Research

JAMA Pediatrics | Original Investigation

Association Between Moderate and Late Preterm Birth

and Neurodevelopment and Social-Emotional Development
at Age 2 Years
Jeanie L. Cheong, MD; Lex W. Doyle, MD; Alice C. Burnett, PhD; Katherine J. Lee, PhD; Jennifer M. Walsh, MD; Cody R. Potter, PhD;
Karli Treyvaud, PhD; Deanne K. Thompson, PhD; Joy E. Olsen, PhD; Peter J. Anderson, PhD; Alicia J. Spittle, PhD

Supplemental content
IMPORTANCE Moderate and late preterm (MLPT) births comprise most preterm infants.
Therefore, long-term developmental concerns in this population potentially have a large
public health influence. While there are increasing reports of developmental problems in
MLPT children, detail is lacking on the precise domains that are affected.

OBJECTIVE To compare neurodevelopment and social-emotional development between

MLPT infants and term-born control infants at age 2 years.

DESIGN, SETTING, AND PARTICIPANTS This investigation was a prospective longitudinal cohort
study at a single tertiary hospital. Participants were MLPT infants (32-36 weeks’ completed
gestation) and healthy full-term controls (ⱖ37 weeks’ gestation) recruited at birth. During a
3-year period between December 7, 2009, and November 7, 2012, MLPT infants were
recruited at birth from the neonatal unit and postnatal wards of the Royal Women’s Hospital,
Melbourne, Australia. The term control recruitment extended to March 26, 2014. The dates of
the data developmental assessments were February 23, 2012, to April 8, 2016.

EXPOSURE Moderate and late preterm birth.

MAIN OUTCOMES AND MEASURES Cerebral palsy, blindness, and deafness assessed by a
pediatrician; cognitive, language, and motor development assessed using the Bayley Scales of
Infant Development–Third Edition (developmental delay was defined as less than −1 SD
relative to the mean in controls in any domain of the scales); and social-emotional and
behavioral problems assessed by a parent questionnaire (Infant Toddler Social Emotional
Assessment). Outcomes were compared between birth groups using linear and logistic
regression, adjusted for social risk.

RESULTS In total, 198 MLPT infants (98.5% of 201 recruited) and 183 term-born controls
(91.0% of 201 recruited) were assessed at 2 years’ corrected age. Compared with controls,
MLPT children had worse cognitive, language, and motor development at age 2 years, with
adjusted composite score mean differences of −5.3 (95% CI, −8.2 to −2.4) for cognitive
development, −11.4 (95% CI, −15.3 to −7.5) for language development, and −7.3 (95% CI, −10.6
to −3.9) for motor development. The odds of developmental delay were higher in the MLPT
group compared with controls, with adjusted odds ratios of 1.8 (95% CI, 1.1-3.0) for cognitive
delay, 3.1 (95% CI, 1.8-5.2) for language delay, and 2.4 (95% CI, 1.3-4.5) for motor delay.
Overall social-emotional competence was worse in MLPT children compared with controls (t
statistic mean difference, −3.6 (95% CI, −5.8 to −1.4), but other behavioral domains were
similar. The odds of being at risk for social-emotional competence were 3.9 (95% CI, 1.4-10.9)
for MLPT children compared with controls.

CONCLUSIONS AND RELEVANCE Moderate and late preterm children exhibited developmental
Author Affiliations: Author
delay compared with their term-born peers, most marked in the language domain. This affiliations are listed at the end of this
knowledge of developmental needs in MLPT infants will assist in targeting surveillance and article.
intervention. Corresponding Author: Jeanie L.
Cheong, MD, Neonatal Services,
Royal Women’s Hospital, Level 7,
JAMA Pediatr. 2017;171(4):e164805. doi:10.1001/jamapediatrics.2016.4805 Parkville, Victoria, Australia 3052
Published online February 6, 2017. (jeanie.cheong@thewomens.org.au).

