Intrauterine Growth Restriction, Head Size at Birth, and Outcome

in Very Preterm Infants

Isabelle Guellec, MD1,2, Stephane Marret, MD, PhD3,4, Olivier Baud, MD, PhD5,6, Gilles Cambonie, MD, PhD7,
Alexandre Lapillonne, MD, PhD8, Jean-Christophe Roze, MD, PhD9, Jeanne Fresson, MD1,10, Cyril Flamant, MD, PhD9,
Marie-Laure Charkaluk, MD, PhD1, Catherine Arnaud, MD10, and Pierre-Yves Ancel, MD, PhD1,11
Objectives To determine whether small head circumference (HC) or birth weight (BW) or both are associated with
neonatal and long-term neurologic outcome in very preterm infants.
Study design All 2442 live births from the 1997 Epipage study between 26 and 32 weeks of gestational age in 9
regions of France were analyzed. A total of 1395 were tested at age 5 years for cognitive performance and 1315 with
school performance reports at age 8 years. Symmetric growth restriction (SGR) was defined by HC and BW <20th
percentile and in the same percentile range, and asymmetric growth restriction by at least 1 of HC and BW <20th
percentile and the other in a higher decile range. There were 2 forms of asymmetric growth restriction: head growth
restriction (HGR) and weight growth restriction (WGR). Appropriate for gestational age was defined by both BW and
HC >20th percentile.
Results Compared with appropriate for gestational age, SGR was significantly associated with neonatal mortality
(aOR 2.99, 95% CI 1.78-5.03), moderate and severe cognitive deficiency (aOR 1.65, 95% CI 1.01-2.71 and aOR
2.61, 95% CI 1.46-4.68, respectively), and poor school performance (aOR 1.79; 95% CI 1.13-2.83). HGR was significantly associated with severe cognitive deficiency (aOR 2.07, 95% CI 1.15-3.74). WGR was not significantly associated with cognitive or school performance despite higher rates of neonatal morbidity.
Conclusions SGR in preterm infants was associated with neonatal mortality and impaired cognitive and school
performance. The outcome of asymmetric growth restriction differed according to HC. HGR was associated with
impaired cognitive function; WGR was not. (J Pediatr 2015;-:---).

hanges in perinatal management have been associated with a substantial increase in the survival of infants at very low
gestational ages, an increase that raises questions about their long-term neurologic outcomes.1 Preterm growthrestricted infants are a population of particular interest because they combine immaturity secondary to low gestational
age with the consequences of growth restriction.
Growth restriction remains a concept difficult to study especially in preterm infants. It intermixes mechanisms including
placental insufficiency, with or without brain sparing,2 congenital abnormalities, toxic, environmental,3 and maternal diseases.4,5 It is difficult to distinguish their consequences from the separate consequences of immaturity. Because these mechanisms might affect various
anthropometric measurements, such as head circumference (HC) and birth

et de la Recherche
From the Institut National de la Sante

dicale (INSERM), UMR 1153, Equipe de recherche en
Me
weight (BW) differently, these measurements might also be associated differently

miologie Obste

tricale, Pe

rinatale et Pe

diatrique;
Epide
with specific outcomes.
^ pitaux de Paris, Department of
Assistance Publique - Ho
Neonatology and Intensive Care, A. Trousseau Hospital,
Previous studies have demonstrated that small for gestational age birth is assoParis; Rouen University Hospital, Neonatal Medicine;
6-9
Institute of Biomedical Research, University, Inserm
ciated with a high mortality rate and impaired cognitive development.
Avenir Research Group, IFR 23, Rouen; INSERM UMR
^ pitaux de Paris,
Although growth restriction is a dynamic process, it is commonly defined by a
1141; Assistance Publique - Ho

