Brain & Development xxx (2016) xxx–xxx

www.elsevier.com/locate/braindev

Original article

Neurodevelopment in full-term small for gestational age infants:

A nationwide Japanese population-based study
Akihito Takeuchi a,⇑, Takashi Yorifuji b, Kyohei Takahashi c, Makoto Nakamura a,
Misao Kageyama a, Toshihide Kubo c, Tatsuya Ogino d, Hiroyuki Doi e
a
Department of Neonatology, Okayama Medical Center, National Hospital Organization, Okayama, Japan
b
Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, Okayama, Japan
c
Department of Pediatrics, Okayama Medical Center, National Hospital Organization, Okayama, Japan
d
Department of Children Studies, Faculty of Children Studies, Chugokugakuen University, Okayama, Japan
e
Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Received 22 June 2015; received in revised form 8 October 2015; accepted 25 December 2015

Abstract

Objective: To investigate neurological development in small for gestational age (SGA) infants, with a focus on full-term SGA
infants.
Methods: We analyzed data from a large, Japanese, nationwide, population-based longitudinal survey started in 2001. We
restricted the study to participants born before 42 weeks of gestation (n = 46,563). Parents were asked questions about motor
and language development when the children were 2.5 years old, and about behavioral development at 5.5 years. We analyzed
the relationships between SGA status and development by logistic regression. Odds ratios (ORs) and 95% confidence intervals
(95% CI) were calculated for each outcome for full-term and preterm births, adjusting for potential infant- and parent-related con-
founding factors. We also calculated the population-attributable fractions to estimate the public impact of SGA births.
Results: SGA full-term children were more likely to demonstrate developmental delays at 2.5 years, e.g., being unable to walk
alone (OR 3.0, 95% CI: 1.7, 5.3), compose a two-phrase sentence (OR 1.5, 95% CI: 1.2, 1.8), or use a spoon to eat (OR 1.5,
95% CI: 1.1, 1.9). SGA status also had some degree of negative impacts on behavioral problems at 5.5 years among term children,
e.g., being unable to listen without fidgeting (OR 1.2, 95% CI: 1.1, 1.3), or remain patient (OR 1.1, 95% CI: 1.0, 1.2). The public
health impacts were comparable between full-term and preterm SGA children at 2.5 years.
Conclusion: SGA is a risk factor for developmental delay, even in full-term infants, with non-negligible public health impacts.
Ó 2016 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.

Keywords: Behavior; Epidemiology; Growth; Development; Small-for-gestational-age

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AGA, appropriate for gestational age; CI, confidence interval; MHLW, Japanese
Ministry of Health, Labour and Welfare; OR, odds ratio; PAF, population-attributable fraction; SGA, small for gestational age
⇑ Corresponding author at: Department of Neonatology, Okayama Medical Center, National Hospital Organization, 1711-1 Tamasu, Kita-ku,
Okayama 701-1192, Japan. Tel.: +81 86 294 9911; fax: +81 86 294 9255.
E-mail address: gmd18025@s.okayama-u.ac.jp (A. Takeuchi).

