Neonatal Neurobehavior Predicts Medical and Behavioral Outcome

Jing Liu, Carla Bann, Barry Lester, Edward Tronick, Abhik Das, Linda Lagasse,
Charles Bauer, Seetha Shankaran and Henrietta Bada
Pediatrics 2010;125;e90-e98; originally published online Dec 7, 2009;
DOI: 10.1542/peds.2009-0204

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/125/1/e90

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Neonatal Neurobehavior Predicts Medical and

Behavioral Outcome
WHATS KNOWN ON THIS SUBJECT: There is substantial interest
in the use of newborn neurobehavioral assessments to predict
later outcome. Previous attempts have been largely unsuccessful.
Our method suggests continuities between newborn behavior and
later child outcome and has implications for screening and early
detection.
WHAT THIS STUDY ADDS: This study shows that the NNNS can
identify infants who will later manifest developmental decits.
This means that we now have the potential to develop preventive
intervention programs to reduce or ameliorate these decits.

abstract
OBJECTIVE: This study examined the NICU Network Neurobehavioral
Scale (NNNS) as a predictor of negative medical and behavioral ndings at 1 month to 4.5 years of age.
METHODS: The sample included 1248 motherinfant dyads (42% born
at 37 weeks gestational age [GA]) who were participating in a longitudinal study of the effects of prenatal substance exposure on child
development. Mothers were recruited at 4 urban university-based centers and were mostly black and on public assistance. At 1 month of age,
infants were tested with the NNNS. Latent prole analysis was conducted on NNNS summary scales to identify discrete behavioral proles. The validity of the NNNS was examined by using logistic regression
to predict prenatal drug exposure and medical and developmental
outcomes through 4.5 years of age including adjustment for GA and
socioeconomic status.
RESULTS: Five discrete behavioral proles were reliably identied; the
most extreme negative prole was found in 5.8% of the infants. The
proles showed statistically signicant associations with prenatal
drug exposure; GA and birth weight; head ultrasound; neurologic and
brain disease ndings; and abnormal scores on measures of behavior
problems, school readiness, and IQ through 4.5 years of age.

AUTHORS: Jing Liu, PhD,a Carla Bann, PhD,b Barry Lester,

PhD,a Edward Tronick, PhD,c Abhik Das, PhD,b Linda
Lagasse, PhD,a Charles Bauer, MD,d Seetha Shankaran,
MD,e and Henrietta Bada, MDf
a

Department of Pediatrics, Brown Center for the Study of

Children at Risk, Warren Alpert Medical School, Brown
University, Women and Infants Hospital, Providence, Rhode
Island; bResearch Triangle Institute, Research Triangle Park,
North Carolina; cDepartment of Pediatrics, University of
Massachusetts Boston and Harvard Medical School, Boston
Childrens Hospital Boston, Boston, Massachusetts; dDepartment
of Pediatrics, University of Miami, Miami, Florida; eDepartment
of Neonatal and Perinatal Medicine, Wayne State University
School of Medicine, Detroit, Michigan; and fDepartment of
Pediatrics, University of Kentucky, Lexington, Kentucky
KEY WORDS
NNNS, neonatal assessment, neurobehavioral, developmental
outcomes, in utero drug exposure, latent prole analysis
ABBREVIATIONS
NNNSNICU Network Neurobehavioral Scale
GA gestational age
CBCLChild Behavior Checklist
DIAL-RDevelopmental Indicators for the Assessment of
Learning
LPAlatent prole analysis
BICBayesian Information Criteria
SESsocioeconomic status
OR odds ratio
CI condence interval
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0204
doi:10.1542/peds.2009-0204
Accepted for publication Jul 10, 2009
Address correspondence to Barry Lester, PhD, Brown Center for
the Study of Children at Risk, 101 Dudley St, Providence, RI
02905. E-mail: barrylester@brown.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.