Hospital, Paris;
Department of Neonatology, R. Debre
BW <10th percentile. Moreover, preterm growth reference curves underestimate
Montpellier University Hospital Center, Neonatal and
10
Pediatric
Intensive
Care
Unit,
Montpellier;
Assistance
growth restriction. Growth restriction because of placental insufficiency
^ pitaux de Paris, Department of
Publique - Ho
Neonatology, Necker Hospital, Paris; Nantes University,
should, thus, be studied as a dynamic process that reduces the fetuss growth caDepartment of Neonatology, Maternite Regionale,
pacity secondary to the failure of compensation mechanisms or the severity of the
Clinical Epidemiology and Biostatistics Department
France, Nantes University, INSERM CIC004; Clinical
illness.11 It is thought that growth-restricted fetuses attempt to compensate for
Epidemiology and Biostatistics Department, CHRU

miologie et
Nancy;
and Centre de Recherche Epide
the substrate limitation associated with placental insufficiency by preferentially


1

10

11

Statistique Sorbonne Paris Cite DHU Risques et

Paris Descartes, Paris, France
grossesse Universite

AGA
BW
HC
HGR
SGR
WGR

Appropriate for gestational age

Birth weight
Head circumference
Head growth restriction
Symmetric growth restriction
Weight growth restriction

et de la ReFunded by Institut National de la Sante

dicale (INSERM), Directorate General for
cherche Me
Health of the Ministry for Social Affairs, and Hospital
Program for Clinical Research 2001 (AOMO1117) of the
French Department of Health. The authors declare no
conflicts of interest.
0022-3476/$ - see front matter. Copyright 2015 Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2015.08.025

THE JOURNAL OF PEDIATRICS

www.jpeds.com

perfusing the central nervous system.12,13 If so, development

would be limited first by a reduction in BW and only thereafter by smaller head size. If growth restriction occurs early in
pregnancy or if no adaptive mechanism protects the fetus,
growth restriction might be symmetric. If it occurs later,
however, or is accompanied by adaptive phenomena, it might
result in asymmetric growth restriction involving BW only. If
this hypothesis is correct, head growth restriction (HGR) appears to be due to another mechanism and may be associated
with a different outcome.
Accordingly, we analyzed growth restriction in its different
clinical forms by examining 2 specific anthropometric
measurements (BW and HC) and their relations to 3
different outcomes in very preterm children: short-term
mortality and morbidity and long-term neurodevelopmental
outcomes.

Methods
Our data come from the 1997 Epipage cohort study, which
included all live births between 22 and 32 weeks of gestation
in 1997 in 9 regions on France.14 Because 65% of those born
at 22-25 weeks died before discharge, we limited our analysis
to children born alive at 26-32 weeks (n = 2694) for whom
HC and BW were available (n = 2442, 90.6%). Two regions
with large samples included only 1 of every 2 infants for
follow-up (70 infants not included). Parent refusal resulted
in exclusion of 89 infants from follow-up. At 5 years of age,
1648 (80%) had medical examinations and 1395 (68%)
cognitive assessments, all by trained physicians and psychologists. The parents of 1520 children (74%) also completed
questionnaires. Around the childrens eighth birthdays,
parents received a questionnaire about their school performance. In all, 1315 (64%) responses were available for
analysis (Figure 1; available at www.jpeds.com).
The Commission Nationale de lInformatique et des Libert
es
(French Data Protection Authority) approved the study.
Parents provided verbal consent. Ethics committee approval
was not required because this was an observational study of
usual care, with no intervention.
Gestational age was defined by completed weeks of gestation, determined from the date of the last menstrual period
and early ultrasound findings. Maternal and obstetric data
were recorded on standardized questionnaires at birth in
each maternity unit. Maternal data included nationality,
age at birth, and parity. Family socioeconomic status was recorded according to the French classification of occupations
and social position, defined by the higher-status parental
occupation (or the mothers, if she did not live with the
father). Obstetric data included type of pregnancy (singleton
or higher-order) and antenatal corticoid use.
Infant Characteristics and Neonatal and Long-Term
Outcomes
Neonatal data were prospectively collected at each hospital.
This study considers sex, BW, and HC, measured by the
2