http://dx.doi.org/10.1016/j.braindev.2015.12.013
0387-7604/Ó 2016 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
2 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx
1. Introduction
Small for gestational age (SGA) infants are reported
to be at increased risks of short stature, obesity, hyper-
tension, insulin resistance, and neurological sequelae in
later life [1]. The neurological prognoses of SGA infants
have been the focus of recent attention [2]. Several pre-
vious studies demonstrated that SGA was a significant
risk factor for neurodevelopmental delays among
preterm infants [3–5]. However, there are more SGA
full-term than preterm infants, and the neurological con-
sequences among full-term SGA infants may represent
more of a public health concern. A recent meta-
analysis showed that neurological development in
full-term SGA infants was poorer than in full-term
appropriate for gestational age (AGA) infants [6].
However, findings from large population-based birth
cohorts (tens of thousands of participants) were limited
in this meta-analysis. To the best of our knowledge, only
two large population-based birth cohorts have evaluated
the association between birth weight or SGA status and
neurological consequences in full-term infants [7,8].
However, the neurological outcome that one large
cohort study evaluated was limited to gross motor devel-
opment [7]. In addition, another cohort study covered
the period from 1959 to 1966 [8]. Thus, an analysis of
a more recent cohort on wide neurological outcomes is
warranted to take into account improvements in medical
and educational supports for SGA infants.
In the present study, we therefore examined neuro-
logical developmental outcomes in SGA infants using
data from a Japanese nationwide survey begun in
2001, focusing on full-term SGA infants, and then esti-
mated public health impacts of SGA births among both
full-term and preterm infants.
2. Methods
2.1. Study participants
The Japanese Ministry of Health, Labour and
Welfare (MHLW) has implemented a survey of newborn
babies and their parents, the Longitudinal Survey of
Babies in the 21st Century, annually since 2001 [9,10].
Briefly, baseline questionnaires were distributed to all
families throughout the country with 6-month-old
infants born between the 10th and 17th January or the
10th and 17th July, 2001. Of 53,575 mailed question-
naires, 47,015 were completed and returned (88%
response rate). Follow-up questionnaires were sent to
the initial respondents every year, beginning at
18 months. Birth records were also linked to each child
included in this survey. Birth-record data included
length, weight, gestational age, singleton, twin or other
multiple births, sex, parity, and parental age.
Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
We excluded children without information on birth
weight (n = 14) and then gestational week (n = 24).
SGA status of the newborns was determined using pub-
lished Japanese standards for birth weight according to
pregnancy duration [11,12]. The standards do not
include information for newborns after 42 weeks of ges-
tational age; therefore we also excluded children born
after 42 weeks (n = 414), leaving 46,563 children for
analysis. We targeted children whose data were collected
in the third and sixth surveys (at 2.5 and 5.5 years,
respectively). A total of 4,362 children were lost to
follow-up at the third survey, leaving 42,201 children,
and 8,877 children were lost to follow-up at the sixth
survey, leaving 37,686 children in the analysis.
2.2. SGA status
According to the International Classification of
Diseases-10, SGA is defined as both birth weight and
birth height below the 10th percentile for gestational
age. However, SGA has been defined simply by birth
weight in many previous studies [6], because of inaccura-
cies in birth height measurements. We therefore
classified SGA babies as those whose birth weight
was < 10% of the population according to pregnancy
duration, based on published Japanese standards, estab-
lished by the Committee for Newborns in Japanese
Pediatric Society, which provide specific birth weight
percentiles [11,12] for each gestational week and day.
Birth weight and gestational age data were collected
from birth records.
2.3. Behavioral development outcomes
Behavioral development outcomes were assessed by
survey questions about age-appropriate behavior
[9,10]. The questions at 2.5 years old were: (1) Can your
child walk?; (2) Can your child run?; (3) Can your child
climb stairs?; (4) Can your child say words with mean-
ing?; (5) Can your child compose two-phrase sentences?;
(6) Can your child say his or her own name?; and (7)
Can your child use a spoon to eat? The following ques-
tions were not included, because the behaviors were
potentially heavily dependent upon parenting practices:
(1) Can your child brush his/her teeth by him/herself?;
(2) Does your child wear a diaper during the day?; and
(3) Can your child put on clothes by him/herself? The
MHLW obtained the behavioral questions from the
Maternal and Child Health Handbook, which is a
record of health and child development given to every
pregnant mother in Japan, and in which all information
from postnatal visits is recorded until the child is 6 years
old. The dissemination and use of the Handbook is
mandated under Japanese law and has been imple-
mented for several decades.
 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx
The questions at 5.5 years old were: (1) Can your
child listen without fidgeting?; (2) Can your child focus
on one task?; (3) Does your child remain patient?; (4)
Can your child express emotions appropriately?; (5)
Can your child act with others in a group setting?; and
(6) Can your child keep promises? According to the
MHLW, these questions were developed to capture
early signs of behavioral and developmental problems.
The Ministry has aimed to track the prevalence of
behavioral and developmental problems over the past
decade, but we were unable to confirm if these questions
have been externally validated.
2.4. Statistical analyses
We compared baseline characteristics according to
SGA status among eligible children. We then analyzed
the relationships between SGA status and behavioral
development at 2.5 and 5.5 years old using logistic
regression to estimate odds ratios (ORs) and 95% confi-
dence intervals (95% CI) for each outcome. The study
participants were stratified into full-term births P37
gestational weeks) and preterm births (<37 gestational
weeks). Statistical interactions were examined to evalu-
ate whether ORs for the associations between SGA sta-
tus and behavioral developments differed between
preterm and full-term births and P values for statistical
interactions <0.05 (two-sided) were considered
significant.
We controlled for potential confounding child- and
parent-related factors based on previous studies [9,10].
Child factors included sex (dichotomous), singleton or
not (dichotomous), gestational week (continuous), and
parity (0 or >1, dichotomous). Parental factors included
maternal age at delivery (continuous), maternal smoking
habits (dichotomous), maternal educational attainment
(categorical), and paternal educational attainment (cate-
gorical). The child’s sex, singleton or not, gestational
week, parity, and maternal age at delivery were listed
in the birth record. Maternal smoking status was ascer-
tained at the first survey. Maternal and paternal educa-
tional attainments were obtained from the second survey
(age 18 months) and compressed into three categories:
6high school; junior college (2 years) or vocational
school; and university (4 years) or higher. We excluded
missing and incomplete cases.
We estimated the public impacts of SGA births
among full-term and preterm infants by calculating the
population-attributable fraction (PAF) for each devel-
opmental outcome. We combined SGA status with
full-term/preterm status into new birth status categories:
full-term non-SGA; full-term SGA; preterm non-SGA;
and preterm SGA. The associations between birth status
and behavioral developments were then assessed using
full-term non-SGA as the reference category. PAFs
show the proportion by which the incidence rate of the
Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
3
outcome in the entire population would be reduced if
the exposure (i.e., full-term SGA, preterm non-SGA,
and preterm SGA in the present study) was eliminated
(13). We calculated PAFs using the following formula:
PAFð%Þ ¼ PeðOR  1Þ=ð1 þ PeðOR  1ÞÞ  100
where Pe is the proportion exposed in the entire popula-
tion [13]. ORs were estimated after adjusting for the
same covariates mentioned above, except gestational
age.
In the sensitivity analyses, we excluded children who
had visited clinics or hospitals for congenital diseases
between 7 and 18 months of age to remove possible
selection bias, as children with disabilities might have
been born with SGA. Again, the impacts of SGA births
on neurodevelopmental outcomes were evaluated sepa-
rately in full-term and preterm births. We had no infor-
mation on visits made before 6 months of age.
All confidence intervals (CIs) were calculated at the
95% level. All analyses were performed using Stata
statistical software (Stata SE version 13, Stata Corp.,
Texas, USA). This study was approved by the Okayama
University Graduate School of Medicine, Dentistry, and
Pharmaceutical Sciences Institutional Review Board
(No. 881).
3. Results
Table 1 shows the baseline characteristics of the eligi-
ble children and their parents according to SGA status.
SGA children were more likely to be born as multiple
births and preterm births. In addition, non-SGA chil-
dren were more likely to have non-smoking mothers
and parents with higher academic attainments. We also
show the baseline characteristics of the eligible children
separated by term and preterm birth (Online Table 1);
preterm births tended to be boys, be born as multiple
births, and had parity more than one. With regard to
lost to follow-up, children who were lost to follow up
were more likely to have young mothers, mothers who
smoked, and parents with lower educational level in
comparison with eligible children (Online Table 2).
Table 2 shows the associations between SGA status
and behavioral developmental outcomes at 2.5 years in
full-term and preterm children. SGA children were more
likely to demonstrate developmental delays in all the
behaviors examined, although estimates for preterm
children did not reach statistical significance, probably
because of the small sample size. For example, full-
term SGA children were more likely to be unable to
climb stairs and compose a two-phrase sentence (ORs
1.3 (95% CI: 1.0, 1.7) and 1.5 (95% CI: 1.2, 1.8), respec-
tively) compared with non-SGA children. The P values
for interaction were not significant.
We observed similar relationships between SGA
status and being unable to perform age-appropriate
4 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx

Table 1
Demographic characteristics of eligible children (n = 46,563).
Non-SGA SGA
(N = 42,825) (N = 3,738)
Characteristics of children
Sex, n (%)a
Boys 22,231 (51.9) 1958 (52.4)
Girls 20,594 (48.1) 1780 (47.6)
Singleton birth, n (%)a 42,155 (98.4) 3432 (91.8)
Multiple birth, n (%)a 670 (1.6) 306 (8.2)
Mean gestational age, weeks (SD)a 38.9 (1.6) 38.7 (2.0)
Full-term birth, n (%)a 40780 (95.2) 3403 (91)
Preterm birth, n (%)a 2045 (4.8) 335 (9.0)
Parity, n (%)a
0 20,804 (48.6) 1840 (49.2)
P1 22,021 (51.4) 1898 (50.8)
Parental characteristics
Mean maternal age at delivery, years (SD)a 30 (4.5) 30 (4.5)
Maternal smoking status, n (%)b
Non-smoker 35,229 (82.9) 2900 (78.1)
Smoker 7277 (17.1) 812 (21.9)
Maternal educational attainment, n (%)c
University or higher 5511 (13.8) 453 (13.2)
Junior college 16483 (41.4) 1393 (40.5)
Less than or equal to high school 17,833 (44.8) 1598 (46.4)
Paternal educational attainment, n (%)c
University or higher 14311 (36.3) 1165 (34.4)
Junior college 6194 (15.7) 504 (14.9)
Less than or equal to high school 18,895 (48.0) 1718 (50.7)
There were 275 cases missing on maternal smoking, 3292 cases missing on maternal educational attainment, and 3776 cases missing on paternal
educational attainment.
a
Obtained from the birth record.
b
Obtained from the first survey (at the age of 6 months).
c
Obtained from the second survey (at the age of 18 months).
Table 2
Adjusteda ORs for associations between SGA status and behavioral developments at age 2.5 years.
Full-term births Preterm births p-value for
Non-SGA SGA Non-SGA SGA interaction