CONCLUSIONS: The NNNS may be useful to identify infant behavioral

needs to be targeted in well-infant pediatric care, as well as for referrals to community-based early intervention services. Pediatrics 2010;
125:e90e98

e90

LIU et al

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There has been a long-standing interest in the predictive validity of neonatal

neurobehavioral assessments. From a
scientic point of view, relations between neonatal neurobehavior and
later behavioral outcome would support developmental theories that argue for the continuity and biological
basis of later child outcome by ruling
out the effects of the postnatal environment. From a practical point of
view, the early detection of infants with
poor developmental outcome would invite the study of preventive interventions that could ameliorate or reduce
the severity of long-term developmental decits.1
Although the short-term predictive validity of neonatal neurobehavioral assessments has been shown, the longterm prediction of these assessments
has been inconsistent and disappointing.2,3 The NICU Network Neurobehavioral Scale (NNNS) is a comprehensive
evaluation of the neurobehavioral performance of the high-risk infant4 that
includes neurologic and behavioral
measures and signs of stress. In previous work, infant performance on the
NNNS has been related to prenatal
drug exposure including cocaine5,6
methamphetamine,5,7 marijuana8 and
tobacco9,10; prematurity11,12; MRI ndings in preterm infants11; intrauterine
growth retardation13; fetal behavior14;
infant temperament15; maternal depression16; infants of adolescent mothers17; treatment of neonatal withdrawal18; treatment with cocaine-using
mothers19; and a parenting intervention with low birth weight infants.20
In this study, we describe a method to
classify infants into discrete risk categories or proles on the basis of previously established NNNS summary
scores.4,21 We then examine the ability
of the proles to predict problematic
medical and behavioral ndings in infancy and early childhood.
PEDIATRICS Volume 125, Number 1, January 2010

METHODS

TABLE 1 NNNS Summary Scale Score

Denitions

Participants were enrolled in the Maternal Lifestyle Study, a multisite, longitudinal study of children who were at
risk as a result of factors such as prenatal exposure to cocaine and other
substances and prematurity.5 Details
of enrollment and exclusion criteria
are described elsewhere.2225 The
study was approved by the institutional review board at each study site,
and written informed consent was obtained. The exposed group (n 658)
was based on mother report of cocaine use during pregnancy and/or a
positive meconium assay for cocaine.22
The comparison group (n 730) included children who were born to
mothers who denied cocaine use,
which was conrmed by negative
meconium results; the comparison
group was matched to the exposed
group by gestational age (GA) categories (32 weeks, 3336 weeks, and
36 weeks), child gender, race, and
ethnicity within study site. Background
substances that were associated with
cocaine use, alcohol, tobacco, and
marijuana, were included in both
groups. Children were seen at 10 visits
from 1 month to 4.5 years with an average retention rate of 78%.
Measures
NICU Network Neurobehavioral Scale
The NNNS was administered by certied, blinded psychometrists at the
hospital clinic 1-month visit to 1248
(90%) of the original 1388 infants.
Items from the NNNS were scored by
using previously established summary
scores4 (Table 1).
Prenatal Drug Exposure
Prenatal drug exposure during pregnancy includes maternal use of cocaine, opiate, tobacco, alcohol, and
marijuana. On the basis of previous
work,5 prenatal drug exposure was described as present or absent, and the

Attention: ability to localize and track (follow?)

animate and inanimate auditory and visual
stimuli
Asymmetric reexes: number of asymmetric
responses to elicited reexes
Excitability: high levels of motor, state, and
physiologic reactivity
Habituation: response decrement to repeated
auditory and visual stimuli during sleep
Handling: extent to which handling strategies
were used during attention sequence to
maintain alert state
Hypertonicity: hypertonic responses in arms, legs,
or trunk or in general tone
Hypotonicity: hypotonic response in arms, legs, or
trunk or in general tone
Lethargy: low levels of motor, state, and
physiologic reactivity
Quality of movement: attributes of motor control,
including smoothness, maturity, and lack of
startles and tremors
Regulation: capacity to modulate arousal and
organize motor activity, physiology, and state
in response to stimulation
Nonoptimal reexes: number of poor scores to
elicited reexes
Stress/abstinence: number of stress and
abstinence signs observed during the
examination
Arousal: level of arousal maintained during the
examination, including state and motor
Summary scores for the NNNS were developed by using an
approach that combined conceptual and statistical (coefcient ) aggregation of items and scores. The summary
scores were rst developed on a random selection of one
half of the sample and then replicated on the second half
of the sample. Scores on the summary variables indicate
higher/more or lower/less of the behavior, not necessarily better or worse. For example, a high score on
handling refers to an infant who requires substantial
handling to elicit attention, indicating that they are difcult to test; a high score on hypertonia means that the
infant was more hypertonic, and a high score on hypotonia
means that the infant was more hypotonic. The habituation scale was not used in this analysis because too few
infants were asleep at the 1-month visit to the clinic.

level of exposure (heavy versus some

versus none) was recorded for cocaine,
tobacco, alcohol, and marijuana.
Medical Outcomes
Newborn medical characteristics included GA divided into 3 groups (32
weeks, 3336 weeks, and 37 weeks),
birth weight, length, head circumference, small for GA, and intracranial
ultrasound reading at 44 weeks
postmenstrual age (in both term and
preterm infants). Results of intracra-