(Reprinted) 1/7

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 Research Original Investigation Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years
P
rematurity is a recognized risk factor for developmen-
tal problems in childhood and adolescence.1 For many
years, the focus of research has been on developmen-
tal outcomes of infants born very preterm (<32 weeks’ gesta-
tion). However, in recent times, data are emerging that chil-
dren born moderate and late preterm (MLPT) between 32 and
36 weeks’ completed gestation are also at greater risk of de-
velopmental problems compared with their term-born peers.2-5
Because MLPT infants comprise the largest group of preterm
infants (approximately 80%),6,7 small increases in adverse out-
comes in this population have the potential to be a consider-
able public health burden. Recent reports on early childhood
outcomes of MLPT infants highlight deficits in cognitive and
motor domains, as well as social functioning.5,8-10 However,
limitations of the studies include reliance on questionnaire as-
sessments (rather than direct) and low follow-up rates, which
potentially underestimate the prevalence of developmental
problems. Furthermore, a better understanding of the spe-
cific developmental deficits in MLPT children is needed to in-
form public health policy, as is targeted surveillance and in-
tervention in developmental domains at greatest risk. This
study aimed to fill this gap in the literature by comparing neu-
rosensory outcomes and cognitive, language, motor, and social-
emotional development between MLPT children and term-
born control children at 2 years’ corrected age. Given that there
may be differences in developmental outcomes within the
MLPT group, which spans from 32 to 36 weeks’ completed ges-
tation, we also aimed to explore whether there was an asso-
ciation between gestational age at birth and developmental out-
comes within this group.
Methods
Participants
The Late Preterm MRI Study11 is a longitudinal cohort study of
brain development and outcomes in MLPT children compared
with term-born children. During a 3-year period between De-
cember 7, 2009, and November 7, 2012, MLPT infants were re-
cruited at birth from the neonatal unit and postnatal wards of
the Royal Women’s Hospital, Melbourne, Australia, the largest
of the 3 perinatal centers in the state of Victoria where tertiary
neonatal care is provided. The dates of the data neurodevelop-
mental assessments were February 23, 2012, to April 8, 2016.
It is hospital policy for all infants born less than 36 weeks’
gestation to be admitted to the neonatal unit. Infants with con-
genital abnormalities or genetic syndromes known to affect de-
velopment were excluded from the study. Healthy term-born
infants (≥37 weeks’ gestation and birth weight ≥2500 g) were
recruited from the postnatal wards at the Royal Women’s Hos-
pital. Term infants were excluded from the study if they were
unwell at birth, received resuscitation, were admitted to the
neonatal nursery, or were identified as having conditions af-
fecting growth or development.
Perinatal, neonatal, and maternal details were recorded by
medical record review at the time of recruitment. Social risk
was assessed using sociodemographic factors known to be as-
sociated with outcomes in preterm infants, including family
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Key Points
Question What is the influence of moderate and late preterm
birth on neurodevelopment and social-emotional development at
age 2 years?
Findings This longitudinal cohort study found that, compared with
term-born children, children born moderate and late preterm are
delayed in cognitive, language, and motor development. In addition,
they have poorer social competence at 2 years’ corrected age.
Meaning Developmental surveillance is important given the risk
of developmental delay in moderate and late preterm children.
structure, education of the primary caregiver, employment sta-
tus of the primary income earner, occupation of the primary
income earner, language spoken at home, and maternal age at
birth of the child. Each variable was scored on a 3-point scale,
where zero represented lowest risk and 2 represented highest
risk, and summed to give a total score (range, 0-12). Social risk
was then dichotomized to higher (total social risk score of ≥2)
