Early Human Development 87 (2011) 5559

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Early Human Development

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev

Neurodevelopmental outcomes of very low birth weight and extremely low birth
weight infants at 18 months of corrected age associated with prenatal risk factors
Shunsuke Tamaru a, Akihiko Kikuchi a,, Kimiyo Takagi a, Masao Wakamatsu a, Kyoko Ono a,
Tsuguhiro Horikoshi a, Hideki Kihara b, Tomohiko Nakamura c
a
b
c

Department of Obstetrics, Center for Perinatal Medicine, Nagano Children's Hospital, Nagano, Japan
Department of Rehabilitation, Nagano Children's Hospital, Nagano, Japan
Deparment of Neonatology, Center for Perinatal Medicine, Nagano Children's Hospital, Nagano, Japan

a r t i c l e

i n f o

Article history:
Received 20 August 2010
Received in revised form 13 October 2010
Accepted 26 October 2010
Keywords:
Extremely low birth weight infant
Kyoto Scale of Psychological Development
Neurodevelopmental outcome
Prenatal risk factor
Very low birth weight infant

a b s t r a c t
Background: Very premature infants occasionally have neurodevelopmental disabilities. However, there have
been quite limited data on prenatal risk factors associated with their neurodevelopmental outcomes.
Aim: To clarify the relationship between prenatal risk factors and neurodevelopmental outcomes of very
premature infants.
Study design: The study design is a retrospective review.
Subjects: One hundred seventy Japanese women with a singleton pregnancy and their infants whose birth
weight being less than 1500 g were included. We classied those infants into 118 appropriate for gestational
age (AGA) and 52 small for gestational age (SGA) infants.
Outcome measures: Infants' neurodevelopmental outcomes at 18 months of corrected age were evaluated by
the Kyoto Scale of Psychological Development 2001 (KSPD). We analyzed and compared the infants'
outcomes and prenatal risk factors between two groups.
Results: Mortality and rate of infants unevaluable by KSPD because of severe impairment were not
signicantly different between those groups. However, the developmental quotient score of the cognitive
adaptive area in SGA infants born between 25 and 31 weeks of gestation was signicantly lower than that in
AGA infants randomly selected as gestation-matched controls. More advanced gestational age and heavier
birth weight protected against adverse neurodevelopmental outcomes in both groups. Moreover, male infants
were related to the excess risk of adverse neurodevelopmental outcomes in the SGA group.
Conclusion: In view of the neurodevelopment of the infants, it seems that the most efcient obstetric strategy
for improving prognosis of premature infants should be targeted to prolong the pregnancy period as long as
the reassuring fetal status and maternal stable health condition are being conrmed.
2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
In the last decade, improvements in perinatal care have resulted in
increased survival rates of very preterm and/or very low birth weight
(VLBW) infants. However, new social and health problems related to
their high risk of brain damage and neurological sequelae have arisen
[1]. Long-term follow-up studies have also emphasized the occurrence
of signicant neuropsychological and behavioral decits at school age of
those who survive without major neurological decits [2]. Moreover,
some studies point out that the problems such as academic under
achievement, behavioral problems, and decits in higher-order neuro-

Corresponding author. Department of Obstetrics, Center for Perinatal Medicine,

Nagano Children's Hospital, 3100 Toyoshina, Azumino, Nagano 399-8288, Japan. Tel.: +81
263 73 6700; fax: +81 263 73 5432.
E-mail address: dr-kiku@yj8.so-net.ne.jp (A. Kikuchi).
0378-3782/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2010.10.004

cognitive functions of the majority of nondisabled survivors persist

throughout childhood and young adulthood [35]. Preventing preterm
delivery, therefore, has been one of the impending problems in
obstetrics practice.
Intrauterine infection, dened as chorioamnionitis (CAM) and
funisitis, has been recently identied as a major cause of preterm
delivery and the inammatory response syndrome of the infants has
been proven to be mediated by cytokines [6,7]. A recent report has
also revealed that CAM is a risk factor for both cerebral palsy (CP) and
cystic periventricular leukomalacia of the infants [8]. However, CAM
and funisitis are most often clinically silent and the histological
examination of the placenta after delivery is the gold standard for
their diagnosis [9]. It is also recognized that the relation between
infection and preterm delivery is not consistent throughout gestation.
That is, infection is present in most cases with early preterm deliveries
before 30 weeks of gestation as shown by histologic examinations,
and is rare in late preterm deliveries after 34 weeks [10]. It is therefore