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nial ultrasound reading (abnormal

versus normal) were based on agreement by 2 experts. Diagnosis of cerebral
palsy, chronic neurologic abnormalities
(eg, hypoxic-ischemic encephalopathy,
arrested hydrocephalus), and illness
with clear risk to the brain (eg, trauma
involving the head, meningitis, shunt infection, shunt obstruction, convulsions,
encephalopathy, near sudden infant
death syndrome, other brain disorders)
was based on a physician medical/neurologic examination and nurse medical
history at the 1-month, 4-month,
8-month, 1-year, 2-year, and 3-year visits.
Developmental Outcomes
The Bayley Scales of Infant Development II26 were administered to the
child and the Mental Developmental Index and Psychomotor Developmental
Index were computed at 1, 2, and 3
years of age. The Child Behavior Checklist (CBCL)27 was administered to the
mother at the 3-year visit and scored
for externalizing, internalizing, and total behavior problems. School readiness was evaluated at age 4 with the
Developmental Indicators for the Assessment of Learning (DIAL-R),28 which
yields standardized motor, concept,
language, and total scores. At 4.5
years, the Wechsler Preschool and Primary Scale of Intelligence29 was used
to measure child IQ. All of the developmental outcomes were coded into dichotomous variables to dene children who scored in the problem range
by using clinical cutoffs according to
the assessment manuals.
Data Analyses
Latent prole analysis (LPA), a probabilistic, model-based variant of traditional nonhierarchical cluster analysis,30 was used to classify infants into
discrete categories or behavioral proles. LPA assumes that the population
consists of a number of unobserved
subgroups that are referred to as
latent proles, or latent classes. Indie92

LIU et al

viduals within a latent prole share

similarities in their responses on measured variables. Individuals in different proles have different patterns of
responses on measured variables. The
best solutions of LPA minimize the heterogeneity of responses on measured
variables within 1 prole and maximize
the heterogeneity of responses across
different proles.
LPA was implemented on 12 NNNS summary scales by using nite mixture
modeling in Mplus 4.1.31,32 Membership
for categorical latent proles that represent heterogeneous subgroups was
inferred from the 12 NNNS variables.
LPA models with different numbers of
proles were tted. Determination of
the best model t was assessed via
Bayesian information criteria (BIC) adjusted for sample size, whereby the
smallest BIC value indicates the best
t as well as minimization of crossclassication probabilities. BIC has
been shown to identify the appropriate
number of proles in nite mixture
models33 and penalizes the models for
number of parameters that may indicate model overt. Parameters for
class probabilities were estimated by
using maximum likelihood solutions,
and assignment of class membership
was also based on Bayesian probabilities. Various random start values were
specied for the LPA models to avoid
local maxima problems. The LPA models in this study were specied with
correlated errors for summary scores
with overlapping components and with
unequal variances for the summary
scales across different proles. Validity of the NNNS proles was examined

by comparing proles on prenatal

drug exposure, infant medical characteristics, and developmental outcomes
up to age 4.5 years by using logistic
regression analysis.

RESULTS
LPA Analysis
We tted LPA models with 2 to 6 proles to determine the optimal number
of proles. As the number of proles
increased from 2 to 6, the sample size
adjusted BIC values decreased, suggesting improvement in the goodness
of t. Although the 6-prole model had
the smallest BIC, 1 prole was composed of only 10 individuals, an indication of spurious ndings. Model t statistics are shown in Table 2. Both the
size of each latent prole and the average class probabilities for the 5-prole
solution suggested that the model was
the best solution.
The normality distribution of the 12
NNNS summary scales across the proles was examined for potential outliers and extreme values by using histograms, box plots, and Shapiro-Wilks
test of normality. No extreme values or
outliers were found on attention, handling, self-regulation, arousal, quality
of movement, and nonoptimal reexes.
Extreme values were observed on
stress abstinence, excitability, and
lethargy; however, no observations
were found to be consistent outliers on
all of the NNNS summary scales in any
proles.
We examined whether the 5-prole solution yielded 5 unique classes by testing the differences in the NNNS sum-

TABLE 2 Model Fit Statistics for the 5-Prole Solution

Prole

BIC Values Adjusted

for Sample Size

Average Posterior Class

Probability, OR (95% CI)

