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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:
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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.
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LIU et al
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ARTICLES
METHODS
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
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LIU et al
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-
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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ARTICLES
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
.001
.001
.001
.001
.001
.001
.001
.001
.001
.001
.001
.001
FIGURE 1
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TABLE 4 Comparison of Prole 5 and Proles 4 and 5 With Other Proles as Predictors of Child
Outcomes
Variable
Prole 5 vs Proles 14
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
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ARTICLES
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).
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e95
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.
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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
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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e97
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