or lower (total social risk score of <2) risk.12 All participants were
followed up at age 2 years, corrected for prematurity, at The
Royal Children’s Hospital Melbourne.
This study was approved by the Human Research Ethics
Committee of the Royal Women’s Hospital. Written informed
consent was obtained from parents of all participants.
2-Year Assessments
Cerebral palsy was diagnosed in children with abnormal tone
and function, after the exclusion of other causes of motor dys-
function, by a pediatrician. The topography and severity of ce-
rebral palsy were classified according to the Gross Motor Func-
tion Classification Scale.13 Blindness and deafness were also
assessed by a pediatrician. Blindness was defined as having vi-
sual acuity of less than 6/60 in the better eye, and deafness was
defined as a hearing impairment requiring amplification or a
cochlear implant or worse.
Cognitive, language, and motor development were as-
sessed using the Bayley Scales of Infant Development–Third Edi-
tion (Bayley-III).14 The Bayley-III is age standardized, is widely
used in research and clinical settings, and has published norms
that have a mean (SD) of 100 (15). Given the concerns about
underestimation of developmental delay in the Australian
population,15,16 delay in any developmental domain was de-
fined as less than −1 SD relative to the mean for the control chil-
dren in the present study. We also defined moderate to severe
developmental delay as less than −2 SDs relative to the mean
for the control children. All assessors (one of us, C.R.P., and
other nonauthors) were experienced in both the Bayley-III and
neurological assessments and were unaware of group alloca-
tion and perinatal history.
Social-emotional and behavioral problems were assessed
using the Infant Toddler Social Emotional Assessment (ITSEA).17
The ITSEA is a parent-report questionnaire developed for chil-
dren aged 12 to 36 months. Aspects of child behavior are rated
on 135 items using a 3-point Likert-type rating scale (0 is not true
or rarely, 1 is somewhat true or sometimes, and 2 is very true or
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 Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years
often [“no opportunity” is available for some questions]). Age-
and sex-specific t statistics (mean [SD], 50 [10]; range, 25-80)
are calculated for the following 4 domains: externalizing be-
havior problems, internalizing behavior problems, dysregula-
tion, and social-emotional competence. The mean scores at or
above the 90th percentile for externalizing behavioral prob-
lems, internalizing behavioral problems, and dysregulation at
or below the 10th percentile for social-emotional competence
were defined as being at risk of behavioral or social-emotional
problems. The ITSEA has good test-retest reliability and good
criterion validity.18
Statistical Analysis
The expected rate of developmental delay for the controls
based on previous literature was 16%.19 With a sample size of
201 participants in each group, the study was powered to de-
tect an increase in the prevalence of developmental delay to
27.5% or higher among the MLPT children (equivalent to an
odds ratio [OR] of 2) with 80.0% power based on a 2-sided test
with type I error of 5.0%, which would represent a clinically
important difference.
Participant characteristics were compared between those
who were assessed at age 2 years and those who were not using
means (SDs) for continuous variables and proportions for cat-
egorical variables. Two-year development was compared be-
tween groups using linear regression, with a separate model for
each developmental outcome. The analysis was first performed
unadjusted and then adjusted for social risk, which is known to
affect development. Rates of cerebral palsy, blindness, deafness,
developmental delay, and social-emotional problems were com-
pared between groups using logistic regression, both unadjusted
and adjusted for social risk, which is an important factor influ-
encing development. All regression analyses were fitted using
generalized estimating equations and are reported with robust
(sandwich) estimates of standard errors to account for cluster-
ing because of multiple births within the same family. Linear re-
gression was also used to determine the association between ges-
tational age at birth and developmental outcomes at age 2 years