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S. Tamaru et al. / Early Human Development 87 (2011) 5559

mandatory to establish treatment strategies for intrauterine infection

in early gestational age.
On the other hand, it is revealed that antenatal diagnosis of fetal
growth restriction (FGR) is associated with an increased risk of CP [11],
and absent or reversed end-diastolic ow velocity (AREDFV) in the
umbilical artery (UA) is an independent predictor of either neonatal
decease or CP in preterm FGR infants [12]. FGR is a multifaceted
condition which results in the birth of a small for gestational age (SGA)
infant. It is also pointed out that being born SGA is associated with lower
intelligence, poor academic performance, low social competence and
behavioral problems [1315], and some studies have indicated that
children born SGA have long-term global cognitive impairment [1618].
Although underlying mechanisms for FGR are heterogeneous, the most
common cause is utero-placental dysfunction [19]. Fetal health during
FGR may be determined from changes in regional fetal growth, behavior,
cardiotocography and from studies of umbilical and regional fetal ow
velocities using Doppler ultrasound. Because these changes may be
related to the severity of the perinatal morbidity, the policy of delivery
may be essential for short and long-term outcomes. In other words, if
infants are delivered after fetal conditions have deteriorated with poor
heart rate variability, they may be complicated by general issues relating
to fetal hypoxia superimposed on prematurity that may worsen both of
short and long-term outcomes. In contrast, early preterm delivery
before fetal health deteriorates may increase the risk of complications
due to prematurity [20]. In such a dilemma and under quite limited
knowledge of long-term prognosis estimation, we obstetricians have
been deciding when to deliver FGR infants with no established idea of
what is the best prenatal management plan for short and long-term
consequences of those premature infants.
Therefore, the purpose of the present study should be targeted to
clarify the relationship between prenatal risk factors and neurodevelopmental outcomes of VLBW and extremely low birth weight (ELBW)
infants.
2. Materials and methods
2.1. Participants
This retrospective study investigated cases of Japanese women
cared for through their pregnancy and delivery in our hospital during
the period between October 2000 and December 2007. One hundred
seventy women with a singleton pregnancy and their infants whose
birth weight being less than 1500 g were included in this study. This
study was approved by the Ethics Committee of Nagano Children's
Hospital. We classied those infants into two groups, that is, 118
appropriate for gestational age (AGA) and 52 SGA infants. AGA and
SGA were dened by the birth size standards data of Japanese [21], as
birth weight between the 10th and the 90th percentile and below the
10th percentile for gestational age, respectively.
2.2. Exclusion criteria
The following cases were excluded from both groups: chromosomal anomalies, major malformations, stillbirth and abruptio
placentae. In addition, cases complicated by pregnancy-induced
hypertension (PIH) were excluded from the AGA group. PIH was
dened as hypertension (systolic blood pressure 140 mm Hg
systolic and/or diastolic blood pressure 90 mm Hg) after 20 weeks
of gestation in the absence of a history of hypertension. As there were
a small number of cases with PIH in AGA group in contrast with in SGA
group and most of such cases in the former group delivered
premature infants articially based on maternal medical indications,
PIH patients were excluded from AGA group. The gestational age was
estimated by the date of the last menstrual period and conrmed by
fetal growth measurement with ultrasound during the rst trimester.

