige,which is a weighted average of educational and oc-cupational levels. Years of education completed areclassified into 7 categories, and occupations are clas-sified into 9 categories of increasing status. The Holl-ingshead scale has the advantage of combining edu-

cation and occupation across 1 or 2 adult wageearners in the household as an algorithm for classi-fication into SES levels. An important disadvantageis that the original combination rules are designedfor nuclear families. Other disadvantages are that theHollingshead Scale is insensitive to heterogeneitywithin a social class category, and the categories foroccupation were developed almost 30 years ago. In-clusion of income level or percent of poverty levelprovides better discrimination among families.34

Composite scores that combine several SES indica-tors and a standardized assessment of the homeenvironment (Caldwell’s HOME scale38) have beenused to overcome some of these limitations. TheHOME scale is highly predictive of school perfor-mance but is generally too expensive for standarduse.39 Attempts to define a question or set of ques-tions that capture family-life characteristics, eg,monthly rent or mortgage,34 as recommended by theWorld Health Organization for the developingworld, have been less successful in the United States,because many of the questions are subject to non-SESinfluences. Overall, the Hollingshead Scale is a solidmeasure and remains a powerful predictor of out-come. It is one of the best measures of poverty,single-parent families, and the lifetime consequencesof low education.

Any analysis of differences between study groupsthat does not account for SES either by equivalentgroups or statistical adjustment may be flawed, be-cause SES may be an important moderator of peri-natal risk and developmental outcome. The choice ofhow to manage the variance accounted for by SESdepends on the study hypothesis. SES is frequentlyadjusted even with equivalent groups to reduce errorvariance. With very preterm infants or infants sus-taining biological insult, there can be an interactionbetween perinatal risk status and SES such that high-risk infants raised in high-SES families have morepositive outcomes, whereas those raised in low-SESfamilies have poorer outcomes.39 There are numer-ous additional environmental factors that have beenshown to be associated with outcomes, includingmaternal depression, substance abuse, crowding inthe home, and availability of educational materialsand early-intervention services. Investigators mustidentify which variables are important at their centerand which variables contribute to the specific re-search question being asked. In addition, most pro-grams currently collect data on resource utilization,including early intervention, physical therapy, occu-pational therapy, speech therapy, day care, special-ized educational services, and rehospitalizations.These data are collected to determine if the child isreceiving adequate services so that referrals can bemade or information shared as needed. In addition,resource utilization is an important variable to beevaluated in outcome studies.

OBJECTIVE 3A: DETERMINE THE OPTIMAL AGESOF ASSESSMENT

Although long-term follow-up of complete cohortsis optimal for determining the ultimate function ofhigh-risk infants and the safety of antenatal and pre-


natal interventions, most follow-up studies are short-term (�2 years). The selection of age of assessment isdriven by several factors: developmental acquisitionsavailable at a given age; availability and applicabilityof appropriate test instruments at specific ages;trends found in extant studies; and the cost andfeasibility of long-term tracking in the population inquestion.

Assessment schedules should reflect the questionasked in a specific research protocol. For surveillancepurposes, a center may propose periodic enrollment(eg, ELBW infants may be enrolled for 1 year every 5years and followed for 5 years, after which a newcohort may be enrolled).

In many NICU programs, all very low birth weight(VLBW) infants are referred to early intervention atthe time of discharge from the NICU. Eligibility forearly-intervention services, however, varies by state.If a developmental assessment is needed before 12months to establish eligibility for a referral to aninfant stimulation program, a 6- to 8-month correct-ed-age evaluation is recommended, using the BayleyScales of Infant Development-II (BSID-II) MDI. The util-ity of assessment before this age is questionable.

12 Months’ Corrected AgeEnvironmental factors are less influential on per-

formance at 12 months’ corrected age, and biomedi-cal issues such as oxygen supplementation forchronic lung disease have resolved and may be lessintrusive on testing procedures. By 12 months’ cor-rected age, a more varied behavioral repertoire isavailable, and cognitive processes and emerging lan-guage can be assessed. Evaluation at this age alsoencourages family involvement in the program.However, cognitive and motor functions are stillhighly intertwined at 12 months’ corrected age, andthe period of developmental acquisition is a time ofvariability. Also, some neurologic abnormalities thatare identified in the first year of life are transient orimprove, whereas findings in other children mayworsen over time.40

18 to 24 Months’ Corrected AgeBy 18 to 24 months’ corrected age, environmental

factors begin to exert a stronger influence on testresults, cognitive and motor abilities diverge, lan-guage and reasoning skills are developing, and thereis improved prediction to early school-age perfor-mance.41–43 A potential problem is that many intelli-gence tests have weak floors at this age, therebyrestricting use to developmental tests, and thereforeimpairments may be overestimated or underesti-mated. Application of corrected age (the sum of chro-nologic age in weeks minus the difference betweengestational age at birth and 40 weeks’ gestation) to 2or 2 1/2 years is controversial but generally accept-ed.44,45 Standard follow-up for many multicenter net-works is currently at 18 to 24 months’ corrected age.

3 to 4 YearsAt 3 to 4 years, “intelligence” can first be assessed,

as well as concept development, preacademic skills,early indicators of executive function, and visual-

motor integrative abilities. Verbal and nonverbalskills can be better differentiated. There is also anacceptable level of prediction46 from scores at thisage to later IQ scores. SES and social support, as wellas other environmental factors, influence test resultsmore strongly from age 3 years onward.

6 YearsBy 6 years of age, a variety of tests and procedures

can be used, and attention problems and schoolachievement (approximately first grade) can be as-sessed. The array of possible tests that can be used ismore restricted at age 5 than at age 6.

8 YearsIQ, neuropsychological function, learning disabil-

ities, school performance, and behavioral adjustmentcan be adequately assessed at 8 years (approximatelythird grade). IQ measured at 8 years predicts later IQmore accurately than at earlier ages.

OBJECTIVE 3B: DETERMINE THE APPROPRIATEASSESSMENTS FOR ADMINISTRATION AT THE

RECOMMENDED AGESTen different domains of development were iden-

tified and are related to age of assessment in Table 2.Three areas are basic (growth, neurologic status, anddevelopmental status) and should be included inevery follow-up program. The measures presentedare based on the extensive experience of the partici-pants in the workshop. It is anticipated that the in-formation provided will assist follow-up programsto make choices based on this report and practicalconsiderations.

GrowthAssessment of growth should include birth

weight, birth length, and birth head circumferencerelative to an appropriate growth chart and an accu-rate determination of gestational age at birth. Themost commonly used fetal growth charts are those ofLubchenco et al47,48; however, these charts reflectpreterm deliveries at �1 mile above sea level. Theintrauterine growth standards developed by Usherand McLean49 do not reflect the cohort at greatestrisk (22–24 weeks’ gestation); they were published in1969 for infants between 25 and 44 weeks’ gestation.More recent population-based intrauterine growthstandards have been published for the Canadianpopulation for infants between 22 and 44 weeks’gestation.50 The NICHD Neonatal Research Networkuses fetal growth charts developed by Alexander etal51 that provide reference weights for infants bornfrom 20 to 38 weeks’ gestation for US infants. Thesefetal growth charts are often used to plot postnatalgrowth, although the environmental and metabolicdemands of postnatal growth are very different fromthose during fetal development. The NICHD Neona-tal Research Network has developed postnatalgrowth charts for VLBW infants52; however, thesegrowth trajectories should not be considered opti-mal, because �15% of VLBW infants have a weight�10th percentile at birth but 90% are �10th percen-tile for their corrected fetal age at hospital discharge.