in the MLPT group. Data were analyzed using statistical software
(Stata, version 14.0; StataCorp LP).
Results
Two hundred one MLPT infants and an equal number of term-
born controls were recruited. Participant characteristics are
summarized in Table 1. Compared with controls, the MLPT in-
fants were more likely to be small for gestational age at birth.
Compared with mothers of control infants, mothers of MLPT
infants had higher rates of pregnancy-related complications,
such as preeclampsia and antepartum hemorrhage, and higher
rates of assisted conception, multiple births, antenatal corti-
costeroid use, and cesarean delivery. Moderate and late pre-
term infants had higher rates of neonatal morbidity com-
pared with controls, although the overall rates were low. Social
risk was comparable between the groups.
The follow-up rates were high for both groups at 98.5% (198
of 201) for MLPT children (1 was living abroad and 2 were un-
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Original Investigation Research
able to be contacted) and 91.0% (183 of 201) for controls (1 with-
drew from the study, 3 were living abroad and 14 were unable
to be contacted). Compared with those who were assessed at
age 2 years, MLPT children who were not assessed had younger
mothers (26.7 vs 34.1 years) and higher social risk (100% [3 of
3] vs 32.8% [63 of 192]). Compared with those who were as-
sessed at age 2 years, controls who were not assessed had
younger gestational age (39.2 vs 39.8 weeks), younger moth-
ers (30.6 vs 33.5 years), and higher birth weight z score (0.80
vs 0.16). Other characteristics were similar.
Two-year outcomes are summarized in Table 2. There were
2 children in the MLPT group with cerebral palsy, one with
hemiplegia (Gross Motor Function Classification System level
1) and another with quadriplegia (Gross Motor Function Clas-
sification System level 3) (P = .17 for adjusted by logistic re-
gression). No children had blindness or deafness in either
group. There was evidence that MLPT children performed more
poorly than controls in all domains of development, most
marked in language, with a mean difference of approxi-
mately 0.7 SD. This finding appeared to be driven equally by
performance in the receptive and expressive language subdo-
mains. There was also evidence that the MLPT group had
poorer social-emotional competence compared with con-
trols, with a mean difference of 0.4 SD, but were similar to con-
trols in the other emotional and behavioral domains. Adjust-
ment for social risk did not alter the conclusions and had little
effect on the mean differences. Adjustment for imbalances in
perinatal characteristics, including birth weight z score and
multiple birth, did not alter any conclusions.
There was evidence that rates of a developmental delay
were higher in the MLPT group than in controls in all do-
mains, with weaker evidence for moderate or severe cogni-
tive delay (Table 3). Compared with controls, MLPT children
were more likely to be at risk in the social-emotional compe-
tence domain but not other behavioral domains. Adjustment
for social risk did not alter any conclusions.
Within the MLPT group, there was little evidence of an as-
sociation between gestational age at birth and neurodevelop-
ment or social-emotional development at age 2 years. These
results are summarized in the eTable in the Supplement.
Discussion
This study adds to the growing body of evidence that MLPT
birth is associated with an increased risk of developmental
problems compared with term birth. Using direct, objective,
standardized assessments, MLPT children at 2 years’ cor-
rected age performed more poorly in cognitive, language, and
motor domains compared with term-born controls. The dis-
parity was greatest in the language domain, where MLPT chil-
dren had 3 times higher odds of language impairment than their
term-born peers, with both receptive and expressive lan-
guage equally affected. It is also of great concern that MLPT
children appear to be at much greater risk of motor impair-
ment, with the odds of MLPT children scoring less than −2 SDs
being 9 times higher than their term-born peers (after adjust-
ment for social risk). We also found evidence of poorer social-
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 Research Original Investigation Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years