Age of 2.5 years

Unable to walk
Ncase/N 66/37,009 18/3087 41/1810 13/295
OR (95% CI) 1 (ref) 3.0 (1.7–5.3) 1 (ref) 1.8 (0.9–3.5) 0.17
Unable to run
Ncase/N 157/37007 29/3086 52/1809 17/294
OR (95% CI) 1 (ref) 2.1 (1.4–3.3) 1 (ref) 1.7 (0.9–3.2) 0.48
Unable to climb stairs
Ncase/N 656/36979 74/3084 86/1807 22/294
OR (95% CI) 1 (ref) 1.3 (1.0–1.7) 1 (ref) 1.3 (0.8–2.3) 0.92
Unable to say words with meaning
Ncase/N 197/36996 31/3086 36/1809 10/295
OR (95% CI) 1 (ref) 1.8 (1.2–2.7) 1 (ref) 1.4 (0.6–2.9) 0.51
Unable to compose a two-phrase sentence
Ncase/N 1366/36978 164/3083 156/1808 37/294
OR (95% CI) 1 (ref) 1.5 (1.2–1.8) 1 (ref) 1.2 (0.8–1.8) 0.50
Unable to say his or her own name
Ncase/N 4004/36944 427/3076 354/1802 71/294
OR (95% CI) 1 (ref) 1.4 (1.2–1.5) 1 (ref) 1.2 (0.8–1.6) 0.44
Unable to use a spoon to eat
Ncase/N 631/36991 75/3087 69/1809 22/294
OR (95% CI) 1 (ref) 1.5 (1.1–1.9) 1 (ref) 1.6 (0.9–2.7) 0.71
CI, confidence interval; OR, odds ratio; SGA, small for gestational age; ref, reference.
a
Adjusted for child factors (sex, singleton or not, gestational age, and parity) as well as parental factors (maternal age at delivery, maternal
smoking status, maternal educational attainment, and paternal educational attainment).

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx 5

Table 3
Adjusteda ORs for associations between SGA status and behavioral developments at age 5.5 years.
Full-term births Preterm births p-value for
interaction
Non-SGA SGA Non-SGA SGA
Age of 5.5 years
Unable to listen without fidgeting
Ncase/N 5772/33071 546/2716 354/1583 66/251
OR (95% CI) 1 (ref) 1.2 (1.1–1.3) 1 (ref) 1.2 (0.9–1.6) 0.94
Unable to focus on one task
Ncase/N 4252/33123 373/2724 235/1587 48/252
OR (95% CI) 1 (ref) 1.0 (0.9–1.2) 1 (ref) 1.3 (0.9–1.9) 0.25
Unable to remain patient
Ncase/N 8131/32949 704/2717 425/1576 83/249
OR (95% CI) 1 (ref) 1.1 (1.0–1.2) 1 (ref) 1.4 (1.0–1.9) 0.09
Unable to express emotions
Ncase/N 7390/32916 672/2715 408/1581 62/249
OR (95% CI) 1 (ref) 1.1 (1.0–1.2) 1 (ref) 0.9 (0.6–1.2) 0.14
Unable to act in a group
Ncase/N 2069/33069 192/2725 131/1582 25/252
OR (95% CI) 1 (ref) 1.1 (1.0–1.3) 1 (ref) 1.0 (0.6–1.7) 0.73
Unable to keep promises
Ncase/N 6348/32773 543/2693 341/1571 51/244
OR (95% CI) 1 (ref) 1.0 (0.9–1.1) 1 (ref) 0.9 (0.6–1.3) 0.46
CI, confidence interval; OR, odds ratio; SGA, small for gestational age; ref, reference.
a
Adjusted for child factors (sex, singleton or not, gestational age, and parity) as well as parental factors (maternal age at delivery, maternal
smoking status, maternal educational attainment, and paternal educational attainment).