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Weight, length, and head circumferences should becollected routinely and serially in all programs byexaminers trained to reliability using standard tech-niques. For children �2 years, weight should beobtained with the child completely undressed. Re-cumbent length is obtained until age 2 by using apediatric length board, and maximal occipital frontalhead circumference is recorded to the nearest milli-meter by using a nonstretch measuring tape. Anthro-pometric measures in the United States are plottedaccording to gender and age (adjusted until age 2) onNational Center for Health Statistics growth charts.Poor growth is defined as weight, length, head cir-cumference, or weight-to-length ratio �10th percen-tile.53 Other measures of growth used in researchprotocols include skinfold thickness,54 calculatedmeasures of weight-to-length ratios, growth velocity,protein and caloric intake, energy expenditure, andbone density.

Neurologic OutcomeThe neurologic examination of the toddler and

older child40,55–57 is an integral part of the neurode-velopmental follow-up assessment, yet it remainspoorly described and standardized in many researchprotocols. This early assessment can identify infantswith mild, moderate, and severe abnormalities. Thisassessment is of interest because infants with mild ortransient neurologic abnormalities often improveover time, unlike infants with severe early neurologicdysfunction, who are less likely to improve and havethe worst neurodevelopmental outcome.40 The neu-rologic examination of the toddler and older childcan be used to determine resource needs such asearly intervention. Follow-up programs need to de-velop a manual of operations for the entire assess-ment, use a standardized neurologic examination,establish definitions, and train and certify examinersto reliability on an annual basis. Components of theexamination should include assessment of gross mo-tor function, tone, reflexes, cerebellar function, cra-nial nerves, and language. In addition, excellent ob-servation skills, adherence to examination protocol,good interpersonal skills, and flexibility are the keyto an accurate assessment of the young child; muchcan be learned by observation of posture, movement,and quality of movement before the onset of the“formal” examination.

ImagingThe application of MRI to predicting outcome in

high-risk children or for evaluating them later in lifeis an evolving field.58–66 Conventional MRI is effec-tive for detecting developmental abnormalities of theCNS and PVL virtually any time after birth. Diffu-sion magnetic resonance methods measure changesin water apparent diffusion coefficient and are usedas an early indicator of brain injury becoming sensi-tive 2 to 5 days after injury in infants. T1- and T2-weighted images also detect CNS injury, althoughtheir sensitivity varies with the time after the injury.Conventional T1- and T2-weighted MRI is routinelyused to assess myelin development and maturationstatus in children and preterm infants. Functional

MRI may be used to assess the cortical reorganiza-tion associated with injury and recovery. These tech-niques and the development of age-based norms areunder continuous development. Imaging technolo-gies are currently being used in the NICU to evaluateCNS injury to determine risk category and potentialpostdischarge needs and to predict outcome. Currentstudies are evaluating the use of MRI in older chil-dren to evaluate the association between neurocog-nitive skills and brain injury.

Gross Motor SkillsSpecific tests of gross motor function are currently

frequently combined with the standard neurologicexamination. The Gross Motor Function Classifica-tion System (GMFCS)67 is the first reliable and vali-dated system available to describe the severity ofmotor dysfunction in children with cerebral palsyand has been shown to be reasonably stable betweenthe ages of 2 and 12 years.68 The GMFCS for cerebralpalsy provides classification of age-adjusted varia-tions in 5 levels of gross motor function, with thehighest level of mobility expected between 6 and 12years of age. Descriptions are available for children�2 years, 2 to 4 years, 4 to 6 years, and 6 to 12 years.The GMFCS is quick and easy to use; classification ismade by determining which level best represents thechild’s present abilities and limitations in gross mo-tor function. The description for each level is broadand not intended to describe all aspects of the motorfunction of individual children. Distinctions betweenlevels of gross motor function are based on func-tional limitations, the need for assistive mobility de-vices (eg, walkers, crutches, canes), wheeled mobil-ity, and, to a lesser extent, quality of movement. Thescale is ordinal, with no intent that the distancesbetween levels be considered equal or that childrenwith cerebral palsy are equally distributed amongthe 5 levels. The 5 levels of function (level 1 is thehighest) are:

1. Walks without restrictions; limitations in moreadvanced gross motor skills

2. Walks without assistive devices; limitations walk-ing outdoors and in the community

3. Walks with assistive mobility devices; limitationswalking outdoors and in the community

4. Self-mobility with limitations; children are trans-ported or use power mobility outdoors and in thecommunity

5. Self-mobility is severely limited even with the useof assistive technology

The algorithm shown, based on the GMFCS, wasdeveloped to classify infants at 24 to 28 months’corrected age in the NICHD- and National Instituteof Neurologic Diseases and Stroke-sponsored ran-domized clinical trial of the Beneficial Effects of An-tenatal Magnesium Sulfate in the Maternal FetalMedicine Units Network (Fig 1). In addition, thecharacteristics of upper extremity function includingbimanual function and bilateral pincer grasp areneeded to differentiate among right hemiplegia, lefthemiplegia, diplegia, and other minor motor impair-ments.


Cognitive and Developmental SkillsThe emergence of high-prevalence/low-severity

dysfunction (borderline IQ, learning disabilities, at-tention-deficit/hyperactivity disorder [ADHD], neu-ropsychologic deficits, and behavior problems) inchildren at biological risk has underscored the needfor detailed assessment of cognitive development.Although major deficits can be detected in infancy,more subtle high-prevalence/low-severity dysfunc-tions become increasingly obvious as the child growsolder, which is assumed to be because of continuedcortical development and increased demands forperformance in emerging areas of cognitive function.Moreover, there is some evidence that the cognitivefunction of infants with severe CNS injury tends todeteriorate over time, whereas the cognitive scores ofneurologically intact but immature infants tend toimprove as they mature.69 These data support theimportance of long-term follow-up to obtain school-age outcomes on high-risk infants.

IQsEarlier meta-analyses of cognitive deficits in low

birth weight (�2500 g) infants indicated a 5- to7-point deficit in comparison to term infants. Morerecent comparisons suggest a 0.3- to 0.6-SD decreasein IQ in children born prematurely, producing areported decrement that ranges from 4.5 to 9.0points. Therefore, in VLBW infants free of majordisabilities, mean group IQs fall in the borderline toaverage range, with low average scores being themode. However, use of IQ scores masks more subtledeficits; a verbal, performance, or area index score isthe average of various subtests (ie, verbal compre-hension, processing speed, etc), whereas a full-scaleIQ is an average of averages. IQ scores are influenced

by socioeconomic variables, particularly with respectto verbal function.

Visual-Motor SkillsThe majority of children born at ELBW and VLBW,

even those with average IQs, manifest visual-motorproblems that include deficits on neuropsychologicaltasks such as copying, perceptual matching, spatialprocessing, finger-tapping, pegboard performance,visual memory, and visual-sequential memory. Esti-mates of visual-perceptual and visual-motor integra-tion problems are in the 11% to 20% range; finemotor problems are as high as 71%. These deficitsseem mostly related to biological risks rather thanenvironmental risks.