Vol. -, No. maximum occipital-frontal HC at birth. Congenital abnormalities were also recorded. In-hospital mortality was
defined as death in the delivery room or neonatal unit.
Length of hospitalization was defined as the number of
days until discharge home. Bronchopulmonary dysplasia
was defined as oxygen dependency at 28 days. Duration of
central line was defined as the total number of days during
which a central line was maintained, regardless of the reason.
Intraventricular hemorrhage and white matter damage
were diagnosed from cranial ultrasonography, performed
by qualified neonatologists or radiologists. Major brain
lesions included intraventricular hemorrhage with ventricular dilatation (grade III) or intraparenchymal hemorrhage
(grade IV), according to the Papile classification, cystic periventricular leukomalacia, or hyperechogenicity persisting
more than 14 days without cystic formation.15
We used the European definition to define cerebral palsy,
which requires at least 2 of the following: abnormal posture
or movement, increased tone and hyperreflexia (spastic cerebral palsy), involuntary movements (dyskinetic cerebral
palsy), or absence of coordination (ataxic cerebral palsy).16
The French version of the Kauffman assessment battery for
children was used to assess cognitive function, expressed as
a mental processing composite score (IQ equivalent), standardized with a mean of 100 and a SD of 15 in a French population born in the 1990s.17 Moderate cognitive deficiency
was defined by a score between 70 and 84, and
severe cognitive deficiency <70.
Behavioral problems were assessed by the French versions
of the strength and difficulties questionnaire,18 completed by
parents. It includes 4 scales (inattention-hyperactivity,
conduct, emotional, and peer problems) that were added
together for a total behavioral difficulties score. The cut-off
was defined by the 90th percentile of the scores observed in
the reference group of term infants included in Epipage.
School difficulties were assessed at age 8 years based on a
parental questionnaire. Special schooling (institution, special
school and special class in mainstream school, compared
with mainstream class) or low grades were considered school
difficulties.19
Growth Restriction
Percentiles of BW and HC were determined by gestational
age and sex from the data of this cohort of very preterm births
(Figure 2). Our population was divided into 4 different
categories according to the percentile of their HC and BW.
Symmetric growth restriction (SGR) was defined by BW
and HC percentiles both <10th percentile or both between
10th and 19th percentile. Two different types of asymmetric
growth restriction were defined. HGR was defined by a HC
<20th percentile, with BW in at least the next higher decile
group, and weight growth restriction (WGR) by a BW
<20th percentile, with HC in at least the next higher decile
group. The group without growth restriction, that is, appropriate for gestational age (AGA), was defined by BW and HC
both above the 20th percentile.
Guellec et al

- 2015

ORIGINAL ARTICLES

Figure 2. Description of the population.

Statistical Analyses
We studied the relations between maternal and obstetric
characteristics and growth restriction at birth. We examined
these different forms of growth restriction at birth in relation
to neonatal and long-term outcomes. c2 tests were used, and
a P value of <.05 was considered significant. We used the ANOVA test for continuous variables, with the same P value
defining significance.
Logistic regression models were used to analyze associations between growth restriction and each binary outcome
(ie, mortality, major brain lesions, cerebral palsy, behavioral
difficulties, and school difficulties). Multinomial logistic
regression models were used for cognitive outcomes (ie, no
cognitive deficiency, moderate cognitive deficiency, and
severe cognitive deficiency). Associations were quantified
by ORs and their 95% CIs. Covariates were included in logistic regression models if they were known risk factors and
associated with the outcome with a P value of <.2 in the univariate analysis. All analyses were adjusted for gestational age
and sex.6 For in-hospital mortality, factors included in the
final model were antenatal corticosteroids (P < .01) and
family social class (P = .06); for major brain abnormalities,
nationality (P = .12), and antenatal corticosteroids
(P < .01); and for cerebral palsy, the type of pregnancy
(singleton vs higher-order) (P = .14). Finally, the same factors were included in the models for both behavioral problems and school difficulties: family social class (P < .01 for
both), maternal age (P < .01 for both), parity (P = .05
and <.01, respectively), and type of pregnancy (P = .03 and
.08, respectively). Associations between growth restriction
and cognitive outcomes were studied after adjustment for so-

cial class (P < .01), age (P = .01), nationality (P = .01), and

parity (P < .01). All analyses were performed with Stata 10
SE (StatCorp, College Station, Texas).