Table 1. Demographic Data

MLPT Group Term Group
Variable (n = 201) (n = 201) P Value
Maternal age, mean (SD), y 34.0 (4.8) 33.2 (4.7) .12
Maternal preeclampsia, No. (%) 36 (17.9) 3 (1.5) <.001
Assisted conception, No./total No. (%) 39/198 (19.7) 20/199 (10.1) .01
Gestational age at birth, mean (SD), wk 34.4 (1.2) 39.8 (1.2) <.001
Antepartum hemorrhage, No. (%) 19 (9.5) 6 (3.0) .01
Antenatal corticosteroid use, No. (%) 121 (60.2) 6 (3.0) <.001
Antenatal magnesium sulfate use, No. (%) 15 (7.5) 0 NA
Induction of labor, No./total No. (%) 15/200 (7.5) 79 (39.3) <.001
Multiple birth, No. (%) 74 (36.8) 2 (1.0) <.001
Twins, No. 71 2 NA
Triplets, No. 3 0 NA
Cesarean delivery, No. (%) 137 (68.2) 77 (38.3) <.001
Male birth, No. (%) 96 (47.8) 107 (53.2) .27
Birth weight, mean (SD), g 2161 (463) 3538 (447) <.001
Birth weight z score, mean (SD) −0.35 (1.16) 0.21 (0.82) <.001
Apgar score, median (IQR)
At 1 min 8 (6-9) 9 (8-9) <.001
At 5 min 9 (8-9) 9 (9-9) <.001
Major resuscitation at birth, No. (%)a 5 (2.5) 0 NA
Respiratory support, No. (%)b 28 (13.9) 0 NA
Jaundice requiring treatment, No./total No. (%) 147/201 (73.1) 5/200 (2.5) <.001 Abbreviations: IQR, interquartile
range; MLPT, moderate and late
Sepsis, No. (%)c 1 (0.5) 0 NA
preterm; NA, not applicable.
Necrotizing enterocolitis, No. 0 0 NA a
Received positive-pressure
Oxygen therapy at 36 wk, No. 0 0 NA ventilation, cardiopulmonary
Postnatal corticosteroid use, No. 0 0 NA resuscitation, or adrenaline.
b
Any intraventricular hemorrhage, No./total No.d 0 0/88 NA Includes both invasive and
noninvasive respiratory support.
Cystic periventricular leukomalacia, No./total No.d 0 0/88 NA c
Culture positive or raised white
Surgery in the newborn period, No. 0 0 NA blood cell count or C-reactive
Days in the hospital, median (IQR) 20 (14-27) [n = 199] 2 (2-3) [n = 142] <.001 protein level with at least 5 days of
antibiotic treatment.
Higher social risk, No./total No. (%) 66/195 (33.8) 48/184 (26.1) .10
d
As noted on magnetic resonance
Corrected age at follow-up, mean (SD), mo 25.3 (1.3) [n = 198] 25.6 (1.2) [n = 183] .01
imaging at term-equivalent age.

emotional competence in the MLPT group. The competence
domain of the ITSEA reflects aspects of children’s attention,
compliance, and motivation, as well as social relationships (eg,
play, empathy, and prosocial behavior). It is possible that these
early signs of challenge are precursors for some of the school-
age behavioral and learning problems described in MLPT
children.20,21
In our MLPT sample, cognitive, language, and motor de-
velopment were delayed compared with term-born controls
in the order of 0.5 to 0.7 SD (−6.3 to −11.8 points), which are
clinically important differences. Although our findings con-
cur with other studies that MLPT children demonstrate poorer
development as early as age 2 to 3 years, the disparity be-
tween MLPT children and term-born controls was larger in our
study. Voigt et al9 reported a mean difference of −5.4 on the
Bayley-II Mental Development Index between MLPT chil-
dren and term-born controls using a sample from a single cen-
ter. The population-based Early Childhood Longitudinal Sur-
vey–Birth Cohort study reported a mean t statistic difference
of −1.4 (95% CI, −2.7 to −0.2) on the Bayley mental score using
a short form of the Bayley-II modified specifically for that
study.22 They did not report differences in motor develop-
ment. Only late preterm children (34-36 weeks’ gestation) were
included in the Early Childhood Longitudinal Survey–Birth Co-
hort study. Our findings of greater disparity between groups
may be partially explained by our sample, who were re-
cruited from a tertiary hospital and included moderate pre-
term infants. It is possible that our cohort included a greater
proportion of sicker MLPT infants who were admitted to the
neonatal nursery than in the general population, especially in
the more mature gestational age range.
Rates of developmental delay in all domains were higher
in the MLPT children compared with controls. In this study,
we calculated rates of delay based on means (SDs) of the con-
temporaneous control group, which are higher than the nor-
mative mean (SD) of 100 (15) in the Bayley-III. Nonetheless,
the values of our present full-term control cohort are compa-
rable to data from contemporary term-born controls as-
sessed using the Bayley-III.19,23 Previous studies have simi-
larly reported higher rates of developmental delay in MLPT
children than in controls in this age group. Using a parent ques-
tionnaire, a large regional cohort from the United Kingdom had

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 Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years Original Investigation Research