Neuropsychological FunctionsPreliminary data suggest an increased incidence of

executive-function problems in planning, organiza-tion, problem-solving, working memory, and inhibi-tion as well as attention. Related to this, a sizeablenumber of children born VLBW display nonverballearning disabilities (in which verbal cognitive skillsare better developed than nonverbal abilities, pro-ducing verbal IQ/performance IQ discrepancies)and associated problems in visual-motor integration,visual perception, mathematics, spatial skills, andfine motor speed. Verbal abstracting, reading com-prehension, written output, and social skills are alsoareas of deficit with nonverbal learning disabilities.Neuropsychologic deficits are related to both biolog-ical and environmental risks.

The array of potential problems found in the fol-low-up of preterm infants mandates that assessmentextend beyond traditional IQ and achievement test-ing. The pattern of developmental change or im-

Fig 1. Gross motor function classification system at 24 months corrected age.


provement may be more informative than the mid-point score in a given area of function. These processissues, which have often been overlooked, may beinformative and useful for intervention and predic-tive purposes. Assessment of intelligence in fol-low-up studies to school age should include 5 keyelements: reasoning, knowledge, quantitative rea-soning, visual/spatial processing, and workingmemory.

Areas of AssessmentSpecific tests and rating scales that assess the fol-

lowing areas should be considered in follow-up pro-tocols (those falling under a broad categorization of“cognitive” are in italic type):

1. Intelligence (including verbal and nonverbal as-pects) and executive function

2. Achievement3. Functional status (self-care, mobility, communica-

tion)4. Language (phonological awareness, syntax, ver-

bal fluency, comprehension of instructions, speednaming, higher-order abstracting functions)

5. Sensorimotor functions (visual-motor precision, finemotor speed)

6. Visual spatial processes (design-copying, visual clo-sure)

7. Memory and learning (list-learning, delayed recall,narrative memory, and use of semantic/strategicand rote/episodic verbal and visual tasks)

8. Behavioral adjustment (ADHD, internalizing andexternalizing behaviors, and social functioning).

Table 3 lists specific tests recommended to evalu-ate developmental/cognitive function.70–85 Tests inthe first row are those considered most desirable,and tests in subsequent rows are acceptable alterna-tives; listed tests are not necessarily all administeredat any given time. Moreover, some tests have notbeen included because of lack of valid test norms orbecause they do not sample cognitive constructs ofinterest. Finally, certain functions (eg, visual percep-tion) may be measured on several different tests (eg,Neuropsychological Test [NEPSY]78 and Motor FreeVisual Perception Test86).

Most IQ tests require so-called level C qualification

for administration, meaning that they should be ad-ministered by qualified masters-level or above psy-chologists: pediatric, clinical, child, and school psy-chologists and child neuropsychologists. Centersthat use limited assessment batteries because of lim-itations of staff or funding require level B qualifica-tions for administration. Examples of these tests in-clude the Bayley Infant NeurodevelopmentalScreener (BINS),87 Kaufman Brief Intelligence Test,88

Developmental Test of Vision Motor Integration,70

rating scales, and similar instruments. Adequatelytrained support staff can administer level B tests, andappropriately trained developmental pediatriciansand psychologists can administer the BSID-II.37

Minimizing Barriers to AssessmentAssessment of children with sensorimotor impair-

ments remains challenging for new examiners. Chil-dren with visual impairment are extremely difficultto evaluate before the preschool age, because mosttest items are sensorimotor in nature. Evaluation isrestricted to verbal behaviors and gross motor mile-stones. The Mullen Scales of Early Learning,89 Lan-guage Receptive Organization (LRO), and LanguageExpressive Organization (LEO) scales may be usefulfor children with vision impairment, although itemsof an “intersensory” (ie, auditory and visual) natureare eliminated or scored in a prorated fashion. Withincreasing age, verbal subtests can be used, althoughmany still require viewing pictures and then produc-ing a response. Auditory memory as well as auditoryattentiveness can be measured with the auditoryContinuous Performance Test (CPT)73 at later ages,and verbal IQs can be obtained. The standard use ofthe BSID-II is not appropriate for children who arelegally blind.

Hearing impairment precludes adequate assess-ment of verbal abilities; sensorimotor subtests can beadministered, but an overall BSID-II MDI cannot becomputed. The Mullen Scales of Early Learning89

may be considered, using the LRO and LEO scalesfor children with hearing impairment, although in-tersensory items (requiring hearing and vision orhearing and motor skills) must be addressed. Withincreasing age, nonverbal tests can be used (allowingcomputation of nonverbal indexes), but the hearing-

TABLE 3. Comprehensive Cognitive Assessment Protocol

12 mo CA 24 mo CA 3–4 y 6 y 8 y

BSID-II37 BSID-II37 DAS75 WISC-IV85 WISC-IV85

MDI and PDI MDI and PDI BSID-II (36 mo)Bayley MDI Bayley MDI McCarthy79 WASI84 WASI84

Stanford Binet-V81 Stanford Binet-V81 Stanford Binet-V81

WPPSI-III83 NEPSY78 NEPSY78

Bracken Basic Concepts-R71 VMI70 BRIEF76

Grooved Pegboard80 Parent and teacher versionsK-ABC77 (sequencing simultaneous

processing subscales)Conners CPT checklists73 Conners CPT checklists73

WRAML82/CMS72

CVLT-C74

DAS indicates Differential Ability Scale; MSCA, McCarthy Scales of Children’s Abilities; SB-V, Stanford-Binet V; WPPSI-IV, WechslerPreschool and Primary Scale of Intelligence-IV; K-ABC, Kaufman Assessment Battery for Children; WISC-IV, Wechsler Intelligence Scalefor Children-IV; WASI, Wechsler Abbreviated Scale of Intelligence; VMI, Developmental Test of Visual Motor Integration; BRIEF,Behavior Rating Index of Executive Function (questionnaire); WRAML, Wide Range Assessment of Memory and Learning; CMS,Children’s Memory Scale; CVLT-C-California Verbal Learning Test–Children’s Version.


impaired child still may find it difficult to under-stand directions and provide the required response.In these settings, performance IQs can be derived,and visual CPTs,73 visual memory tasks,90 visual-motor integration,70 rating scales, and more specificneuropsychological tests may be used. The LeiterInternational Performance Scales-R91 is a useful testfor use in the hearing-disabled population (2–20years), because auditory skills are not required.

Finally, it is important to realize that the referencenorms of most tests are children without sensoryimpairments; hence, administration to children withvisual or hearing deficits may affect the tests’ psy-chometric qualities. The NICHD protocol codes spe-cifically for children who have a sensory loss (code 6indicates that the child cannot be tested but appearsnormal; code 5, the child cannot be tested but ap-pears to be mild to moderately delayed; code 4, thechild is severely developmentally delayed). For thechild classified as severely developmentally delayed,a Bayley score of 49 is assigned.