2.3. Therapy for cases with threatened premature delivery

In cases with threatened premature delivery, the patients
underwent tocolytic therapy with i.v. infusion of the -2 stimulant
ritodrine hydrochloride and/or magnesium sulfate, and an urinastatin
vaginal suppository (5000 U) was used once or twice a day until
34 weeks of gestation. Antibiotics were administered until delivery in
the presence of premature rupture of membranes (PROM). Cervical
cerclage was not performed after 22 weeks of gestation. We routinely
injected the mother with 12 mg betamethasone i.m. twice per 24 h
interval unless contraindications were present, in a case where
preterm delivery before 34 weeks might not be avoided due to
preterm labor or might be needed because of medical indications.
2.4. Measures
Neurodevelopmental outcomes of infants at 18 months of corrected age were evaluated in our hospital by the well-trained
occupational therapists using the Kyoto Scale of Psychological
Development 2001 (KSPD). KSPD is a Japanese standard developmental test and is used to assess disabled children at public health
centers. The purpose of KSPD is to examine children's general
developmental progress and delay, the presence of balance, and
other ndings over a wide range of mental development [22]. It is
based on Gesell's developmental diagnosis and refers to the
assessment items of the Binet test. It is an individualized face-toface test administered by experienced psychologists to assess child's
development in the following three areas: postural-motor (P-M; ne
and gross motor functions); cognitiveadaptive (C-A; non-verbal
reasoning or visuospatial perceptions assessed using materials [e.g.
blocks, miniature cars, and marbles]); and language-social (L-S;
interpersonal relationships, socializations and verbal abilities) [23]. In
each of the three areas, a sum score is converted to a developmental
age (DA), and an overall DA is also obtained. The developmental
quotient (DQ) is obtained by dividing the estimated DA by the
chronological age and then multiplying the quotient by 100.
To compare neurodevelopmental outcomes between the two
groups, we rst analyzed KSPD scores of 38 AGA and 19 SGA infants
born from 25 to 31 weeks of gestation that were randomly selected as
gestation-matched controls.
We then collected the following data from the whole study
population of AGA group by reviewing patients' records: gestational
age at delivery, birth weight, gender, presence of PROM, CAM, funisitis,
and non-reassuring fetal status (NRFS) before delivery. The diagnosis
of CAM and funisitis was histopathologically made according to the
criteria by Blanc [24]. We dened NRFS as the condition in which the
fetus should be delivered as soon as possible in this study. We made a
decision on emergent delivery in cases with NRFS based mainly on
cardiotocography (CTG) analysis, along with biophysical prole,
Doppler ultrasound analysis of UA and fetal middle cerebral artery
(MCA), and gestational age. On the other hand, the following data were
collected in the whole SGA group: gestational age at delivery, birth
weight, standard deviation (SD) of estimated fetal weight (EFW) before
delivery, gender, presence of oligohydramnios, PIH, NRFS before
delivery, AREDFV in UA and fetal brain sparing effect. EFW and SD of
that were calculated by the method of Shinozuka et al. [25,26]. We
adopted SD of EFW as an indicator of the severity of FGR. Oligohydramnios was dened as the amniotic uid index (AFI) of less than 5 cm.
Doppler ow measurements of UA and MCA were performed, and
resistance index (RI) were calculated. Fetal brain sparing effect was
dened as the RI ratio (RI of MCA/UA) 1. Results of SD of EFW, AFI,
presence of AREDFV in UA and RI ratio of MCA/UA of the last examination
conducted within a week prior to delivery were used for analysis.
Prognosis of the infants at 18 months of corrected age was classied
into 3 groups by total DQ score for all three areas of KSPD. We dened
the normal development group as DQ score being over 85, the

S. Tamaru et al. / Early Human Development 87 (2011) 5559

Table 1
Characteristics of the study population.

Birth weight (g)a

Gestational age at delivery
(weeks)a
Maternal age (years)b
Male infantsc
Cesarean sectionc
Infant's death before 18
months of corrected agec
Severe impairment unable
to be evaluated by KSPDc
Infants who could be
evaluated by KSPDc

AGA group (n= 118)

SGA group (n= 52)

P value

944.5 (4351474)
26.9 (22.031.6)

882.5 (2971480)
30.4 (22.934.7)

0.311
b 0.001

30.4 4.5
60 (50.9%)
65 (55.1%)
9 (7.6%)

31.3 4.6
23 (44.2%)
47 (90.4%)
8 (15.4%)

0.243
0.426
b 0.001
0.12

3 (2.5%)

1 (1.9%)

0.806

106 (89.8%)

43 (82.7%)