behaviors at 5.5 years (Table 3), though the effect esti-
mates were attenuated. For example, full-term SGA
children were more likely to be unable to listen without
fidgeting, remain patient, express emotions, and act in a
group compared with non-SGA children (ORs 1.2 (95%
CI: 1.1, 1.3), 1.1 (95% CI: 1.0, 1.2), 1.1 (95% CI: 1.0,
1.2), and 1.1 (95% CI: 1.0, 1.3), respectively). Preterm
SGA children were also significantly more likely to be
unable to remain patient (OR 1.4, 95% CI: 1.0, 1.9) com-
pared with non-SGA children. The P values for interac-
tion were not significant.
The adjusted ORs and PAFs (and 95% CI) for asso-
ciations between birth status category (non-SGA; full-
term SGA; preterm non-SGA; and preterm SGA) and
behavioral developments at 2.5 years of age are shown
in Table 4. Neurodevelopmental outcomes were poorest
among preterm SGA infants, though the PAFs among
full-term SGA infants were similar to those in preterm
SGA infants. For example, preterm non-SGA infants
showed the highest PAF value for being unable to walk
(36.6%, 95% CI: 26.5, 47), followed by preterm SGA
infants (15.2%, 95% CI: 8.1, 26.4), and full-term SGA
infants (13.7%, 95% CI: 5.6, 24.9). Similar findings were
observed at 5.5 years of age (Table 5), though the ORs
were attenuated and the PAFs were either very small
or virtually zero across outcomes at this age.
In the sensitivity analyses, 931 and 840 children with
congenital diseases were excluded at 2.5 and 5.5 years of
age, respectively, though the main findings were not sub-
stantially affected (Online Tables 3 and 4).
4. Discussion
The present study examined the impact of SGA birth
on behavioral development in a large Japanese popula-
tion, with a focus on full-term births. Motor and lan-
guage development were assessed by questionnaires at
2.5 years of age, and behavioral problems relevant to
social development or attention were assessed at
5.5 years of age. SGA status had negative impacts on
neurodevelopmental outcomes in full-term children at
both ages, consistent with previous studies [6]. The pub-
lic health impacts were similar for full-term and preterm
SGA children at 2.5 years.
The survey questions at 2.5 years could be divided
into three categories dealing with gross motor develop-
ment, fine motor development, and language develop-
ment. The results indicated that SGA status had
adverse effects on gross motor development. Stoknes
et al. reported an increased risk of cerebral palsy in
SGA children (OR, 2.6), based on a large Norwegian
population-based survey of more than 400,000 children
born at full-term [8]. Similar results were found even
after excluding children with congenital anomalies or
birth asphyxia, and they therefore suggested that fetal
risk factors might lead to developmental delay in SGA
children. In the present study, most children who were
unable to walk alone or run at 2.5 years might be diag-
nosed with cerebral palsy, and the ORs for these abilities
(3.7 and 2.2, respectively) were comparable with the
results of the Stoknes et al. study [8].

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
6 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx

Table 4
Adjusteda ORs and PAFs (with 95% CI) for associations between combined SGA and preterm status and behavioral developments at age 2.5 years.
Ncase/N Adjusted OR Adjusted PAF (%)
Age of 2.5 years
Unable to walk
Full-term & Non-SGA 66/37009 1 (ref)
Full-term & SGA 18/3087 3.1 (1.8–5.3) 13.7 (5.6–24.9)
Preterm & Non-SGA 41/1810 13.2 (8.7–20) 36.3 (26.5–47.0)
Preterm & SGA 13/295 23.7 (12.1–46.3) 15.2 (8.1–26.4)
Unable to run
Full-term & Non-SGA 157/37007 1 (ref)
Full-term & SGA 29/3086 2.1 (1.4–3.3) 8.0 (2.9–14.8)
Preterm & Non-SGA 52/1809 7.6 (5.4–10.6) 23.5 (17.1–30.9)
Preterm & SGA 17/294 13.5 (7.5–24.0) 8.9 (4.9–15.4)
Unable to climb stairs
Full-term & Non-SGA 656/36979 1 (ref)
Full-term & SGA 74/3084 1.3 (1.0–1.7) 2.1 (0.1–4.8)
Preterm & Non-SGA 86/1807 2.9 (2.3–3.7) 8.1 (5.6–11.2)
Preterm & SGA 22/294 4.2 (2.6–6.8) 2.4 (1.2–4.4)
Unable to say words with meaning
Full-term & Non-SGA 197/36996 1 (ref)
Full-term & SGA 31/3086 1.8 (1.2–2.6) 5.6 (1.4–11.2)
Preterm & Non-SGA 36/1809 3.5 (2.4–5.2) 10.6 (6.2–16.2)
Preterm & SGA 10/295 5.0 (2.4–10.2) 3.0 (1.1–6.8)
Unable to compose a two-phrase sentence
Full-term & Non-SGA 1366/36978 1 (ref)
Full-term & SGA 164/3083 1.5 (1.2–1.7) 3.4 (1.7–5.4)
Preterm & Non-SGA 156/1808 2.2 (1.8–2.7) 5.4 (3.8–7.3)
Preterm & SGA 37/294 2.9 (2.0–4.2) 1.5 (0.8–2.5)
Unable to say his or her own name
Full-term & Non-SGA 4004/36944 1 (ref)
Full-term & SGA 427/3076 1.3 (1.2–1.5) 2.6 (1.5–3.8)
Preterm & Non-SGA 354/1802 1.8 (1.6–2.1) 3.8 (2.8–4.9)
Preterm & SGA 71/294 2.3 (1.7–3.0) 1.0 (0.5–1.6)
Unable to use a spoon to eat
Full-term & Non-SGA 631/36991 1 (ref)
Full-term & SGA 75/3087 1.4 (1.1–1.8) 3.3 (0.9–6.1)
Preterm & Non-SGA 69/1809 2.2 (1.7–2.9) 5.5 (3.2–8.3)
Preterm & SGA 22/294 3.8 (2.3–6.2) 2.1 (1.0–3.9)
CI, confidence interval; OR, odds ratio; PAF, population-attributable fraction; SGA, small for gestational age; ref, reference.
a
Adjusted for child factors (sex, singleton or not, and parity) as well as parental factors (maternal age at delivery, maternal smoking status,
maternal educational attainment, and paternal educational attainment).