Assessment of cognitive abilities in children withmotor impairments is particularly difficult beforepreschool because of the interweaving of cognitiveand motor function. Substantial alterations of testprocedures are necessary that, in turn, may have animpact on comparability to norm-referenced data.Subsequently, verbal tasks as well as nonverbal tasksthat do not require a motor response (eg, matrices)can be used. Assistive devices/technology also maybe used in such situations. Tests recommended forprograms with comprehensive follow-up protocolsinclude the Differential Ability Scales,75 McCarthyScales of Children’s Abilities,79 Stanford Binet,81

Wechsler Intelligence Scales for Children,85 KaufmanAssessment Battery for Children,77 Wechsler Pre-school and Primary Scale of Intelligence-III,83

Wechsler Abbreviated Scale of Intelligence,84 theNEPSY,78 Developmental Test of Visual Motor In-tegration,70 CPTs,73 Behavior Rating Inventory ofExecutive Function,76 Wide Range Assessment ofMemory and Learning,82 Children’s Memory Scale,72

and the California Verbal Learning Test-Children74

(Table 3).Cognitive tests recommended for programs

with limited assessment protocols include theBINS,87 the BSID-II MDI,37 Ages and Stages,92 andthe Cognitive Adaptive Test/Clinical Linguistic andAuditory Milestone Scale93 (CAT/CLAMS) (Table 4).

Additional assessments are brief versions of some ofthe tests listed in Table 3.70,73,77–79,84,85,88,94

Functional SkillsInstruments for measuring functional status in es-

sential activities of self-care, mobility, communica-tion, and learning are assessed with the FunctionalIndependence Measure for Children,95 the VinelandAdaptive Behavior Scale,96 the Battelle,97 and thePediatric Evaluation of Disability Inventory98 psy-chometric properties of these assessments are shownin Table 5. Examination of the functional strengthsand challenges of children with neurodevelopmentalimpairments provides additional information re-garding disablement (attitudes, barriers, and policiesthat restrict opportunities) and enablement (supportsthat break down barriers). A similar assessment offunctional skills obtained by parent interview wasdeveloped by Stein et al.99 Functional assessmentshave important strengths including the need for aminimal database, use of criterion referencing, ob-taining information on typical performance, andability to measure severe disability. In addition,functional assessments can be administered to a re-liable observer/informant by staff trained in a vari-ety of disciplines and by telephone interview andmay be linked to population surveys.

LanguageEffective receptive and expressive language is fun-

damental for communication, adaptive behavioraland academic success, and literacy. Assessing recep-tive and expressive language is particularly challeng-ing, because different language skills emerge and aremastered at different ages, the rate of developmentof different language skills is not linear, and differentmeans of assessment are suitable for different ages.Comprehensive language testing including expres-sive and receptive language, organization, and gram-mar is required to obtain a complete assessment oflanguage function. Parental checklists of expressivelanguage are available including the McArthur100 forages �1 year. Receptive language can be tested fromages 2 to adulthood with the Peabody Picture Vocab-ulary Test-III.101 The combination of receptive andexpressive language can be assessed with the Expres-sive One-Word Picture Vocabulary Test102 and theReceptive One-Word Picture Vocabulary Test.103

Language organization can be assessed with the

TABLE 4. Limited Cognitive-Assessment Protocol

12 mo 24 mo 3–4 y 6 y 8 y

BINS87 BINS87 K-BIT88 WASI84 WASI84

Ages and Stage92 Ages and Stage92

CAT/CLAMS93 CAT/CLAMS93

BSID-II MDI37 BSID-II MDI37 WRIT94 4 subtests from WISC-IV85 4 subtests from WISC-IV85

BSID-II MDI (3)37

McCarthy Screener79/K-ABC77

short formConners CPT73 Selected NEPSY78 subtests

Conners CPT73

DTVMI70 DTVMI70 DTVMI70

K-BIT indicates Kaufman Brief Intelligence Test; WRIT, Wide Range Intelligence Test; WASI, Wechsler Abbreviated Scale of Intelligence;MSCA, McCarthy Scales of Children’s Abilities; WISC-IV, Wechsler Intelligence Scale for Children Subtests; DVTMI, Developmental Testof Vision Motor Integration.


Mullen Scales of Early Learning,89 which has bothLRO and LEO scales. Assessment of grammar usingthe Rice/Wexler Test for Grammatical Impair-ment104 targets elements of morphosyntax known tobe weak in children with language impairments. Ithas strong predictive validity for children 4 to 6 yearsof age and has been standardized for ages 3 to 8years. The Clinical Evaluation of Language Funda-mentals III105 is another language test that assesseshigher-level language function for children �6 years.

Behavior and AttentionThe choice of which behavioral domain to measure

is a difficult decision for individuals designing afollow-up study. Target outcomes should be selectedon the basis of theoretical and clinical concerns forthe specific at-risk group. These concerns are com-bined with known stages of development to deter-mine when to assess. Fig 2 describes the timeline forbehavioral domains relevant to high-risk children.Cognition and motor control may be a higher prior-ity among ELBW children, whereas psychopathol-ogy and antisocial behavior may be of greater con-cern in drug-exposed children. Specific methodologyissues such as what measures to use, where to con-duct the assessment, and how to train testers areguided by good research practices and practical con-sideration of time and resources.

In general, the easiest, least demanding method isparent report. The next easiest are tests and childinterviews. The most difficult are procedures thatrequire specific settings and extensive scoring. Com-

puter implementations have helped to bring somedifficult procedures within reach (eg, CambridgeNeuropsychological Test Automated Battery,106 Di-agnostic Interview Schedule for Children,107 andTest of Variables of Attention [TOVA]90), but thesetests are demanding in terms of equipment and soft-ware.

Parent questionnaires are useful in cases in whichthe child exhibits a behavior but is too young toself-report or when brief observation is insufficient tocapture the outcome of interest. A behavior assess-ment administered by questionnaire is the Brief In-fant-Toddler Social Emotional Assessment Version1.0.108 It is designed as a first step in the early iden-tification of 1- to 3-year-olds with social-emotionalproblems and/or delays in social competence. It con-sists of 60 interview questions. A trained medical ornonmedical professional may administer this scale tothe primary caretaker of the child. Estimated time toadminister the Brief Infant-Toddler Social EmotionalAssessment is 15 minutes. Another good example ofa behavior assessment for children is the AchenbachChild Behavior Check List (CBCL).109,110 The CBCLis a comprehensive measure of parental perceptionof children’s behaviors designed to assess the socialcompetencies and behavioral problems of childrenaged 2 to 3 (CBCL 2-3) and 4 to 18 (CBCL 4-18) in astandardized format. The CBCL provides norms forinterpretation, can be administered by interview forparents with low reading skills, and has a simpleyes/no response format. There are versions forteachers and adolescents, which can be useful. Re-

Fig 2. Timeline: child outcomes.

TABLE 5. Levels of Follow-up Program Intensity

Level 1 Level 2 Level 3 Level 4

Telephone interview to screen:developmental screeners;Ages and Stages92 andCAT/CLAMS93

In-clinic single visit: growth;neurologic exam; screen;developmental screeners;Ages and Stages92 andCAT/CLAMS93

developmental screeners:BINS87

Single visit: comprehensiveassessment; growth;neurologic exam;developmentalassessment (Tables 2 and3) (behavior, otherreduced comprehension

Serial comprehensive assessments:growth; neurologic exam;developmental assessment,behavior (may includevideotapes, MRIs, actigraphy,parent IQ, telemedicine,biochemical parameters,

or comprehension) geneticsRefer for diagnostic or

intervention services asneeded

Refer for diagnostic orintervention services asneeded

Refer for diagnostic orintervention services asneeded

Refer for diagnostic orintervention services as needed

Collect data Collect data Collect data Collect dataClinical Clinical Clinical/Research Clinical/Research


sults from all parent-report questionnaires must beinterpreted with caution, because they reflect theparent’s own bias and relationship with the child aswell as the child’s behavior. Therefore, it is probablybest among school-aged children to have both parentand teacher versions. The Conners111,112 parent andteacher rating forms are frequently used when as-sessing school-aged children for attention deficit andhyperkinesis.