1
2
3
4
5

34 993.891
32 866.523
32 108.694
31 683.395
31 254.125

.0000
.0000
.0000
.0000

0.91 (0.900.93)
0.85 (0.840.87)
0.87 (0.840.89)
0.85 (0.830.87)
0.85 (0.830.87)

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TABLE 3 NNNS Summary Scores by 5 Proles (N 1248)

NNNS Summary

Scores, Mean (SD)

Prole 1
(n 276; 22.1%)

Prole 2
(n 409; 32.8%)

Prole 3
(n 217; 17.4%)

Prole 4
(n 274; 22.0%)

Prole 5
(n 72; 5.8%)

6.12 (1.29)
0.23 (0.21)
6.00 (0.55)
3.58 (0.40)
1.27 (1.08)
3.86 (1.82)
0.28 (0.54)
0.34 (0.68)
5.00 (1.72)
0.98 (1.18)
4.86 (0.54)
0.12 (0.07)

5.35 (1.22)
0.61 (0.24)
5.28 (0.50)
4.32 (0.42)
3.76 (1.32)
3.19 (1.77)
0.29 (0.58)
0.11 (0.34)
3.91 (1.65)
0.89 (1.17)
4.79 (0.53)
0.15 (0.07)

4.57 (1.20)
0.72 (0.20)
4.12 (0.53)
4.98 (0.45)
7.08 (1.36)
3.12 (2.20)
0.45 (0.74)
0.01 (0.10)
2.70 (1.84)
0.69 (1.05)
4.03 (0.64)
0.21 (0.07)

5.37 (1.40)
0.56 (0.27)
4.73 (0.52)
4.58 (0.50)
5.81 (1.36)
2.98 (2.20)
0.98 (1.16)
0.47 (0.77)
6.35 (1.72)
0.95 (1.16)
4.06 (0.64)
0.22 (0.07)

4.66 (1.49)
0.76 (0.21)
3.63 (0.53)
5.55 (0.45)
9.61 (1.35)
2.76 (2.15)
1.88 (1.63)
0.25 (0.52)
5.57 (2.56)
0.51 (0.82)
2.94 (0.62)
0.34 (0.11)

Attention
Handling
Self-regulation
Arousal
Excitability
Lethargy
Hypertonicity
Hypotonicity
Nonoptimal reexes
Asymmetric reexes
Quality of movement
Stress abstinence

mary scales across the proles (Table

3) and plotting the 5 proles. In Fig 1,
standardized scores were used for the
graph because the original scores
were not on the same scale.
Prole 1 (Fig 1) included 276 (22.1%)
infants. These infants showed the highest attention (0.5 SD) with less handling; the highest self-regulation; low
arousal and excitability; average lethargy, hypertonicity, hypotonicity, and
nonoptimal and asymmetric reexes;

high quality of movement; and less

stress abstinence when compared
with other proles. The 409 (32.8%) infants in prole 2 showed high quality
of movement but otherwise showed
mostly average performance on the
other summary scores. Compared
with proles 1 and 2, prole 3 infants
(n 217 [17.4%]) had lower attention
with more handling, lower selfregulation, higher arousal and excitability, similar lethargy and hypertonicity,

.001
.001
.001
.001
.001
.001
.001
.001
.001
.001
.001
.001

less hypotonicity, fewer nonoptimal and

asymmetric reexes, lower quality of
movement, and more stress abstinence
signs. Prole 4 infants (n 274 [22.0%])
showed average performance on attention, handling, self-regulation, arousal,
excitability, and lethargy but had more
hypertonicity than proles 1 to 3, more
asymmetric reexes than proles 1 to 3,
lower quality of movement and more
stress abstinence than proles 1 and 2,
and the most hypotonicity and nonopti-

FIGURE 1

Five NNNS proles (N 1248).

PEDIATRICS Volume 125, Number 1, January 2010

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e93

mal reexes among the 5 proles. Prole

5 (n 72 [5.8%]) showed the most extreme negative scores. These infants
showed the lowest attention with more
handling; the lowest self-regulation; the
highest arousal, excitability, and hypertonicity; average lethargy, hypotonicity,
and nonoptimal and asymmetric reexes;
the lowest quality of movement; and the
most stress abstinence signs. Given that
infants in prole 5 showed the poorest
performance, we hypothesized that this
group would more likely have medical
and developmental sequelae than infants in the other 4 proles. Infants in
prole 4 had extremes in tone (either hypertonic or hypotonic), the most nonoptimal reexes, poor quality of movement,
and a high number of stress signs;
therefore, we also predicted that infants in the prole 4 and 5 groups
would show more medical and developmental problems than infants in
the other 3 prole groups.
Validation and Prediction
Prenatal Drug Exposure
Infants in the prole 5 group were
more likely to be exposed to cocaine
plus opiates, tobacco, and marijuana
in utero than infants in the other 4 proles. Infants in the combined proles 4
and 5 group were more likely to be exposed to heavy cocaine use, tobacco,
and marijuana in utero than infants in
proles 1 to 3 (Table 4).