The ability to use a spoon to eat at 2.5 years corre-
sponds to fine motor development [14], and this ability
was delayed in SGA children in this study. Roth et al.
investigated differences in the developmental quotient
between full-term SGA and non-SGA infants at 1 year,
and found no differences in the subscale scores of fine
motor development [15], though the sample size of their
study was small. In contrast, Savchev et al. investigated
the difference in development between 112 full-term
SGA and 111 full-term AGA children at 2 years, using
the Bayley scales of infant development III
(Bayley-III), and reported that SGA children had signif-
icantly lower motor scores than AGA children [16].
Although fine motor development was evaluated by
the Bayley-III scale, there were no data specific to fine
motor development in the Savchev et al. study.
Questions corresponding to language development in
the present study included the ability to say words with
meaning, compose a two-phrase sentence, and say one’s
name at 2.5 years old. Most children can say words with
meaning by 1.5 years and compose a two-phrase
sentence by 2.5 years [17]. However, the results of the
current study indicated that SGA status had adverse
effects on these language developments. The previous
study by Savchev et al. also found that full-term SGA
children aged 2 years were at significantly increased risk
of having poor language development according to the
Bayley-III score (OR, 2.63) after adjustment of covari-
ates [16].
Regarding behavioral development at 5.5 years, SGA
status had some degree of negative impacts on the abil-
ity to listen without fidgeting, remain patient, express
emotions, and act in a group. Specifically, the ability
to listen without fidgeting and remain patient are
thought to be associated with the function of attention,
and impulse control. Yang et al. evaluated the behavior

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
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 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx 7

Table 5
Adjusteda ORs and PAFs (with 95% CI) for associations between combined SGA and preterm status and behavioral developments at age 5.5 years.
Ncase/N Adjusted OR Adjusted PAF (%)
Age of 5.5 years
Unable to listen without fidgeting
Full-term & Non-SGA 5772/33071 1 (ref)
Full-term & SGA 546/2716 1.2 (1.1–1.3) 1.3 (0.5–2.3)
Preterm & Non-SGA 354/1583 1.3 (1.1–1.5) 1.3 (0.6–2.1)
Preterm & SGA 66/251 1.5 (1.1–2.1) 0.4 (0.1–0.8)
Unable to Focus on One Task
Full-term & Non-SGA 4252/33123 1 (ref)
Full-term & SGA 373/2724 1.0 (0.9–1.2) 0.3 (0.6–1.3)
Preterm & Non-SGA 235/1587 1.1 (0.9–1.3) 0.4 (0.3–1.2)
Preterm & SGA 48/252 1.4 (1.0–2.0) 0.3 (0–0.8)
Unable to Remain Patient
Full-term & Non-SGA 8131/32949 1 (ref)
Full-term & SGA 704/2717 1.1 (1.0–1.2) 0.5 (0.2–1.2)
Preterm & Non-SGA 425/1576 1.1 (1.0–1.2) 0.4 (0.2–1.0)
Preterm & SGA 83/249 1.5 (1.1–2.0) 0.4 (0.1–0.8)
Unable to Express Emotions
Full-term & Non-SGA 7390/32916 1 (ref)
Full-term & SGA 672/2715 1.1 (1.0–1.2) 0.8 (0.1–1.6)
Preterm & Non-SGA 408/1581 1.1 (1.0–1.3) 0.7 (0.1–1.3)
Preterm & SGA 62/249 1.0 (0.7–1.3) 0 (0.2–0.3)
Unable to Act in a Group
Full-term & Non-SGA 2069/33069 1 (ref)
Full-term & SGA 192/2725 1.1 (1.0–1.3) 0.9 (0.3–2.3)
Preterm & Non-SGA 131/1582 1.2 (1.0–1.5) 0.9 (0.1–2.0)
Preterm & SGA 25/252 1.2 (0.8–1.9) 0.2 (0.2–0.7)
Unable to Keep Promises
Full-term & Non-SGA 6348/32773 1 (ref)
Full-term & SGA 543/2693 1.0 (0.9–1.1) 0.1 (0.7–0.9)
Preterm & Non-SGA 341/1571 1.1 (1.0–1.3) 0.6 (0–1.4)
Preterm & SGA 51/244 1.0 (0.7–1.4) 0 (0.2–0.3)
CI, confidence interval; OR, odds ratio; PAF, population-attributable fraction; SGA, small for gestational age; ref, reference.
a
Adjusted for child factors (sex, singleton or not, and parity) as well as parental factors (maternal age at delivery, maternal smoking status,
maternal educational attainment, and paternal educational attainment).