Parent and child report as well as tests are subjectto sources of error. As noted, parent reports aresubject to parental bias. Child reports are also subjectto the child’s desire to please or hide bad things andto the child’s understanding of the questions and theresponse scale. Tests with good psychometric prop-erties typically have highly constrained acceptableanswers and strict instructions for administration.Thus, children’s spontaneous responses and strate-gies, including how they reach their conclusion, arenot typically measured.

For older children (7–17 years), the Children’s De-pression Inventory113 and the Behavior AssessmentSystems for Children114 may be useful. The BehaviorAssessment Systems for Children is a broad-bandtool that provides a good representation of thechild’s behavioral functioning. Diagnostic and Statis-tical Manual of Mental Disorders, Fourth Edition115 cri-teria are used to establish diagnostic categories.

TOVA90 is a computerized test that provides acontinuous performance task involving sustained at-tention and response inhibition. It is less fun for thechildren by design but provides data that can becompared with norms (separately for girls and boys).The Gordon Diagnostic System,116 which is similar,is a microprocessor-based system with tasks for di-agnosing attention deficits, especially ADHD. Bothtests give insight into attention and impulsivity dis-orders. The Conners111,112 parent and teacher ratingforms, which are frequently used when assessingschool-aged children for attention deficit and hy-perkinesis, differ somewhat but also give compara-ble information. Finally, the Diagnostic InterviewSchedule for Children107 has the advantage of gen-erating psychiatric diagnoses without professional-level staff, which makes it accessible for a researchstudy, but it is demanding for children, particularlythose who are lower functioning.

School-Age OutcomesStudies of school-age outcomes of high-risk chil-

dren to date have been predominantly descriptiverather than hypothesis driven. Assessments have in-cluded measurement of growth; parent and teacherquestionnaires concerning health, school perfor-mance, behavior and psychiatric disorders, quality oflife (QOL), self-esteem, impact on the family, andexamination and testing of children for neurosensorydisorders, cognition, specific neuropsychologic andmotor functioning, and academic achievement. Theimpact on society of the increased survival of high-risk children and the costs to the health and educa-tional system at school age have not been fully ex-amined.

At school age and older, it becomes important to

know how the children and their families function inthe various outcome categories; however, a noncat-egorical combined or functional approach may pro-vide better information concerning the overall im-pact of modern intensive care methods.117

The traditional assessment of high-risk outcomesbased on specific diagnoses or problems has limita-tions. Health problems in normal child populationsare reported to occur in clusters, with many childrenhaving �1 type of problem.118 Additionally, highhealth utilization tends to be associated with thepresence of a variety of health problems rather thanwith a particular type of illness.119 Extremely pre-term or high-risk children epitomize the pattern ofmultiple health and educational problems. Categori-zation of the medical, neurologic, developmental,and behavioral problems individually thus will notreflect the impact of the combined effects on theiroverall health status and health care and educationalservice utilization. The use of diagnostic labels hasadditional disadvantages in that there may be incon-sistency in diagnoses. A diagnosis, furthermore, doesnot convey the extent of morbidity, especially func-tional consequences, for individual children, caregiv-ers, and health and educational providers.

The noncategorical approach provides for compre-hensive assessment of the functional impact of neo-natal intensive care survival on health and psycho-logical outcomes. It can be applied to meet variousservice- and policy-related objectives such as identi-fication of needs for service, functional impact, andprogram eligibility for Title V programs.120,121 Thisapproach does not preclude assessment of the obvi-ous biological differences that distinguish one dis-ease from another but complements the more tradi-tional categorical approach. It has been advocated forperinatal outcomes research but has rarely beenused.122–124

The 2 health instruments based on the generic ornoncategorical approach for late childhood andyoung-adult studies124–126 are the Child Health Ill-ness Profile (CHIP-CE)127 and the Questionnaire forIdentifying Children With Chronic Conditions(QuICC).128 The 2 questionnaires complement eachother in that the CHIP-CE examines the profile of thechild’s general health and developmental status,whereas the QuICC examines functioning and spe-cial health care and educational needs attributed tochronic illness. The CHIP-CE includes 6 domains: (1)satisfaction with health, (2) discomfort, (3) achieve-ment, (4) risk, (5) resilience, and (6) medical andpsychosocial disorders. It is applicable from 6 to 11years of age. The adolescent version (the CHIP-E129)can be used from 11 years old until late adolescence.The QuICC incorporates the consequences of chronicphysical, cognitive, psychological, and behavioralhealth conditions into 3 domains: (1) functional lim-itations, (2) dependence on compensatory mecha-nisms, and (3) need for services beyond routinecare.128,130 It was developed for children with specialhealth care needs. The Child Health Questionnaire(CHQ)131 is an instrument that has been designedand normed for children 5 to 18 years of age. TheCHQ can be used independently or in conjunction


with Health Act condition-specific surveys in re-search or clinical settings.

QOLThere has been increasing interest in the parent

and child perception of “well-being” regarding as-pects of health that are relevant to the child andfamily, which has resulted in the concept of measure-ment of QOL.132 Although health status, functionalabilities, and QOL are 3 different concepts, they areused interchangeably. Broadly speaking, QOL is anall-inclusive concept that incorporates many factorsthat impact on the life of an individual, of whichhealth is only 1 domain. Health-related QOL(HRQL),132–135 on the other hand, is a multidimen-sional measure that takes into account all aspects ofhealth and implicitly reflects the personal values ofan individual. These values may be unrelated todisease state or severity. It is the characteristic ofpersonal values that distinguishes HRQL from othermeasures of health. It is important to take into ac-count the fact that young children are constantlydeveloping and have varying capabilities thatchange over time.136 In addition, their personal val-ues also evolve over time and generally differ fromadults in their views about QOL. Investigators re-cently attempted to involve older children in mea-suring their own HRQL. Others have also obtainedparallel proxy ratings from parents.137

Which Groups Should Have Measurement of HRQLIt is useful to learn from the personal perspectives

of the premature children and their parents.135,137 Todate, self-reported HRQL has been measured for in-fants of �1000-g birth weight at adolescence137; re-cent studies of preschool-aged children have shownthat, by parent report, the HRQL of infants �32weeks’ gestational age was significantly lower thanthat for infants �32 weeks’ gestation and the refer-ence group.138 HRQL measures also may have thepotential of providing complementary informationon subjects in pediatric clinical trials, although littlework has been done on this.

Practical ConsiderationsIt is important that the HRQL measures include

those aspects of functioning that are important to thechild and family: they should reflect the multipledomains of age-appropriate activities, and theyshould be reliable, valid, and sensitive to changes inQOL of the child.136,139,140 In addition, because of theshort attention span of the children, the question-naires should be brief and impose as little burden aspossible to the respondents and staff. It is also essen-tial that the self-completed measures are phrased inways that children can understand and are at theappropriate reading level of the child.