0.192

KSPD, the Kyoto Scale of Psychological Development 2001; AGA, appropriate for
gestational age; SGA, small for gestational age; Data are presented as mean standard
deviation, median (range) or number (percentage).
a
MannWhitney test.
b
Student t test.
c
2 test.

borderline development group as that from 70 to 84, and the poor

prognosis group as that less than 70 or infants unable to be evaluated by
KSPD because of severe impairment or decease before 18 months of
corrected age [27]. We nally analyzed the relationship between
prognosis of the infants at 18 months of corrected age and the prenatal
risk factors in each of AGA and SGA groups.
2.5. Statistical analysis
Variables were described using mean and SD or median and
ranges. Categorical variables were compared by the 2 test, and for
continuous variables, the MannWhitney test, Student t test, or oneway factorial analysis of variance (ANOVA) were used. Differences
associated with P-values less than 0.05 were regarded as statistically
signicant. Data were analyzed using Statcel 2 for Windows (OMS,
Tokyo, Japan).
3. Results
Table 1 shows the characteristics of the study population.
Gestational age at delivery of the AGA group was signicantly earlier
than that of the SGA group (P b 0.001). Mortality (7.6% vs 15.4%,
P = 0.12) and rate of infants who could not be evaluated by KSPD
because of severe impairment (2.5% vs 1.9%, P = 0.806) were not
signicantly different between the two groups.
Table 2 shows the characteristics of the study population born
between 25 and 31 gestational weeks. The gestational age at delivery
of the AGA group and that of the SGA group was not signicantly
different (P = 0.576). Mortality (8.1% vs 12.9%, P = 0.204) and rate of
infants who could not be evaluated by KSPD because of severe

Table 3
The KSPD scores of 38 AGA and 19 SGA infants born between 25 and 31 weeks of
gestation that were randomly selected as gestation-matched controls.

KSPD score of P-M areaa

KSPD score of C-A areab
KSPD score of L-S areab
KSPD score of total of
three areasb

Gestational age at delivery

(weeks)a
Infant's death before
18 months of corrected ageb
Severe impairment unable
to be evaluated by KSPDb
Infants who could be
evaluated by KSPDb

SGA group (n= 31)

P value

27.8 (2531.6)

28 (2531.7)

0.576

7 (8.1%)

4 (12.9%)

0.204

2 (2.3%)

1 (3.2%)

0.786

79 (91.9%)

26 (83.9%)

0.209

KSPD, the Kyoto Scale of Psychological Development 2001; AGA, appropriate for
gestational age; SGA, small for gestational age; data are presented as median (range) or
number (percentage).
a
MannWhitney test.
b
2 test.

AGA group (n = 38)

SGA group (n = 19)

P value

92.5 (31118)
95.8 14.4
95.3 16.3
94.4 13.7

87.3 (64112)
87.2 13.4
93.7 17.7
88.4 14.1

0.436
0.034
0.738
0.131

KSPD, the Kyoto Scale of Psychological Development 2001; AGA, appropriate for
gestational age; SGA, small for gestational age; data are presented as mean standard
deviation or median (range).
a
MannWhitney test.
b
Student t test.

impairment (2.3% vs 3.2%, P = 0.786) were not signicantly different

in the two groups.
Table 3 shows KSPD scores of 38 AGA and 19 SGA infants born
between 25 and 31 weeks of gestation that were randomly selected as
gestation-matched controls. The mean gestational age of the former
was 28.1 and that of the latter was 28.2 (P = 0.82, 2 test). KSPD DQ
score of the C-A area was signicantly lower in this SGA group
(P = 0.034). Although the total KSPD DQ score was not signicantly
different between these two groups (P = 0.13), the value was also
lower in this SGA group.
Tables 4 and 5 show the prognosis of infants at 18 months of
corrected age and prenatal risk factors in the AGA and SGA groups,
respectively. Advanced gestational age at delivery and heavier birth
weight protected against adverse neurodevelopmental outcomes in
both groups (P b 0.001). Mean gestational age of male and female
infants in the SGA group were 29.1 and 30.0, respectively (P = 0.316,
Student t test). Although no signicant difference of gestational age
was observed between male and female infants in the SGA group,
male infants were related to the excess risk of adverse neurodevelopmental outcomes in this group (P = 0.007). The presence of PIH
seemed to be related to better prognosis in the SGA group (P = 0.005).
However, mean gestational age with and without PIH were 30.5 and
28.4, respectively (P = 0.024, Student t test).
4. Discussion
According to the website of the Vital Statistics in Japan (http://www.
mhlw.go.jp/toukei/saikin/hw/jinkou/kakutei04/) and the World Health
Statistics of WHO (http://www.who.int/whosis/whostat/2009/en/
index.html), mortality rates of neonates and infants in Japan in 2004
were 1.5 and 2.8 per 1000 live births, respectively and those are among
the lowest gures in the world. And those of Nagano Prefecture where
Table 4
Prognosis of 118 infants at 18 months of corrected age and prenatal risk factors in the
AGA group.