TABLE 4 Comparison of Prole 5 and Proles 4 and 5 With Other Proles as Predictors of Child
Outcomes
Variable

Prenatal drug exposure

Cocaine
Heavy cocaine
Cocaine and opiate
Tobacco
Heavy tobacco
Alcohol
Heavy alcohol
Marijuana
Heavy marijuana
Medical outcomes
GA 32 wk
GA 3336 wk
Birth weight 1500 g
Birth weight 2500 g
Abnormal ultrasound reading at 1 mo
Chronic neurologic abnormalities by 3 y
Any disease related to brain risk by 3 y
CP diagnosis by 3 y
Behavioral outcomes
Bayley
MDI 2 SD, 1 year
MDI, 2 SD, 2 y
MDI 2 SD, 3 y
PDI 2 SD, 1 year
PDI 2 SD, 2 y
PDI 2 SD, 3 y
CBCL at 3 y
Externalizing Problems 63
Internalizing Problems 63
Total Problems 63
DIAL-R at 4 y
Potential motor problem
Potential concept problem
Potential language problem
Potential total problem
WPPSI at 4.5 y
IQ verbal 2 SD
IQ performance 2 SD
IQ full 2 SD

Prole 5 vs Proles 14

Proles 4 and 5 vs Proles

13

OR (95% CI)

OR (95% CI)

1.36 (0.842.18)
1.62 (0.803.28)
3.86 (1.808.28)
2.07 (1.243.47)
1.29 (0.662.52)
1.61 (0.962.70)
1.29 (0.662.52)
1.73 (1.042.87)
1.44 (0.504.13)

.209
.183
.001
.005
.182
.069
.460
.035
.500

1.13 (0.881.45)
1.71 (1.142.56)
1.72 (0.973.07)
1.33 (1.041.71)
1.21 (0.891.64)
1.23 (0.951.59)
1.42 (0.992.05)
1.39 (1.051.85)
1.31 (0.712.42)

.327
.009
.064
.026
.222
.111
.060
.023
.383

2.07 (1.173.66)
1.15 (0.632.09)
2.17 (1.203.95)
1.75 (1.092.82)
2.77 (1.405.46)
2.80 (1.684.65)
1.89 (1.093.31)
3.12 (1.049.37)

.013
.647
.011
.022
.003
.000
.025
.042

1.74 (1.262.42)
1.23 (0.911.65)
1.77 (1.232.55)
1.57 (1.232.02)
1.19 (0.741.91)
2.51 (1.853.41)
2.31 (1.683.17)
2.40 (1.095.33)

.001
.179
.002
.000
.478
.001
.001
.031

3.34 (1.229.10)
1.92 (1.053.52)
1.57 (0.763.24)
1.67 (0.644.37)
1.80 (0.615.25)
1.17 (0.353.94)

.019
.034
.225
.298
.285
.798

1.89 (0.884.05)
1.26 (0.871.83)
1.23 (0.821.84)
1.22 (0.672.22)
2.18 (1.174.04)
1.24 (0.692.20)

.102
.215
.310
.516
.014
.474

2.07 (1.173.67)
2.70 (1.504.87)
2.38 (1.344.20)

.013
.001
.003

1.08 (0.781.51)
1.29 (0.901.85)
1.26 (0.911.76)

.631
.173
.163

1.75 (0.923.34)
2.06 (1.093.90)
1.99 (0.894.46)
1.42 (0.722.79)

.088
.027
.094
.315

1.43 (1.012.01)
1.47 (1.042.08)
1.68 (1.062.67)
1.36 (0.961.94)

.041
.029
.027
.084

1.74 (0.863.48)
1.01 (0.442.34)
1.99 (1.023.90)

.120
.977
.044

1.10 (0.741.64)
1.45 (0.972.17)
1.26 (0.861.83)

.627
.070
.235

CP indicates cerebral palsy; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; WPPSI, Wechsler
Preschool and Primary Scale of Intelligence.