Strictly speaking, because HRQL measures are de-signed to reflect the personal perspective of the pa-tient, it is not possible to accurately obtain the datafrom children younger than 7 to 8 years. However,investigators recently showed that young childrenare capable of recognizing their emotions, althoughthey may have limited memory and ability to carry

out logical thinking of tasks. Given the opportunityand correct context, children as young as 7 years areable to answer questions regarding their own healthstatus. However, at least grade 2 skills are necessaryfor rating the feeling thermometer, and grade 6 read-ing skills are required to complete the StandardGamble technique.141 In older children, the opinionof the child should be sought whenever possible.Thus, unless parental proxy responses are obtained,it is not possible to obtain HRQL measures accu-rately for children �8 years old.

There are several modalities of administration ofthe HRQL measures: self-administered question-naires at the study site, mailed questionnaires (self-administered at home), telephone interview, face-to-face interview questionnaires at the study site orhome visit, and face-to-face interviews for youngerchildren (�8 years) using interactive pictures, vid-eos, and computer programs. A self-completed ques-tionnaire at the study site is obviously the mostcost-effective and suitable for older children and ad-olescents. A self-completed mailed questionnaire isalso cost-effective but less reliable, and the responserates are lower than with other modes of adminis-tration.142 Telephone interviews achieve a highercompliance than mailed questionnaires, but the va-lidity is questionable in young children. Face-to-faceinterviews are the most costly, but compliance isgreater and the data are more reliable.143

Finally, despite the growing literature, there con-tinues to be skepticism by the medical community inaccepting self-reported HRQL as relevant and validinformation.136 Eiser and Morse136 suggests thatQOL measures need to be used more routinely inevaluation of alternative treatments to understandthe burden experienced by the family.

The following is a brief description of the availablemeasures for young children:

1. The PedsQL144 is a generic 23-item developmen-tally appropriate questionnaire for children aged2 to 4, 5 to 7, 8 to 12, and 13 to 18 years. Pediatricself-report measures are available for children andadolescents aged 5 to 18 years, and parent proxy-report measures of child HRQL are available forchildren aged 2 to 18 years. A complementaryPedsQL disease-specific measure for chronichealth conditions is also available. The PedsQL isthe only generic self- and proxy-reported pediat-ric HRQL instrument that spans a wide range of 2to 18 years while maintaining items and scale.144

2. The TACQOL145 is a 108-item parent form thattaps 7 domains and also measures the child’s emo-tional reaction to his or her health problems.

3. The Quality of Life Preschool Children (TAPQOL)questionnaire133 has 43 items, taps 12 domains,and is also weighted by the emotional response toproblems in health states. In a study of preschoolpreterm infants between ages 1 and 4 years, whowere infants of �32 weeks’ gestation, differenceswere found between neonatologists’ and parents’perception of the HRQL of preterm children.138

4. The CHQ131 is a generic QOL instrument that has14 unique physical and psychosocial concepts. A


parent-completed form is available for children 5to 11 years of age (full-length, 50 items; shortform, 28 items). In addition, a parent-completedInfant/Toddler Health Questionnaire with 8 in-fant concepts and 5 parent concepts is also avail-able. The CHQ and Infant/Toddler Health Ques-tionnaire essentially provide health profiles anddo not have a valuative component.

5. Health Status Classification System-PS146,147 isadapted from the widely used HU12/3 sys-tems.148 It is comprised of 12 dimensions encom-passing a broad range of physical and develop-mental parameters, each with 3 to 5 levels perdimension.

OBJECTIVE 4: DETERMINE THE RELEVANT ISSUESRELATED TO SELECTION OF CONTROLS AND

TRACKING OF SUBJECTSWell-selected control populations with back-

ground variables similar to study subjects are impor-tant for the assessment of outcomes of high-risk chil-dren. Variables to consider in selecting controlsinclude those related to sociodemographic status,ethnicity, gender, and age of the child. Measures ofsociodemographic status most commonly used in-clude parental education, age, marital status, type ofhealth insurance, and area of residence. Maternalrather than paternal sociodemographic status is usu-ally considered in the United States, because manymothers of high-risk children are unmarried, and thefathers may have little contact with their children.Siblings have been suggested as ideal controls, be-cause they share the same sociodemographic andgenetic background as the study child. However,siblings are rarely used, because they need to be ofthe same gender and of an age fairly close to that ofthe study child. Additional problems in using sib-lings are that they, themselves, are often preterm,and even if born at term gestation, their behavior andschool performance may be influenced by having a“special-born” sibling.

Normal birth weight control populations are usu-ally not needed when RCTs of perinatal therapies areundertaken. Normal birth weight controls are oftennot included when comparing the outcome of low-risk versus high-risk birth weight groups, eg, in stud-ies assessing the effects of chronic lung disease, brainhemorrhage, jaundice, etc.149

In contrast to school-age studies, descriptive stud-ies of early-childhood outcomes of high-risk children(�3 years) have often not included control subjects.However, it is currently recommended that if thetrue impact of prematurity is to be identified, “nor-mal” control populations should be included at allages. In 1992, Gross et al150 stressed the importanceof concurrent controls, because the cognitive testsused in earlier time periods may be outdated. Expe-rience with the BSID-II presents problems in thatrates of cognitive impairment are overestimatedwhen compared with those found at school age. Inaddition, average IQ scores increase by 0.5 points peryear or 5 points per decade. Ideally, controls shouldbe selected at birth by matching the study infant withthe next born infant of the same race, gender, se-

lected maternal characteristics (age, parity, etc), andhospital of birth, excluding infants with intrauterineinfections and major congenital malformations.151–155

Race is often used as a proxy for SES in inner-citypopulations. Hospital of birth may serve as a proxyfor type and quality of perinatal care and area ofresidence, although high-risk mothers may be trans-ported to tertiary perinatal centers from other areasof residence.

Because many early-childhood studies have notincluded birth controls, it may be necessary to findcontrols at school age.156–160 The most commonlyused method is to randomly select a classmate of thesame gender, race, and age (within 3–6 months) asthe study child. The school serves as a proxy for areaof residence and type and quality of education. Ide-ally, all the children of the same age in the child’sschool, rather than class, should be considered aspotential controls, because high-risk children repeatgrades more often than low-risk children. When chil-dren are home-schooled, attend special schools forthe disabled, or have moved out of the area, matchesare usually selected from the school the child wouldhave attended. Other study-design methods includerandom selection of controls from regional school-system records.158,161 Studies of large regional ornational populations have obtained outcomes throughlinkage of birth records to school records162,163 orlinkage of birth records to military-recruitmentrecords164,165 with comparison of the subjects to therest of the population.

Follow-up rates of at least 90% should be achievedat early childhood, at least 80% at early school age,and at least 70% at middle-school age and duringadolescence.124,159 Follow-up rates of control subjectsare usually 10% to 20% lower than those of studysubjects. In addition, despite the best attempts, con-trol subjects usually have subtly better home envi-ronments than study subjects. Intervention and con-trol subjects who are lost to follow-up are usually oflower SES than those followed. Because there arehigher rates of loss to follow-up among control low-er-SES subjects, the controls are usually of higher SESthan study subjects.166,167 Also, families of childrenconsidered healthy may be less likely to return.Therefore, it is imperative that strategies be devel-oped to maintain compliance, because it is difficult todetermine the “true” outcome of lost infants.