Table 2
Characteristics of the study population born between 25 and 31 gestational weeks.
AGA group (n= 86)

57

Gestational age (weeks)a

Birth weight (g)a
Male infants (%)b
Presence of PROM (%)b
Presence of CAM (%)b, c
Presence of funisitis (%)b, c
Presence of NRFS (%)b

Normal
development
(n= 68)

Poor
Borderline
development prognosis
(n= 25)
(n = 25)

27.6 2.3
1051.3273.2
33/68 (48.5)
32/68 (47.1)
49/66 (74.2)
32/66 (48.5)
9/68 (13.2)

26.5 2.2
901.2271.5
12/25 (48)
13/25 (52)
18/25 (72)
13/25 (52)
7/25 (28)

P value

25.3 2.0
b0.001
738.2200.3 b0.001
15/25 (60)
0.587
15/25 (60)
0.537
21/25 (84)
0.548
12/25 (48)
0.948
5/25 (20)
0.243

AGA, appropriate for gestational age; PROM, preterm rupture of membranes; CAM,
chorioamnionitis; NRFS; non-reassuring fetal status; ANOVA, analysis of variance; data
are presented as mean standard deviation or number (percentage).
a
One-way factorial ANOVA.
b
2 test.
c
Presence of CAM and funisitis were not investigated in two cases of normal
development group.

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S. Tamaru et al. / Early Human Development 87 (2011) 5559

Table 5
Prognosis of 52 infants at 18 months of corrected age and prenatal risk factors in SGA group.

Gestational age (weeks)a

Birth weight (g)a
SD of EFWa
Male infants (%)b
Presence of oligohydramnios (%)b, c
Presence of PIH (%)b
Presence of NRFS (%)b
Presence of AREDFV in UA (%)b, d
Presence of RI ratio (RI of MCA/UA) 1 (%)b, d

Normal development
(n = 30)

Borderline development
(n = 10)

Poor prognosis
(n = 12)

P Value

31.1 2.8
1022.5320.8
2.23 0.87
8/30 (26.7)
7/28 (25)
23/30 (76.7)
21/30 (70)
6/30 (20)
20/30 (66.7)

28.9 2.6
911.4267.7
1.74 0.8
8/10 (80)
2/6 (33.3)
3/10 (30)
4/10 (40)
1/10 (10)
5/10 (50)

26.5 3.4
582.3277.8
1.98 1.17
7/12 (58.3)
4/9 (44.4)
4/12 (33.3)
8/12 (66.7)
5/10 (50)
7/10 (70)

b0.001
b0.001
0.335
0.007
0.535
0.005
0.225
0.08
0.577

SGA, small for gestational age; SD, standard deviation; EFW, estimated fetal weight; PIH, pregnancy-induced hypertension; NRFS, non-reassuring fetal status; AREDFV, absent or
reversed end-diastolic ow velocity; UA, umbilical artery; RI, resistance index; MCA, middle cerebral artery; ANOVA, analysis of variance; data are presented as mean standard
deviation or number (percentage).
a
One-way factorial ANOVA.
b
2 test.
c
Nine cases of PROM were excluded from the data.
d
Presence of AREDFV in UA and RI ratio (RI of MCA/UA) were not investigated in two cases of poor prognosis group.