of 13,889 full-term children aged 6.5 years using a
Strength and Difficulties Questionnaire, and found that
lower birth weight had a negative impact on social
development and attention [18]. Although other studies
have reported no significant effect of SGA status on the
results of behavioral evaluation tests [19,20], the num-
bers of subjects in these studies were much lower than
in the study by Yang et al. Many hyperactive children
are thought to have attention-deficit/hyperactivity disor-
der (ADHD) in practice, though hyperactivity is also a
component symptom of mental retardation, autism
spectrum disorder, and other central nervous system
pathologies [21,22]. Regarding the relationship between
SGA and ADHD, Heinnonen et al. reported that SGA
status was significantly associated with more severe
ADHD symptoms in 828 children aged 56 months,
though lower gestational age was not associated with
ADHD symptoms [23]. Although we did not investigate
the relationship between ADHD and SGA in the present
study, SGA could be a risk factor for attention problems
or hyperactivity in children with full-term births.
A major strength of the present study was the large,
nationally representative sample analyzed, with about
5% of all children born in Japan in 2001 being included
in the survey. We were therefore able to analyze data for
more SGA and non-SGA infants compared with previ-
ous studies. In addition, the validity of our findings
was supported by a very high baseline response rate.
We also calculated PAFs for each outcome. Although
the PAFs were small at 5.5 years, the PAFs at 2.5 years
were non-negligible, and were greatest for preterm non-
SGA infants, followed by full-term SGA and preterm
SGA infants. For example, about 36%, 14%, and 15%
of cases of being unable to walk could be attributed to
preterm non-SGA, full-term SGA, and preterm SGA
infants, respectively.
This study had several limitations. The conclusions
were limited by the uncertainty regarding the external
validation of the question items used to assess the neu-
robehavioral outcomes. We were unable to use validated
tests such as the Strength and Difficulties Questionnaire,
Personal Inventory for Children, Yale Children’s