Elements needed to maintain good follow-up ratesare:

1. Enrollment of subjects before discharge from hos-pital and identification of a specific contact per-son.

2. Multiple back-up addresses of family and place ofwork.

3. Postdischarge and interim visits during the firstyear of life, for clinical purposes of developmentaland health surveillance, and maintenance of fam-ily involvement even when the first formal studyvisit may only be at 2 years of age; ideally, com-prehensive health care should be provided but isusually not feasible.168


4. Close communication with, and respect for, healthcare providers of the subjects.

5. A dedicated study coordinator who is prepared totrack and call families at night and over weekendsand a research staff prepared to accommodateparent work schedules and to work weekends andperform home visits if necessary.

6. Reimbursement for transportation and parkingand specific financial incentives for time spent forthe collection of study data.

7. Adequate funding for all of the above.

OBJECTIVE 5: DETERMINE ALTERNATE, LESSCOSTLY METHODS AND APPROACHES FOR

FOLLOW-UP AND THE ROLE OF THECOMMUNITY PHYSICIAN

Because of limited funding sources, it is currentlynot feasible for all NICUs to have a comprehensivefollow-up program. NICUs that do not have the re-sources to establish a program need to share infor-mation with the family and primary provider aboutincreased risk of neurodevelopmental, behavioral,growth, and medical sequelae and facilitate referralsto early intervention and/or a child developmentcenter. Clinical programs with limited funding avail-able, however, may use screening methods such as aphone or in-house parent interview as a first-stagescreen to determine if more in depth assessments arewarranted or if referrals to early intervention or ed-ucational resources are indicated. In addition, a clin-ical program with limited resources may by necessityoffer a single follow-up visit. An optimal assessmentage combines a short interval between discharge andassessment age (to minimize tracking) with a devel-opmental age at which the accurate diagnosis ofmotor and developmental handicaps is feasible. Theapproach should facilitate a timely diagnosis andreferrals as needed for families and center surveil-lance objectives. The feasibility of collecting someannual well-defined short-term follow-up data for allNICUs continues to improve. The ability to providefeedback on individual child outcome and supportfor families is available to all NICUs.

The NICHD Network identified 18 to 22 months’corrected age as the optimal time for a single visit.Interim visits or phone contacts are recommendedfor tracking purposes.

Community physicians can take an active role par-ticipating in follow-up by performing periodic devel-opmental screening and responding to requests forhealth information on a child who does not return tothe follow-up program. This requires a partnershipbetween the community physicians and the tertiarycare center and the use of standardized tools. Inaddition, follow-up programs can provide valuableinformation about the child’s growth, neurodevelop-ment, and behavior to the community physician.

Table 6 contrasts 4 levels of management for theindividual provider, for programs with clinical sur-veillance or referral objectives, and for programswith combined research and clinical objectives.Whereas the clinical program may maintain a data-base with a limited number of key variables, screenchildren (an important service for families), and re-

fer, the research program has the opportunity todevelop more sophisticated protocols that are hy-pothesis driven and explore novel assessments.Screening tools such as the Ages and Stages92 andCAT/CLAMS93 may be administered during an of-fice visit or over the phone. Primary care providerswho perform a screen may share information withthe follow-up or diagnostic program and refer fam-ilies as needed. Diagnostic and/or follow-up pro-grams reciprocate by sharing results of comprehen-sive evaluations and recommendations. Primary carephysicians can collaborate by completing studyforms requesting data on growth, medical status,vision, and hearing.

OBJECTIVE 6: DETERMINE THE CHALLENGESENCOUNTERED IN MULTICENTER NETWORKSMulticenter networks have the advantage of being

able to assess low-incidence neonatal illness such asperinatal asphyxia and achieve adequate samplesizes for hypothesis-driven studies within a shorterperiod of time than a single-center study.169,170 How-ever, a number of challenges must be addressed if anetwork is going to succeed:

1. Achieving standardization of study protocols,manuals, definitions, and methodology amongcenters in diverse geographic areas is a majorchallenge for networks. Multicenter networksvary in their approaches to planning well-coordi-nated follow-up studies.

2. Achieving adequate follow-up rates is a majorchallenge, particularly with populations havingdiverse SESs, cultures, and primary spoken lan-guages. The NICHD network endorses a fol-low-up rate of at least 80% for centers at 18 and 30months’ corrected age.

3. A third challenge for multicenter networks is todefine the critical study population and the inter-val for enrollment. Network centers may enrollinfants with a birth weight of �1000 g annuallyand follow them for 18 months as a framework formulticenter trials. This approach facilitates on-go-ing standardization of follow-up protocols andreliability among examiners. An alternate ap-proach is to enroll children born �1000 g every 3years and follow each cohort for 3 years. Thisapproach has somewhat higher costs, follows chil-dren to preschool age, and has changing protocolsconsistent with the age assessed. Networksshould identify their unique study populationswith high illness severity and poor outcomes foradditional study (eg, extracorporeal membraneoxygenation patients).

4. A fourth challenge is to identify and enroll anappropriate cost-effective control population.

The following 4 multicenter networks provide in-sights into the complexities of conducting multi-center follow-up studies.

Vermont Oxford NetworkThe Vermont Oxford Network is a nonprofit vol-

untary collaboration of NICUs dedicated to improv-


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ing the quality and safety of medical care for new-born infants and their families through a coordinatedprogram of clinical trials, research, education, andquality-improvement projects. Established in 1988,the network has grown to �400 member centersrepresenting NICUs throughout the United Statesand 17 other countries. The network maintains adatabase of information about the care and short-term outcomes of VLBW infants. In 1998, the Ver-mont Oxford Network began to collect follow-updata for ELBW infants at 2 years of age. To partici-pate, centers had to have a follow-up clinic, evaluatechildren until 2 years of age, and administer theBSID-II.

Canadian Neonatal NetworkThe Canadian Neonatal Network was developed

in 1996. Data were prospectively collected by trainedabstractors at 17 tertiary-level NICUs across Canada.This network has assessed variations in practice rel-ative to outcome. As a result, more regionalized ap-proaches to follow-up are in place in Canada. Afollow-up network was developed in Quebec in 2001with funds from the Fonds de la Recherche en Santedu Quebec and included all infants already enrolledin 6 follow-up programs.

NICHD Research Follow-up StudyThe NICHD Research Follow-up Study was initi-

ated in 1993 and consists of 16 academic tertiary carecenters. The primary study objective for the NICHDFollow-up Network is to track and successfully eval-uate �80% of infants entered in to the generic data-base with birth weights of 401 to 1000 g born afterJanuary 1, 1993, and infants enrolled in clinical trialswith neurodevelopment as an outcome. Currently,the network is conducting a pilot 30-month neuro-developmental outcome study on infants enrolled inthe glutamine trial. The network has an infrastruc-ture that includes a steering committee, protocol re-view committee, study manuals, standardized defi-nitions, training protocols, and a data-coordinatingcenter. Annual workshops and regular conferencecalls and meetings facilitate communication, coordi-nation, and standardization. The network has estab-lished standardized methods to assess growth, mo-tor skills, cognitive skills, language and behavior,and strict criteria for annual certification of Bayleyexaminers and neurologic examiners. All networkstudy interviews and assessments are available inEnglish and Spanish. Studies and assessments areconducted by network investigators at the individualcenter and have resulted in numerous publications.