our hospital is located were 1.2 and 2.1, respectively. Moreover,

according to the website of the Japanese Ministry of Internal Affairs
and Communications (http://www.soumu.go.jp/menu_news/s-news/
2007/pdf/070912_2_2.pdf), the average gures of those from 1996 to
2005 in our prefecture were 1.2 and 2.4, respectively, and they are the
least in Japan.
We have 10 perinatal medicine centers which deal with high-risk
pregnancies in our prefecture where there are about 20,000 deliveries
per year. Our hospital plays a signicant central role among those
centers and is almost geographically centrally located in the
prefecture. This enables emergent maternal transfer, and many
high-risk pregnant women including those with threatened premature delivery are transported to our hospital from local hospitals
including 9 perinatal medicine centers. We then provide them with
maternal and fetal intensive care. This is well indicated by the fact that
54.4% (206/379) and 36.9% (225/609) of infants whose birth weight
being less than 1000 g and between 1000 g and 1500 g, respectively,
born in our prefecture during the period between October 2000 and
December 2007 were actually born in our hospital. We thus
speculated that such an efcient perinatal medical system in Nagano
Prefecture might have contributed to quite favorable outcomes of the
infants. This led to our present investigation and we herein examined
the relationship between neurodevelopmental outcomes of infants
and perinatal obstetric factors. As far as we know, there have been no
published data in English literature that investigated those aspects in
VLBW and ELBW Japanese infants. We therefore considered that our
study would give signicant information regarding efcient care of
premature fetuses and infants both to obstetricians and pediatricians
not only in Japan but also in the world.
The results of the present study indicated that mortality and rate of
infants who had severe neurodevelopmental impairment at
18 months of corrected age were not signicantly different between
the AGA and SGA groups whose birth weight being b1500 g. However,
the development of the C-A area was signicantly delayed in SGA
infants and although not statistically signicant, the DQ score of the
total of three areas was also lower in the SGA group. Previous studies
showed conicting results on the neurodevelopmental outcomes of
very preterm SGA infants in a short follow-up period. Procianoy et al.
studied 41 AGA and 55 SGA VLBW infants' neurodevelopment at 8, 12,
18, and 24 months of corrected age by the Bayley Scale [28]. They
concluded that SGA and AGA infants whose birth weight being
b1500 g had similar neurodevelopment up to 24 months of corrected
age. Feldman et al. studied 120 singleton premature infants (birth
weight: 5301790 g; gestational age: 2535 weeks) and divided them
into 3 groups [19]. (group 1: 40 SGA infants; group 2: 40 AGA infants
case matched with group 1 for birth weight; group 3: 40 AGA infants
case matched with group 1 for gestational age) The Bayley Scale was

used to assess the cognitive development at 1 and 2 years' corrected

age and SGA infants demonstrated lower cognitive outcomes at
24 months in both the mental and psychomotor domains. Those
studies employed different neurodevelopment scales used for infants'
evaluation, different study designs and time of assessment from ours.
However, like our results it is now revealed that being born SGA is
associated with long-term neurocognitive impairment in many
studies [1318]. Therefore, it is truly important that medical and
psychosocial interventions which aim to reduce the severity of these
impairments be developed and longitudinal follow-up be continued.
Studies of preterm births have shown that there are some obstetric
factors which affect neurodevelopmental outcomes of infants. Shorter
gestational age and lighter birth weight in the SGA and AGA groups,
male sex in SGA group were related to the excess risk of adverse
neurodevelopmental outcomes in our study. Spinillo et al. studied 394
male and 360 female infants born 24 to 33 weeks of gestation and
assessed neurodevelopment by neurological examinations and Bayley
Scale at 2 years of corrected age [29]. They also concluded that male
sex was associated with an increased risk of neurodevelopmental
impairment (odds ratio 1.8) compared with females and that the
excess risk was higher among SGA infants. Although the reason for the
association between fetal sex and infant outcomes are not well
understood, animal studies have shown that some essential neurobiological differences may be present between males and females
with respect to their response to brain injuries [30].
In our present study, neurodevelopmental outcomes at 18 months
of corrected age in SGA infants were better when maternal PIH
existed. Cheng SW et al. investigated 89 infants born before 32 weeks
of gestation and assessed neurodevelopmental outcomes by the
Bayley Scale [31]. More infants born from pre-eclamptic mothers had
a lower Mental Developmental Index score at 2 years of corrected age
as compared to infants without maternal pre-eclampsia, and they
concluded that delivery before 32 weeks because of pre-eclampsia
was associated with an increased risk of poor cognitive outcomes.
Because the mean gestational age at delivery was signicantly later in
infants born from mothers with PIH than those from mothers without
PIH in our SGA group, this might have contributed to our different
results from their study.
The presence of PROM, pathological CAM and funisitis in AGA
infants, oligohydramnios, AREDFV in UA, RI ratio (RI of MCA/UA) 1,
and severity of FGR in SGA infants were not related to infants'
neurodevelopmental outcomes at 18 months of corrected age in our
study, despite it is obvious that all of them are related to the
environmental deterioration in the uterus or of the fetus itself. Longer
gestational period and heavier birth weight protected against an
adverse neurodevelopmental outcomes in both groups, and of course
heavier birth weight is strongly associated with longer gestational