Results
First, we compared the characteristics of children with
missing data for BW, sex, or HC with children with complete
data. They were more frequently male (P = .023), were born
earlier (29 vs 30 weeks gestational age), and died more often
in the hospital (40% vs 9%, P < .001) especially in the delivery
room (18.7% vs 0%). Long-term outcomes did not differ between these 2 groups. Mean mental processing composite
score was 94.2 for missing data group vs 93.7 for complete
data (P = .827), cerebral palsy occurred in 7.7% vs 8.5% of
these groups (P = 1.000), and total behavioral difficulties
percentage were similar (20.8% vs 21.1%, P = .000). School
difficulties also were similar (25.6% vs 22.6%, P = .578).
Figure 2 summarizes the number of total, SGR, HGR,
WGR, and AGA births by decile range of BW and HC. Of
the 2442 live births available for analysis, 213 (8.7%) were
SGR, 209 (8.6%) HGR, 201 (8.2%) WGR, and 1819
(74.5%) AGA. In the SGR group, 63% had both BW and
HC <10th percentile, and 37% between the 10th and 19th
percentiles. In the WGR group, 43% had a BW <10th
percentile, and 57% between 10th and 19th percentiles. In
the HGR group, 34% had a HC <10th percentile, and 66%
between the 10th and 19th percentiles.
Maternal and obstetric characteristics are reported by
growth restriction (Table I; available at www.jpeds.com).
Children of nulliparous women were growth-restricted

Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants

THE JOURNAL OF PEDIATRICS

Vol. -, No. -

www.jpeds.com

Table II. Neonatal outcome according to growth restriction category

In hospital mortality
n/N (%)
OR [95% CI]
aOR* [95% CI]
Major brain pathology
n/N (%)
OR [95% CI]
OR [95% CI]
Bronchopulmonary dysplasia
n/N (%)
OR [95% CI]
ORz [95% CI]

SGR

HGR

WGR

AGA

30/213 (14.1%)
2.04 [1.34-3.12]
2.99 [1.78-5.03]

21/209 (10.0%)
1.39 [0.86-2.26]
1.68 [0.93-3.02]

21/201 (10.5%)
1.46 [0.90-2.36]
1.39 [0.74-2.63]

135/1819 (7.4%)
1
1

.006

41/211 (19.4%)
0.86 [0.60-1.23]
0.83 [0.55-1.26]

40/203 (19.7%)
0.88 [0.61-1.26]
1.04 [0.70-1.54]

42/196 (21.4%)
0.97 [0.68-1.39]
1.06 [0.72-1.57]

388/1773 (21.9%)
1
1

.807

42/206 (20.4%)
3.09 [2.11-4.52]
3.74 [2.48-6.65]

28/203 (13.8%)
1.93 [1.25-2.98]
2.09 [1.32-3.31]

33/194 (17.0%)
2.42 [1.63-3.74]
2.70 [1.74-4.20]

135/1763 (7.7%)
1
1

<.001

*Adjusted for gestational age, sex, family social class, and antenatal corticosteroids.
Adjusted for gestational age, sex, mothers nationality, and antenatal corticosteroids.
zAdjusted for gestational age, sex, mothers age, type of pregnancy, and antenatal corticosteroids.