Centers for Disease Control and Prevention Networkfor Developmental Disabilities and Birth Defects:Surveillance System and Centers of Excellence

This national surveillance system under the Na-tional Center on Birth Defects and DevelopmentalDisabilities was mandated by the Children’s HealthAct of 2000 and implemented in April, 2001. Themission is to prevent birth defects and developmen-tal disabilities, pursue the causes and risk factorsassociated with defects, and promote wellness of

individuals living with a disability. It supports apublic health approach to the prevention of birthdefects with surveillance systems, epidemiologicstudies, and prevention programs. An example of asuccessful population-based surveillance system op-erating continuously since 1968 is the MetropolitanAtlanta Congenital Defects Program. Success ismaintained with intensive case ascertainment, a caseregistry, a surveillance laboratory, and professionaltraining.

OBJECTIVE 7A. IDENTIFY GAPS IN KNOWLEDGEABOUT HIGH-RISK SURVIVORS IN YOUNG

ADULTHOOD

1. Do they attain the social/educational status oftheir parents, or do they demonstrate downwardmobility (measured by comparing educationaland occupational attainment, associated rating ofprestige, and earning capacity)?

2. Can they live independently and support them-selves?

3. Do they develop normal social and family rela-tionships (measured by specific questionnairesand from their history of permanent personal re-lationships of marriage)?

4. Does catch-up growth occur in late adolescence?5. What are the long-term metabolic and cardiovas-

cular implications of growth failure in utero, neo-natally, and during infancy and of catch-upgrowth during various time periods of childhoodand adolescence?

6. What are the long-term health effects of chronicmedical sequelae of prematurity (especially pul-monary, visual, and neurologic)?

7. Do they have higher rates of psychiatric disorders,substance abuse, contact with police, and incarcer-ation?

8. Does the ADHD associated with prematurity per-sist into adulthood?

9. Are there intergenerational effects of high-riskbirth, prematurity, and/or low birth weight, and,if so, is it possible to break the cycle?

OBJECTIVE 7B. FURTHER AREAS OFINVESTIGATION

The following areas of investigation with a poten-tial to improve and optimize the outcomes of high-risk infants were identified. The recommendationswere:

1. to propose hypothesis-driven studies and RCTs toidentify the mechanisms that contribute to bothinjury and plasticity and recovery of the CNS,including animal and tissue studies

2. to identify the assessment strategies and sched-ules that are the most predictive of long-termoutcomes and identify earlier surrogate markersfor long-term outcomes

3. to determine the predictive value of neonatal im-aging modalities in the prediction of neurodevel-opmental outcome

4. to identify perinatal interventions that contributeto positive neurodevelopmental outcomes


5. to conduct population-based studies to determinethe true societal burden of illness within a geo-graphic region or a national sample (currently, thevast majority of studies report on subgroups ofinfants such as VLBW, ELBW, chronic lung dis-ease, asphyxia, small for gestational age, etc); ageographic sample would include all infants bornwithin a geographic region (such a study couldask questions regarding the total population ofinfants born within a specific time interval, in aspecific region, and followed for a predeterminedlength of time)

OBJECTIVE 8: PROPOSE RESEARCH QUESTIONS

1. What are the mechanisms by which intrauter-ine/neonatal inflammation/cytokines and hyp-oxia ischemia produce CNS injury, and what arethe effects on long-term outcome?

2. What are the mechanisms contributing to and theinterventions that can further reduce the severityof chronic lung disease in ELBW infants?

3. Does stress and/or recurrent pain in the neonateresult in permanent physiologic changes in re-sponse to pain?

4. What threshold of bilirubin and what duration ofhyperbilirubinemia result in neurodevelopmen-tal injury?

5. What modalities of resuscitation contribute tooptimal neurodevelopmental outcome of ELBWinfants?

6. What is the outcome of the macro prematureinfant (1500- to 2500-g birth weight)?

7. What is the impact of major congenital malfor-mations and cardiac anomalies on outcome, andwhat are the effective perinatal interventions?

8. What are the neurodevelopmental and growthmorbidities associated with monochorionic twinpregnancy and higher-order multiples?

9. What is the cost/benefit of follow-up care andassessment?

10. What is the impact of neonatal and postdischargenutrition on early catch-up growth and develop-mental outcome?

11. What is the role of early calorie and proteinintake and human milk on brain growth, andwhat are the long-term effects on cardiovascularand endocrine function disorder?

12. What is the impact of specific antenatal and neo-natal interventions (magnesium sulfate, antena-tal steroids, postnatal steroids, repeat doses ofindomethacin antioxidants) on brain growth andfunction?

13. What is the impact of medical and/or surgicalinterventions for NEC on outcomes? What arethe potential interventions to prevent NEC?

14. What are the neonatal neuroimaging techniquesthat best identify neurologic insult and predictneurologic and developmental outcome?

15. What are the genetic factors contributing to CNSmorbidity and recovery? Is there a genomic vul-nerability to injury?

16. What are the mechanisms by which an enrichedenvironment contributes to plasticity? Are therecritical periods for intervention?

17. What are the best screening tools for identifica-tion of infants at risk of adverse neurodevelop-mental sequelae?

18. What are the best early surrogate markers forlong-term neurodevelopmental disability?

Systematic long-term outcome studies of ex-tremely premature or ELBW infants are indispens-able for perinatologists and neonatologists: (1) out-come data facilitate informed decision-making in theNICU and the development of strategies for identi-fying infants at high risk for medical and neurode-velopmental sequelae; (2) families of infants identi-fied as high risk may be guided to comprehensivefollow-up and early intervention, and (3) morbidityrates may be used to estimate resources that societyshould be prepared to provide to optimize QOL ofsurvivors and their families. Considerable chal-lenges, however, secondary to limitations of staffing,costs, and expertise with assessments confront inves-tigators performing long-term outcome studies andthese challenges contribute to a paucity of high-qual-ity outcome data. Limitations of many studies in-clude small sample sizes, heterogeneity of cohorts,heterogeneity of methodology, limited informationabout both perinatal clinical practice and perinatalcomplications associated with long-term sequelae,and heterogeneity of specific neurodevelopmentalassessments and age of outcome.

CONCLUSIONSAlthough single-center studies may address some

of these issues and answer important questions, mul-ticenter research networks with standardized studymanuals, protocols, and methods are needed for rep-resentative surveillance and clinical trials. It is hopedthat this supplement provides information that willhelp follow-up program directors and primary careproviders make choices about assessment protocolsbased on options provided and practical consider-ations.

Unfortunately, ELBW infants remain at increasedrisk of neurodevelopmental sequelae. Well-con-ducted multicenter trials, which include neurodevel-opmental follow-up, continue to be the catalysts thatallow investigators to identify the mechanisms thatcontribute to injury and recovery and the perinatalinterventions that contribute to positive neurodevel-opmental outcome.

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4. Msall ME, Phelps DL, DiGaudio KM, et al. Severity of neonatal reti-nopathy of prematurity is predictive of neurodevelopmental func-tional outcome at age 5.5 years. Pediatrics. 2000;106:998–1005

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