S. Tamaru et al. / Early Human Development 87 (2011) 5559

period. Therefore, longer gestational period is considered to be the most

essential factor especially in early preterm infants' neurodevelopmental
outcomes, even if environmental deterioration in the uterus and of the
fetus is suggested by ultrasound examinations. In addition, the presence
of NRFS was not related to the neurodevelopmetal outcomes of the
infants in both groups in our study. Since our hospital is a center for
perinatal medicine in our prefecture, we are routinely assessing fetal
conditions using CTG twice or thrice-daily at least, and if necessary,
continuously for 24 h in high-risk patients. We speculate that such a
frequent CTG assessment with detailed ultrasound examinations
performed along with various conditions always capable of emergent
delivery in our perinatal medicine center plays a signicant role and
contributes to the results indicating that the presence of NRFS was not
related to the neurodevelopmetal outcomes in our study population.
However, we presented here that only neurodevelopmental outcomes
evaluated at 18 months of corrected age. It is therefore mandatory to
continue longitudinal follow-up for a longer period until we can
establish an efcient perinatal strategy for improving neurodevelopmental prognosis of the premature infants.
We are now continuously following up those infants included in this
study, and we have a plan to be evaluating their neurodevelopmental
outcomes until 9 years of corrected age. As indicated in the Materials
and methods, this retrospective study investigated cases of Japanese
women with a singleton pregnancy and their infants whose birth weight
being less than 1500 g born in our hospital during the period between
October 2000 and December 2007. Between January 2008 and
December 2009, 35 AGA and 34 SGA such infants were born, who can
be included and analyzed in our continuing research in the future.
One of the limitations in the present study is that we could not
exclude the possible inuence of the use of magnesium sulfate on
neurodevelopmental outcomes of the infants. According to the
Committee Opinion of the American College of Obstetricians and
Gynecologists, it is suggested that magnesium sulfate given before
anticipated early preterm birth reduces the risk of cerebral palsy in
surviving infants [32]. In the present study, many patients with
threatened premature delivery in AGA group underwent tocolytic
therapy with i.v. infusion of magnesium sulfate as the second-line
therapy. On the other hand, most of the patients having PIH in SGA
group underwent the therapy to prevent eclampsia. Therefore, the
consequence of our present study might have been inuenced by the
use and dosage of magnesium sulfate to some extent. However, as
gestational age, duration and dosage of the treatment regimens with
magnesium sulfate were different from case to case, we could not
evaluate the possible inuence of this agent in this retrospective study.
In conclusion, at this moment it seems that the most efcient
obstetric strategy for improving prognosis of premature infants should
be targeted to prolong the pregnancy period as long as the reassuring
fetal status and maternal stable health condition are being conrmed. To
achieve this, high-risk fetuses should be monitored intensively in
perinatal medicine centers which can provide a frequent CTG assessment
with specialized ultrasound examinations and can perform emergent
delivery whenever. Systems which make an early maternal transfer to
such tertiary centers possible in cases with impending preterm delivery
should be established in each region. Perinatal medical systems of our
prefecture reported in this article and the results of this current study
may indicate one of the effective models for high-risk infants.
Conict of interest
The authors do not have any conict of interest to disclose.
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