more frequently than those of multiparous women

(P = .032). The SGR group received antenatal
corticosteroids significantly more frequently than the
others (P = .008). Less than 10% of the population had
congenital abnormalities, a proportion that did not differ
according to growth restriction (P = .302).
Neonatal mortality and morbidity were significantly associated with growth restriction categories (Table II). Inhospital mortality was significantly higher in the SGR (aOR
2.99, 95% CI 1.78-5.03) than the AGA group.
Hospitalization time increased significantly (P < .01) from
54 (54) days for AGA children to 65 (37), 71 (43),
and 77 (0) days for HGR, WGR, and SGR children,
respectively. Similarly, duration of central-line placement
varied and was higher in the WGR (27 days [31]) and
SGR groups (28 days [32]) than for HGR (21 days
[19]), and AGA children (17 days [18]). The

bronchopulmonary dysplasia rate was higher in growthrestricted children than in the reference group. Major brain
lesions did not vary by growth status.
The prevalence of intellectual disability varied across
growth restriction categories (Table III). SGR children had
higher risks of both moderate (aOR 1.65, 95% CI 1.012.71) and severe (aOR 2.61, 95% CI 1.46-4.68) cognitive
deficiency, and HGR children only of severe cognitive
deficiency (aOR 2.07, 95% CI 1.15-3.74). Although WGR
was initially associated with moderate cognitive deficiency
(crude OR 1.66, 95% CI 1.08-2.56), this association was
not significant after adjustment. The prevalence of cerebral
palsy (P = .26) and behavioral problems (P = .24) did not
vary significantly by growth-restriction categories before or
after adjustment.
School difficulties varied, although not significantly
(P = .054): 21% in the AGA group, 24% in the WGR group,

Table III. Long-term outcome according to category of growth restriction

Cerebral palsy*
n/N (%)
OR [95% CI]
aOR* [95% CI]
Moderate cognitive deficiency 70# MPC <85
n/N (%)
OR [95% CI]
aOR [95% CI]
Severe cognitive deficiency MPC <70
n/N (%)
OR [95%CI]
aOR [95% CI]
Behavioral problemsz
n/N (%)
OR [95%CI]
aORz [95% CI]
School difficultiesz
n/N (%)
OR [95% CI]
aORz [95% CI]

SGR

HGR

WGR

AGA

8/133 (6.0%)
0.66 [0.30-1.31]
0.63 [0.30-1.34]

8/130 (5.2%)
0.64 [0.30-1.34]
0.63 [0.30-1.32]

8/140 (5.7%)
0.59 [0.28-1.23]
0.60 [0.28-1.26]

116/1245 (9.3%)
1
1

.262

27/112 (24.1%)
1.48 [0.92-2.38]
1.65 [1.01-2.71]

21/107 (19.6%)
1.10 [0.66-1.84]
1.20 [0.70-2.04]

35/126 (27.8%)
1.66 [1.08-2.56]
1.57 [0.99-2.47]

205/1050 (19.5%)
1
1

20/112 (17.9%)
1.99 [1.16-3.42]
2.61 [1.46-4.68]

18/107 (16.8%)
1.71 [0.98-2.99]
2.07 [1.15-3.74]

16/126 (12.7%)
1.38 [0.78-2.46]
1.61 [0.87-2.97]

113/1050 (10.8%)
1
1

28/121 (23.1%)
1.21 [0.77-1.89]
1.28 [0.81-2.03]

33/124 (26.6%)
1.46 [0.95-2.23]
1.42 [0.91-2.19]

31/131 (23.7%)
1.25 [0.81-1.91]
1.34 [0.86-2.10]

228/1144 (19.9%)
1
1

.242

35/115 (30.4%)
1.65 [1.08-2.52]
1.79 [1.13-2.83]

28/98 (28.6%)
1.51 [0.95-2.40]
1.48 [0.90-2.43]

26/110 (23.6%)
1.17 [0.73-1.86]
1.21 [0.74-1.99]

208/992 (21.0%)
1
1

.054

.021

MPC, mental processing composite.

*Adjusted for gestational age, sex, and type of pregnancy.
Adjusted for gestational age, sex, family social class, mothers age, nationality, and parity at birth.
zAdjusted for gestational age, sex, family social class, mothers age and parity, and type of pregnancy.

Guellec et al

- 2015

ORIGINAL ARTICLES

29% in the HGR group, and 30% in the SGR group

(Table III). After adjustment, SGR children had a higher
rate of school difficulties than AGA children (aOR 1.79,
95% CI 1.13-2.83).