Table 2. Two-Year Outcomes Compared Between the Birth Groups

Mean (SD)
MLPT Group Term Group Unadjusted Mean Adjusted Mean Adjusted Adjusted
Variable (n = 198) (n = 183) Difference (95% CI) βa Differenceb (95% CI) βa,b P Valueb
Neurodevelopment
Cognitive 102.5 (13.9) [n = 197] 109.1 (13.7) [n = 181] −6.3 (−9.2 to −3.4) −0.23 −5.3 (−8.2 to −2.4) −0.20 <.001
composite
Language 99.1 (17.7) [n = 190] 111.3 (16.6) [n = 178] −11.8 (−15.5 to −8.2) −0.34 −11.4 (−15.3 to −7.5) −0.31 <.001
composite
Receptive 10.1 (3.3) [n = 190] 12.2 (3.2) [n = 178] −2.0 (−2.7 to −1.4) −0.31 −1.9 (−2.6 to −1.2) −0.29 <.001
language
standard score
Expressive 9.5 (3.2) [n = 191] 11.6 (2.9) [n = 178] −2.0 (−2.7 to −1.4) −0.32 −1.9 (−2.6 to −1.2) −0.30 <.001
language
standard score
Motor composite 103.5 (16.0) [n = 194] 111.5 (15.2) [n = 177] −7.9 (−11.2 to −4.7) −0.25 −7.3 (−10.6 to −3.9) −0.23 <.001
Fine motor 11.8 (2.9) [n = 196] 13.2 (3.0) [n = 181] −1.4 (−2.0 to −0.8) −0.23 −1.2 (−1.8 to −0.6) −0.21 <.001
standard score
Gross motor 9.4 (2.9) [n = 194] 10.5 (3.0) [n = 177] −1.1 (−1.7 to −0.5) −0.19 −1.1 (−1.7 to −0.4) −0.18 <.001
standard score
Social-Emotional Development
Externalizing 47.8 (9.0) [n = 176] 47.3 (7.8) [n = 151] 0.5 (−1.4 to 2.4) 0.02 −0.1 (−1.9 to 1.8) −0.01 .95
behavior
Internalizing 45.7 (10.4) [n = 176] 45.2 (9.3) [n = 151] 0.6 (−1.6 to 2.8) 0.03 0.9 (−1.3 to 3.2) 0.04 .42
behavior
Dysregulation 44.0 (11.8) [n = 176] 44.0 (10.7) [n = 151] 0.2 (−2.4 to 2.7) −0.01 −0.1 (−2.6 to 2.6) −0.01 .99
Social-emotional 48.3 (10.7) [n = 176] 52.5 (8.4) [n = 150] −4.0 (−6.1 to −1.8) −0.21 −3.6 (−5.8 to −1.4) −0.20 .001
competence

Abbreviation: MLPT, moderate and late preterm.

a
Standardized regression coefficient.
b
Adjusted for social risk.

Table 3. Developmental Delay and At-Risk Social-Emotional Development Compared Between the Birth Groups

No./Total No. (%) Odds Ratio (95% CI)

MLPT Group Term Group Adjusted
Variable (n = 198) (n = 183) Unadjusted Adjusteda P Valuea
Neurodevelopment
Cognitive delay
Less than −1 SD 63/197 (32.0) 34/181 (18.8) 2.0 (1.2-3.3) 1.8 (1.1-3.0) .03
Less than −2 SDs 11/197 (5.6) 4/181 (2.2) 2.5 (0.8-8.3) 1.9 (0.6-6.6) .30
Language delay
Less than −1 SD 85/190 (44.7) 34/178 (19.1) 3.3 (2.0-5.4) 3.1 (1.8-5.2) <.001
Less than −2 SDs 26/190 (13.7) 6/178 (3.4) 4.3 (1.7-10.9) 3.9 (1.5-10.2) .005
Motor delay
Less than −1 SD 49/194 (25.3) 20/177 (11.3) 2.7 (1.5-4.8) 2.4 (1.3-4.5) .004
Less than −2 SDs 13/194 (6.7) 1/177 (0.6) 12.3 (1.6-95.9) 9.5 (1.2-74.4) .03
Social-Emotional Development
Externalizing behavior 8/176 (4.5) 3/151 (2.0) 2.3 (0.6-9.3) 1.6 (0.4-6.6) .49
Internalizing behavior 8/176 (4.5) 4/151 (2.6) 1.8 (0.5-6.0) 2.2 (0.5-8.4) .27
Dysregulation 10/176 (5.7) 7/151 (4.6) 1.3 (0.5-3.7) 1.1 (0.4-3.1) .82 Abbreviation: MLPT, moderate and
Social-emotional 23/176 (13.1) 5/150 (3.3) 4.4 (1.6-11.9) 3.9 (1.4-10.9) .008 late preterm.
competence a
Adjusted for social risk.