Medical Outcomes
Prole 5 infants were more likely to be
preterm (32 weeks GA) and have
very low birth weight (1500 g) or low
birth weight (2500 g). They were
more likely to have an abnormal ultrasound reading at 1 month, chronic neurologic abnormalities, brain-related illness, or diagnosis of cerebral palsy by
age 3. These same ndings were observed comparing infants with prole
4 or 5 versus infants with proles 1 to 3
with the exception of the ultrasound
e94

LIU et al

nding. No differences were found in

gender or small-for-GA status related
to prole 5 or proles 4 and 5 combined (Table 4).
Behavioral Outcomes
Prole 5 infants were more likely to
have low Bayley Mental Developmental
Index scores at 1 and 2 years of age;
more CBCL externalizing, internalizing,
and total problems at age 3; more
DIAL-R concept problems at age 4; and

lower IQ at 4.5 years than infants with

proles 1 to 4. Infants with prole 4 or
5 compared with infants with proles 1
to 3 were more likely to show poor Bayley Psychomotor Developmental Index
scores at age 2 and more DIAL-R motor,
concept, and language problems at
age 4.
Prole 5 had the highest proportion of
infants dened as clinically worrisome
on 20 of the 23 outcomes that we exam-

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FIGURE 2
Proportions of infants with nonoptimal medical characteristics by NNNS proles.

FIGURE 3

Proportions of infants with nonoptimal developmental outcomes by NNNS proles (Bayley and Wechsler Preschool and Primary Scale of Intelligence 2 SD).

ined (Figs 2 and 3). Prole 4 seems to

be more sensitive to medical (Fig 2)
than to developmental outcomes (Fig
3), with the exception of the DIAL-R motor (Table 4).
Adjustment for Covariates
We compared the predictive validity of
the NNNS with the predictive validity of
the 2 most likely variables that would
also be expected to predict these outcomes: GA and socioeconomic status
(SES).3436 Forward stepwise logistic
PEDIATRICS Volume 125, Number 1, January 2010

regression analyses were implemented

to determine the predictive validity of
the NNNS proles after controlling for
GA (33 weeks, 3336 weeks, and 37
weeks) and low SES (Hollingshead Index of Social Position Level 5).
The prole 5 group, compared with
children in the other prole groups after controlling for GA and SES, were
more likely to have an abnormal ultrasound reading at 1 month (odds ratio
[OR]: 2.37 [95% condence interval

(CI): 1.17 4.80]), chronic neurologic

abnormalities (OR: 2.35 [95% CI: 0.36
4.02]), brain-related illnesses (OR: 1.86
[95% CI: 1.06 3.27]), externalizing behavior problems (OR: 2.05 [95% CI:
1.153.67]), internalizing behavior problems (OR: 2.72 [95% CI: 1.49 4.98]), and
total behavior problems (OR: 2.37 [95%
CI: 1.33 4.24]) by age 3.
The prole 4 and 5 combined group
compared with children with proles
1 to 3, after controlling for GA and

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e95

SES, were more likely to have birth

weight 2500 g (OR: 1.370 [95% CI:
1.0121.850]); heavy prenatal cocaine
exposure (OR: 1.71 [95% CI: 1.132.58]);
any prenatal exposure to tobacco (OR:
1.40 [95% CI: 1.08 1.81]), alcohol (OR:
1.32 [95% CI: 1.011.72]; P .042),
or marijuana (OR: 1.37 [95% CI: 1.02
1.84]); chronic neurologic abnormalities (OR: 2.42 [95% CI: 1.753.34]) and
brain-related illnesses (OR: 2.34 [95%
CI: 1.70 3.23]) by age 3; and concept
problems (OR: 1.43 [95% CI: 1.012.04])
and language problems (OR: 1.70 [95%
CI: 1.06 2.73]) at age 4. For descriptive
purposes, we compared the number of
children with negative outcomes identied by GA and/or SES with the number of additional children identied by
proles 4 and 5 (Table 5). For example,
of the 88 children with an abnormal
ultrasound nding, 45.5% were identied by GA and/or SES; an additional
17% who were not identied by GA
and/or SES were identied by the proles 4 and 5. In 9 of the 20 outcomes in
Table 5, the proles identied at least
15% of infants with poor outcome not
identied by low GA and/or SES.