Discussion
We found that preterm children with SGR had the poorest
outcomes in terms of mortality, neonatal morbidity, cognitive function, and school performance. The HGR group
had risks of severe cognitive deficiency and school difficulties
significantly higher than the AGA reference group. No
similar associations were observed in children with WGR.
Our study is based on data from the Epipage cohort, one of
the largest population-based cohort studies of very preterm
children. Its greatest strengths are its prospective design
and long follow-up. Gestational age was assessed by early
ultrasound scans. The geographical approach decreased the
bias associated with studies in selected perinatal centers.
We used validated tools to investigate motor deficiency
(cerebral palsy), cognitive function (Kaufman assessment
Battery for Children), and behavioral problems (Strengths
and difficulties Questionnaire). The long-term follow-up at
8 years of age provided a reliable assessment of cognitive
function.
Missing data for BW or HC at birth prevented assessment
of 9% of the cohort. Almost 40% died during the neonatal
period. Thus, underestimation of the growth-restriction
rate and its relation with in-hospital mortality cannot be
excluded. In contrast, among survivors, outcomes did not
differ between children with and without missing data.
Thus, the impact of this selection on the associations between
growth restriction and neurodevelopmental outcome is
unclear.
Loss to follow-up is an important issue in large prospective
population-based cohort studies. Several studies have found
that those lost to follow-up are more likely to have disabilities
than those continuing to participate.20 In our study, children
lost to follow-up more frequently had parents who were
younger or had low socioeconomic status; both factors that
influence cognitive and school outcomes (data not shown).
We used an internal reference to define groups of growth
restriction because of the absence of contemporary references
for BW and HC growth in France for very preterm infants.
Another difficulty is that we might have misclassified some
preterm babies, especially in the SGR group. Nonetheless, if
some of them were constitutionally small for gestational
age instead of growth-restricted, this misclassification
would have reduced rather than increased the association
between SGR and cognitive disabilities.
WGR was associated with neonatal complications (mortality, longer need for central line, length of hospitalization, and
bronchopulmonary dysplasia), but not, or at least to a lesser
extent, with long-term cognitive performance. Interestingly,
despite these high rates of neonatal morbidities, children
with normal HC had better cognitive outcomes than those
with SGR or HGR. These results are consistent with previous

studies reporting that growth restriction defined by BW only

is associated with a higher risk of mortality21,22 and of
bronchopulmonary dysplasia.23 This difference may help
explain the conflict in the literature about the effects of
growth restriction on BW and cognitive performance24-27
in articles that do not distinguish between growth restriction
with and without HC involvement.
Another important result of our study is that HC was
strongly related to cognitive function. Both SGR and HGR
children were at risk of cognitive impairment and school
difficulties. Mechanisms of HGR differ from those for
WGR. HC appears to be a risk marker of future adverse
neurologic outcome. We hypothesize that SGR involves
exhaustion of the compensation enabled by the brainsparing response to placental insufficiency, and HGR might
result from antenatal exposure to infections, drugs,
chemicals, or high levels of ionizing radiation. All of these
events are likely to be underdiagnosed.
McElrath et al13 showed that fetal growth restriction and
preeclampsia correlate strongly with microcephaly.13
Nonetheless, head size at birth is poorly related to intelligence,28,29 even though HC is related to brain volume.30
Businelli et al31 reported accelerated cortical development
in growth-restricted fetuses, despite smaller brain volume,
and Bocca-Tjeertes et al32 found developmental delay
independent of HC at birth. Mechanisms of cognitive delay
have not yet been completely elucidated. Fetal growth
restriction may cause irreversible damage to the developing
brain by disrupting gray matter. Tolsa et al33 used advanced
magnetic resonance imaging techniques to show that
children with growth restriction have significantly reduced
intracranial volume and cortical gray and hippocampus matter compared with a matched control group. Disrupted
network features have been observed in human babies with
intrauterine growth restriction.34 Impairments of synaptic
development and white matter have also been observed in
animal models of intrauterine growth restriction.35
In our study, we observed that a not insignificant percentage of the Epipage population (8.2%) had a small HC
without global growth restriction, associated with severe
cognitive deficiency. We can hypothesize that growth
restriction was limited to head growth and to a decrease
in the number of endothelial and neural cells or connections between them, although adequate nutrition prevented
underweight. In these cases, we suggest that maternal and/
or placental factors have specific deleterious effects on forebrain development. For example, maternal depression, or
alcohol or cocaine use during pregnancy might act specifically on cerebral angiogenesis, neurotransmitter release,
and synaptogenesis.36,37 Moreover some authors have
described genetic particularities, such as the 1245 A-allele
of the IGF1 promoter SNP, which is associated with a small
head size and a reduced brain-sparing effect in small for
gestational age infants.38 Even though we did not find
more congenital abnormalities or chromosomal aberrations
in our populations, genetics may be one path toward understanding cognitive deficiency.

Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants

THE JOURNAL OF PEDIATRICS

Vol. -, No. -

www.jpeds.com

In our population, 40%-66% of the preterm growthrestricted children were between the 10th and 19th percentiles. They are usually not recognized as growth-restricted
because preterm children are smaller than their in-utero
peers.10 The true proportion of growth-restricted children
is, thus, underestimated when the 10th percentile of neonatal
growth curves is used to define growth restriction.39 Accordingly, we found significant associations between neonatal
mortality, various forms of neonatal morbidity (eg, bronchopulmonary dysplasia), cognitive functions, and growth
restriction categories, including moderate growth restriction.
Many studies do not consider these children to be at risk.
Moreover, moderate HGR (ie, 10th-19th percentile) is not
considered at risk, especially when the BW is normal. Our
results provide support for the view that both low BW and
HC are continuums, rather than the discrete categories.
In very preterm babies, small head size at birth, either as
part of SGR or isolated, is associated with long-term
neurologic deficiencies, and isolated WGR is associated
only with poorer neonatal outcome but not with long-term
neurologic deficiencies. These factors aggravate the prognosis
of preterm birth and may be useful for parental counseling
and follow-up. n

10.

11.

12.
13.

14.

15.

16.

17.
18.

Submitted for publication May 22, 2015; last revision received Jul 10, 2015;
accepted Aug 6, 2015.

19.

Reprint requests: Isabelle Guellec, MD, service de reanimation neonatale et

diatrique, ho
^ pital Trousseau, APHP, boulevard A.Netter, 75012 Paris,
pe
France. E-mail: isabelle.guellec@trs.aphp.fr

20.

References
1. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm
birth from infancy to adulthood. Lancet 2008;371:261-9.
2. Flood K, Unterscheider J, Daly S, Geary MP, Kennelly MM,
McAuliffe FM, et al. The role of brain sparing in the prediction of adverse
outcomes in intrauterine growth restriction: results of the multicenter
PORTO Study. Am J Obstet Gynecol 2014;211:288.e1-5.
3. Hannam K, McNamee R, Baker P, Sibley C, Agius R. Air pollution exposure and adverse pregnancy outcomes in a large UK birth cohort: use of a
novel spatio-temporal modelling technique. Scand J Work Environ
Health 2014;40:518-30.
4. Nilsson PM, Li X, Sundquist J, Sundquist K. Maternal cardiovascular
disease risk in relation to the number of offspring born small for gestational age: national, multi-generational study of 2.7 million births. Acta
Paediatr 2009;98:985-9.
5. Boggess KA, Beck JD, Murtha AP, Moss K, Offenbacher S. Maternal
periodontal disease in early pregnancy and risk for a small-forgestational-age infant. Am J Obstet Gynecol 2006;194:1316-22.
6. Morsing E, Asard M, Ley D, Stjernqvist K, Marsal K. Cognitive function
after intrauterine growth restriction and very preterm birth. Pediatrics
2011;127:e874-82.
7. Monset-Couchard M, de Bethmann O, Relier JP. Long term outcome of
small versus appropriate size for gestational age co-twins/triplets. Arch
Dis Child Fetal Neonatal Ed 2004;89:F310-4.
8. Guellec I, Lapillonne A, Renolleau S, Charlaluk ML, Roze JC,
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.
9. Kallankari H, Kaukola T, Olsen P, Ojaniemi M, Hallman M. Very preterm birth and foetal growth restriction are associated with specific
6

21.