an adjusted relative risk of 2.09 (95% CI, 1.19-3.64) for cogni-
tive impairment in MLPT children compared with term-born
children at 2 years’ corrected age.5 If anything, this finding may
be an underestimation of the risk of delay because the fol-
low-up rates were only approximately 60%. The Early Child-
hood Longitudinal Survey–Birth Cohort had increased odds of
developmental delay at 24 months in late preterm children
compared with term-born children for both cognitive (mild de-
lay OR, 1.43; 95% CI, 1.22-1.67) and motor (mild delay OR, 1.58;
95% CI, 1.37-1.83) domains.8 Our findings of higher ORs may
be accounted for by differences in samples, assessment tools,
and definitions of delay.
Social and emotional behavioral problems in early
childhood24 and at school age25,26 have been described in the

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 Research Original Investigation Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years

very preterm population. Early identification of these prob-
lems is important because it is increasingly recognized that they
are associated with later psychopathological conditions.27,28
Although data on MLPT children are scarce, there are reports
of increased externalizing and internalizing problems in MLPT
children at preschool and early school age compared with term-
born controls.29,30 Recently, delays in social competence (but
not other behavioral domains) were identified in MLPT chil-
dren compared with term-born controls.10 Our results concur
with this finding, highlighting the potential importance of so-
cial competence as a basis for longer-term developmental and
behavioral problems described in school-age MLPT children.
It is also possible that the parent-reported concerns about MLPT
children’s social and behavioral competence are a reflection
of cognitive and language developmental delays in everyday
functioning.
The underlying brain basis for developmental problems in
MLPT children is poorly understood. The MLPT period involves
considerable growth and maturation of the brain. Increases in
brain volume, whole-brain weight, and gyral and sulcal devel-
opment are substantial in this period of late gestation.31 There-
fore, there is potential for aberration of these processes after
MLPT birth. Our group has recently reported differences in brain
volumes, maturation, and microstructure at term-equivalent age
in MLPT infants compared with term-born controls.11,32 Larger
volumes of total brain tissue, white matter, and cerebellum were
associated with better cognitive, language, and motor scores at
2 years’ corrected age in MLPT children.33 Moreover, altered neu-
ral activity as measured using functional magnetic resonance
imaging has been reported in the primary motor and sensory re-
gions in MLPT children compared with term-born controls.34
Collectively, there is accumulating evidence that alterations in
MLPT brain growth and development may underlie some of the
deficits described in these children.
In addition to neuroimaging findings, clinical assess-
ment tools in the neonatal period may also provide a valuable
indication of later functioning in MLPT infants. For instance,
developmental delay in MLPT children may manifest at an ear-
lier age as abnormal neurobehavior. In the same cohort, our
group has recently shown that suboptimal neurological and
neurobehavioral assessments, including on the Hammer-
smith Neonatal Neurological Examination and the NICU Net-
work Neurobehavioral Scale, at term-equivalent age were as-
sociated with developmental delay at 2 years of age in MLPT
infants.35 Further research into neurobehavioral deficits as-
sociated with MLPT birth may provide markers for specific de-
velopmental deficits in MLPT children.
Strengths and Limitations
The strengths of our study are that we recruited a large, pro-
spective cohort and achieved high follow-up rates at age 2 years.
We evaluated a range of developmental outcomes using di-
rect criterion standard assessments in addition to parent-
report questionnaires. However, we were limited by the inclu-
sion of participants from a single tertiary center, which may have
included sicker MLPT infants who were admitted to the neo-
natal nursery, especially those who were in the more mature
gestational age range within the MLPT group. This inclusion
potentially limits the generalizability of our findings to MLPT
children in the wider population. However, our results are gen-
eralizable to the population of MLPT children who were more
unwell and needed admission to a neonatal nursery after birth.
Conclusions
In summary, we have presented evidence that MLPT birth is
associated with greater morbidities in neurodevelopment and
social-emotional competence than term-born birth. This popu-
lation is a group of infants who traditionally receive little neu-
rodevelopmental surveillance. While there is good evidence
that early intervention is effective in improving cognitive out-
comes for preterm children up to school age, further research
is needed on effective intervention to improve language and
motor outcomes specifically in the MLPT population.36 To pro-
vide developmental follow-up and intervention to this group,
it will be vital to identify risk factors to target those at highest
risk of developmental problems given the large numbers of
MLPT births. Further research directions into potentially modi-
fiable factors, markers of poor outcome (eg, neuroimaging and
neurobehavioral assessments in the newborn period), and the
spectrum of deficits at school age and older have the poten-
tial to greatly improve the long-term care for this large group
of children.