DISCUSSION
The main ndings from this study are
that NNNS proles discriminate among
infants with medical and behavioral
problems through 4.5 years of age, including infants who would not have
been identied on the basis of medical
and demographic factors alone. We described a method to develop neurobehavioral proles of 1-month-old infants
on the basis of NNNS scores. Five discrete proles were identied; the most
extreme negative scores were shown
by 5.8% of the infants (prole 5). These
infants with clinically worrisome conditions were highly aroused, excitable,
and hypertonic; had poor quality of
movement and self-regulation and
poor attention; required substantial
handling; and were highly stressed. Infants with prole 5 were sensitive to
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LIU et al

TABLE 5 Infants With Developmental Problems Identied by GA 33 Weeks, Low SES, or NNNS
Proles
Outcome

Infants With
Problems, n (%)

Infants Identied
by Either GA 33
wk or Low SES,
n (%)

Additional Infants
Identied by
Proles 4 and 5
Combined, n (%)

88 (7.1)
213 (17.1)
194 (15.5)
25 (2.2)

40 (45.5)
121 (56.8)
75 (38.7)
17 (68.0)

15 (17.0)
40 (18.8)
46 (23.7)
3 (12.0)

28 (3.0)
160 (17.6)
134 (15.4)
52 (5.7)
44 (5.2)
58 (7.1)

15 (53.6)
79 (49.4)
64 (47.8)
30 (57.7)
23 (52.3)
30 (51.7)

3 (10.7)
22 (13.8)
16 (11.9)
6 (11.5)
7 (15.9)
6 (10.3)

226 (25.0)
165 (18.2)
218 (24.1)

104 (46.0)
84 (50.9)
103 (47.2)

37 (16.4)
29 (17.6)
38 (17.4)

213 (26.6)
204 (25.7)
89 (11.3)
197 (25.1)

107 (50.2)
95 (46.6)
42 (47.2)
98 (49.7)

31 (14.6)
33 (16.2)
15 (16.9)
28 (14.2)

147 (19.3)
129 (16.9)
162 (21.5)

67 (45.6)
66 (51.2)
79 (48.8)

19 (12.9)
15 (11.6)
20 (12.3)

Medical outcomes
Abnormal ultrasound reading, 1 mo
Chronic neurologic abnormalities by 3 y
Any disease related to risks to brain by 3 y
CP diagnosis by 3 y
Behavioral outcomes
Bayley
MDI 2 SD, 1 y
Bayley MDI 2 SD, 2 y
Bayley MDI 2 SD, 3 y
Bayley PDI 2 SD, 1 y
Bayley PDI 2 SD, 2 y
Bayley PDI 2 SD, 3 y
CBCL at 3 y
Externalizing problems 63
Internalizing problems 63
Total problems 63
DIAL-R at 4 y
Potential motor problem
Potential concept problem
Potential language problem
Potential total problem
WPPSI at 4.5 y
IQ verbal 2 SD
IQ performance 2 SD
IQ full 2 SD

Denominators vary across the outcomes. MDI indicates Mental Developmental Index; PDI, Psychomotor Developmental
Index; WPPSI, Wechsler Preschool and Primary Scale of Intelligence.

prenatal drug exposure (cocaine and

opiates, tobacco, and marijuana) and
prematurity/low birth weight (ie,
50% of these infants were 2500 g,
20% of whom were 1500 g). Infants
with prole 5 had the highest proportion of ultrasound, neurologic, and
brain disease. Upward of 40% of these
infants had clinically signicant behavior and school readiness problems,
and 35% had low IQ. Thus, infants
with prole 5 are indeed worrisome,
and a substantial proportion of them
will go on to have clinically signicant
follow-up ndings.
We also combined proles 4 and 5 because infants with prole 4 showed extremes in tone, the highest number
of nonoptimal reexes, poor quality of
movement, and a high number of
stress signs. Infants with prole 4 or 5
were more likely to be in the heavy co-

caine exposure group. Although some

of the outcomes were no longer statistically signicant, the addition of prole 4 increased the OR for disease related to the brain and was related to all
3 school readiness domains. Prole 4
also had a higher proportion of infants
with medical conditions than proles 1
to 3.
It is also of interest to ask whether
these neonatal neurobehavioral antecedents are unique. After adjusting for
prematurity and SES, we found that the
NNNS proles were still related to prenatal drug exposure, low birth weight,
neurologic abnormalities, and diseases with risks to the brain, as well as
behavior problems and delayed school
readiness. Measurable antecedents of
later developmental outcome can be
detected in neonatal neurobehavior.
These unique effects accounted for an