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
8 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx
Inventory or child behavior during psychometric testing,
which were used in previous studies. Moreover, the sub-
jective nature of these questions meant that we could not
exclude the possibility of misclassification of neurobe-
havioral outcomes. However, any misclassification
would have similar effects on the SGA and non-SGA
groups, probably moving ORs toward the null. Possible
selection bias caused by children with congenital dis-
eases being born with SGA was unlikely because the
findings were robust in the sensitivity analyses, which
excluded children with congenital diseases. We also have
children who were lost to follow up (Online Table 2),
which may have underestimated negative impacts of
SGA on neurodevelopmental outcomes because loss
was more common among higher-risk groups such as
children with mothers who were smokers or parents with
lower educational level. Finally, there was a possibility
of residual confounding associated with the family envi-
ronment, though we adjusted for several such factors in
the analyses, and the findings were consistent with a
previous study that evaluated birth weight and IQ in
full-term sibships [7].
5. Conclusions
SGA was a risk factor for developmental delay, even
among children with full-term births. The public health
impacts of these deficits were non-negligible, and were
similar in full-term and preterm SGA infants. Appropri-
ate long-term developmental follow-up and support may
therefore be needed for full-term SGA infants.
Conflict of interest statement
The authors have no conflicts of interest to disclose.
Acknowledgements
We appreciate the valuable comments provided by
Dr. Yoshitada Yamauchi, Dr. Kazue Nakamura, Dr.
Hirosuke Morita, Dr. Yuko Yumoto, Dr. Shigehiro
Mori and Dr. Kei Tamai. We also appreciate the valu-
able support of Saori Irie. The authors have no conflicts
of interest to disclose. This work was supported in part
by Health and Labour Sciences Research Grants on
Health Research on Children, Youth and Families
(H24-Jisedai-Ippan-004).
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at http://dx.doi.org/10.
1016/j.braindev.2015.12.013.
Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013
References
[1] Longo S, Bollani L, Decembrino L, Di Comite A, Angelini M,
Stronati M. Short-term and long-term sequelae in intrauterine
growth retardation (IUGR). J Matern Fetal Neonatal Med
2013;26:222–5.
[2] Lundgren EM, Tuvemo T. Effects of being born small for
gestational age on long-term intellectual performance. Best Pract
Res Clin Endocrinol Metab 2008;22:477–88.
[3] Guellec I, Lapillonne A, Renolleau S, Charlaluk M-L, Roze J-C,
Marret S, et al. Neurologic outcomes at school age in very
preterm infants born with severe or mild growth restriction.
Pediatrics 2011;127:e883–91.
[4] Morsing E, Asard M, Ley D, Stjernqvist K, Marsál K. Cognitive
function after intrauterine growth restriction and very preterm
birth. Pediatrics 2011;127:e874–82.
[5] De Jesus LC, Pappas A, Shankaran S, Li L, Das A, Bell EF, et al.
Outcomes of small for gestational age infants born at <27 weeks’
gestation. J Pediatr 2013;168:55–60 e1–3.
[6] Arcangeli T, Thilaganathan B, Hooper R, Khan KS, Bhide A.
Neurodevelopmental delay in small babies at term: a systematic
review. Ultrasound Obstet Gynecol 2012;40:267–75.
[7] Matte TD, Bresnahan M, Begg MD, Susser E. Influence of
variation in birth weight within normal range and within sibships
on IQ at age 7 years: cohort study. BMJ 2001;323:310–4.
[8] Stoknes M, Andersen GL, Dahlseng MO, Skranes J, Salvesen
KÅ, Irgens LM, et al. Cerebral palsy and neonatal death in term
singletons born small for gestational age. Pediatrics 2012;130:
e1629–35.
[9] Yorifuji T, Kubo T, Yamakawa M, Kato T, Inoue S, Tokinobu
A, et al. Breastfeeding and behavioral development: A nationwide
longitudinal survey in Japan. J Pediatr 2014;164:1019–25.
[10] Kato T, Yorifuji T, Inoue S, Yamakawa M, Doi H, Kawachi I.
Associations of preterm births with child health and development:
Japanese population-based study. J Pediatr 2013;163(1578–84):e4.
[11] Itabashi K, Fujimura M, Kusuda S, Tamura M, Hayashi T,
Takahashi T, et al. Adoption of new reference value for birth size
according to gestational age (in Japanese). J Jpn Pediatr Soc
2010;114:1271–93.
[12] Committee on newborn, Japan Pediatric Society. Revision of new
reference value for birth size according to gestational age (in
Japanese). J Jpn Pediatr Soc 2010; 114:1771–806.
[13] Porta M. A dictionary of epidemiology. 5th ed. New
York: Oxford University Press; 2008.
[14] Carruth BR, Skinner JD. Feeding behaviors and other motor
development in healthy children (2–24 months). J Am Coll Nutr
2002;21:88–96.
[15] Roth S, Chang TC, Robson S, Spencer JA, Wyatt JS, Stewart AL.
The neurodevelopmental outcome of term infants with different
intrauterine growth characteristics. Early Hum Dev
1999;55:39–50.
[16] Savchev S, Sanz-Cortes M, Crouz-Martines R, Arranz A, Botet
F, Gratacos E, et al. Neurodevelopmental outcome of full-term
small-for-gestational-age infants with normal placental function.
Ultrasound Obstet Gynecol 2013;42:201–6.
[17] The Japanese society of child health [Japanese Edition Denver II]
(in Japanese). Tokyo: Nihon shouniijisyuppansya; 2008.
[18] Yang S, Platt RW, Kramer MS. Variation in child cognitive
ability by week of gestation among healthy term births. Am J
Epidemiol 2010;171:399–406.
[19] Sommerfelt K, Andersson HW, Sonnander K, Ahlsten G,
Ellertsen B, Markestad T, et al. Behavior in term, small for
gestational age preschoolers. Early Hum Dev 2001;65:107–21.
[20] Cornforth CM, Thompson JMD, Robinson E, Waldie KE, Pryor
JE, Clark P, et al. Children born small for gestational age are not
 A. Takeuchi et al. / Brain & Development xxx (2016) xxx–xxx 9

at special risk for preschool emotion and behaviour problems.
Early Hum Dev 2012;88:479–85.
[21] Ogino T, Hattori J, Abiru K, Nakano K, Oka E, Ohtsuka Y.
Symptoms related to ADHD observed in patients with pervasive
developmental disorder. Brain Dev 2005;27:345–8.
[22] Cappa M, Bizzarri C, Vollono C, Petroni A, Banni S.
Adrenoleukodystrophy. Endocr Dev 2011;20:149–60.
[23] Heinonen K, Räikkönen K, Pesonen A-K, Andersson S, Kajantie
E, Eriksson JG. Behavioural symptoms of attention deficit/
hyperactivity disorder in preterm and term children born small
and appropriate for gestational age: a longitudinal study. BMC
Pediatr 2010;10:91.

Please cite this article in press as: Takeuchi A et al. Neurodevelopment in full-term small for gestational age infants: A nationwide Japanese
population-based study. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2015.12.013