ARTICLE INFORMATION
Accepted for Publication: November 30, 2016.
Published Online: February 6, 2017.
doi:10.1001/jamapediatrics.2016.4805
Author Affiliations: Neonatal Services, Royal
Women’s Hospital, Melbourne, Australia (Cheong,
Doyle, Burnett, Walsh, Olsen, Spittle); Victorian
Infant Brain Studies, Murdoch Childrens Research
Institute, Melbourne, Australia (Cheong, Doyle,
Burnett, Walsh, Potter, Treyvaud, Thompson,
Olsen, Anderson, Spittle); Department of Obstetrics
and Gynaecology, University of Melbourne,
Melbourne, Australia (Cheong, Doyle, Walsh);
Department of Paediatrics, University of
Melbourne, Melbourne, Australia (Doyle, Burnett,
Lee, Thompson, Anderson); Clinical Epidemiology
and Biostatistics Unit, Murdoch Childrens Research
Institute, Melbourne, Australia (Lee); Paediatric
Infant Perinatal Emergency Retrieval, The Royal
Children’s Hospital Melbourne, Melbourne,
Australia (Walsh); Department of Psychology and
Counselling, La Trobe University, Bundoora,
Australia (Treyvaud); Developmental Imaging,
Murdoch Childrens Research Institute, Melbourne,
Australia (Thompson); Florey Institute of
Neuroscience & Mental Health, Melbourne,
Australia (Thompson); Department of
Physiotherapy, University of Melbourne,
Melbourne, Australia (Spittle).
Author Contributions: Dr Cheong had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Cheong, Doyle,
Treyvaud, Anderson, Spittle.
Acquisition, analysis, or interpretation of data:
Cheong, Doyle, Burnett, Lee, Walsh, Potter,
Treyvaud, Thompson, Olsen, Anderson.
Drafting of the manuscript: Cheong, Burnett,
Treyvaud.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Cheong, Doyle, Lee.
Obtained funding: Cheong, Thompson, Anderson,
Spittle.
Administrative, technical, or material support:
Cheong, Walsh, Potter, Treyvaud, Thompson, Olsen.
Study supervision: Walsh, Treyvaud, Anderson,
Spittle.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by the
following grants from the Australian National

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 Association Between Preterm Birth and Neurodevelopment, Social-Emotional Development at 2 Years
Health and Medical Research Council: project
grants 1028822 and 1034516, Centre of Research
Excellence grant 1060733, Early Career Fellowship
grant 1053787 (Dr Cheong), Senior Research
Fellowship grant 1081288 (Dr Anderson), Career
Development Fellowship grant 1085754 (Dr
Thompson), grant 1053609 (Dr Lee), and grant
1108714 (Dr Spittle). This study was also supported
by The Royal Children’s Hospital Foundation and by
the Victorian Government’s Operational
Infrastructure Support Program.
Role of the Funder/Sponsor: The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank the research
coordinators, families, and children for their
participation in this study.
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