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ARTICLES

additional 16.2% to 23.7% of the children with medical or behavioral problems. We selected GA and SES as covariates because of their prominence
in predicting developmental outcome
in high-risk samples3436 and could
therefore be confounding. They also
represent essentially immutable factors (although SES can theoretically
change), whereas the development of
preventive interventions would target
neurobehavior that can be altered.
The presence of confounding factors
does not obviate the justication for
early intervention. The 5.8% prevalence rate of prole 5 in our sample is
consistent with the estimate that 5% to
10% of the pediatric population is at
high risk for later developmental problems.37 Early identication of children
with developmental delay has received
more attention in recent years, because children are believed to benet
the most when they participate in intervention services as early as possible.38 The American Academy of Pediatrics has called for a referral to early
intervention or special education after
a positive screening result, and a
recent commentary recommended
that a diagnosis not be required for
such a referral.39 The NNNS proles
specify the neurobehavioral decits
that are associated with poor outcome and could serve as target behaviors for the development of intervention studies. These ndings can
be used to guide programmatic intervention efforts targeted to those
with indicated dysfunction.
It is widely understood that predictive
validity tests for this population are
problematic because infancy is a period of rapid change. In addition to
measuring a moving target, developmental outcome is determined by postnatal factors. Many infants seem normal as neonates but develop problems

PEDIATRICS Volume 125, Number 1, January 2010

later (low specicity or false-negative

result), and many infants who seem
worrisome as neonates develop normally (low sensitivity or false-positive
result). Thus, infant neurobehavioral
tests may not meet standard criteria
for medical screening; however, our
approach was not designed to maximize sensitivity and specicity. Prole
5 identied 72 (5.8%) infants, and we
demonstrated that a clinically signicant number of these infants will have
developmental sequelae. For example,
42% of the children with prole 5 had
deviant total behavior scores on the
CBCL; however, in the sample as a
whole, 218 children showed deviant total behavior problem scores on the
CBCL. Thus, prole 5 is indicative of
later behavior problems, but because
this prole occurred in only 5.8% of the
sample, it cannot identify clinical conditions with higher prevalence rates.
Prediction is not the only important
criterion for a neonatal assessment.
Diagnosing atypical neurobehavior
and early dysfunctions that are amenable to intervention and specifying
characteristics for targeted pediatric
interventions serve a primary prevention and treatment need as well. Thus,
our ndings could stimulate an important social policy debate. On the 1
hand, if used as screen, then the NNNS
would fail to identify many infants who
will later develop behavior problems
and will identify as deviant many infants who will develop normally. The
latter could suffer the negative effects
of being labeled, and resources would
be used unnecessarily. On the other
hand, the NNNS is noninvasive, early
intervention is benign, and there is the
ethical responsibility of offering early
intervention to parents whose infants
have a 40% chance of having a childhood behavior disorder or school
readiness problem.

A limitation of this study is that these

proles were developed in a sample of
children with prenatal exposure to cocaine and other substances, which
could limit the generalizability of the
ndings. Another limitation is that this
study followed children only through
4.5 years of age, and it would be important to determine the predictive validity of the NNNS in older children.

CONCLUSION
Finding continuities in behavior between the neonatal period and early
childhood provides new evidence that
has implications for our understanding of developmental processes. The
ability to forecast with some precision
which individual infants are most likely
to show developmental decits in early
childhood opens the door for the study
of intervention studies to reduce or
ameliorate these decits. This could
enable us to identify, from the larger
pool of infants who are already at risk,
which infants are at highest risk and
enable us to make better use of increasingly limited resources. NNNS
proles identify infant behavior to be
targeted in well-infant pediatric care,
as well as for referrals to communitybased early intervention services.

ACKNOWLEDGMENTS
This study was supported by the Eunice Kennedy Shriver National Institute
of Child Health and Human Development Neonatal Research Network and
an interinstitute agreement with the
National Institute on Drug Abuse
through cooperative agreements U10
DA 024117-01, U10HD21385 (to Dr Shankaran), U10 DA 024128-06, U10HD2786
(to Dr Bada), U10 DA 024119-01 and
U10HD27904 (to Dr Lester), and U10 DA
024118-01 and U10HD21397 (to Dr
Bann) and Child Health and Human Development contract N01-HD-2-3159 (to
Dr Lester).

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Neonatal Neurobehavior Predicts Medical and Behavioral Outcome

Jing Liu, Carla Bann, Barry Lester, Edward Tronick, Abhik Das, Linda Lagasse,
Charles Bauer, Seetha Shankaran and Henrietta Bada
Pediatrics 2010;125;e90-e98; originally published online Dec 7, 2009;
DOI: 10.1542/peds.2009-0204
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