22.

23.

24.

25.

26.

27.

28.

29.

cognitive deficits in children attending mainstream school. Acta Paediatr

2015;104:84-90.
Hutcheon JA, Platt RW. The missing data problem in birth weight
percentiles and thresholds for small-for-gestational-age. Am J Epidemiol 2008;167:786-92.
Scherjon S, Briet J, Oosting H, Kok J. The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in
very preterm infants with and without hemodynamic signs of fetal
brain-sparing. Pediatrics 2000;105:385-91.
Baschat AA. Fetal responses to placental insufficiency: an update. BJOG
2004;111:1031-41.
McElrath TF, Allred EN, Kuban K, Hecht JL, Onderdonk A, OShea TM,
et al. Factors associated with small head circumference at birth among
infants born before the 28th week. Am J Obstet Gynecol 2010;203:138.
e1-8.
Larroque B, Ancel PY, Marret S, Marchand L, Andre M, Arnaud C, et al.
Neurodevelopmental disabilities and special care of 5-year-old children
born before 33 weeks of gestation (the EPIPAGE study): a longitudinal
cohort study. Lancet 2008;371:813-20.
Ancel PY, Livinec F, Larroque B, Marret S, Arnaud C, Pierrat V, et al.
Cerebral palsy among very preterm children in relation to gestational
age and neonatal ultrasound abnormalities: the EPIPAGE cohort study.
Pediatrics 2006;117:828-35.
Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy
surveys and registers. Surveillance of Cerebral Palsy in Europe (SCPE).
Dev Med Child Neurol 2000;42:816-24.
Kaufman A, Kaufman N. Kaufman assessment battery for children. Circle Pines, MN: American Guidance Service; 1983.
Goodman R. The Strengths and Difficulties Questionnaire: a research
note. J Child Psychol Psychiatry 1997;38:581-6.
Larroque B, Ancel PY, Marchand-Martin L, Cambonie G, Fresson J,
Pierrat V, et al. Special care and school difficulties in 8-year-old very
preterm children: the Epipage cohort study. PLoS One 2011;6:e21361.
Castro L, Yolton K, Haberman B, Roberto N, Hansen NI,
Ambalavanan N, et al. Bias in reported neurodevelopmental outcomes
among extremely low birth weight survivors. Pediatrics 2004;114:404-10.
Katz J, Wu LA, Mullany LC, Coles CL, Lee AC, Kozuki N, et al. Prevalence of small-for-gestational-age and its mortality risk varies by choice
of birth-weight-for-gestation reference population. PLoS One 2014;9:
e92074.
Sharma P, McKay K, Rosenkrantz TS, Hussain N. Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestationalage and appropriate-for-gestational-age premature infants. BMC Pediatr
2004;4:9.
Soudee S, Vuillemin L, Alberti C, Mohamed D, Becquet O, Farnoux C,
et al. Fetal growth restriction is worse than extreme prematurity for the
developing lung. Neonatology 2014;106:304-10.
Karagianni P, Kyriakidou M, Mitsiakos G, Chatzioanidis H,
Koumbaras E, Evangeliou A, et al. Neurological outcome in preterm
small for gestational age infants compared to appropriate for gestational
age preterm at the age of 18 months: a prospective study. J Child Neurol
2010;25:165-70.
Mu SC, Lin CH, Chen YL, Chang CH, Tsou KI. Relationship between
perinatal and neonatal indices and intelligence quotient in very low birth
weight infants at the age of 6 or 8 years. Pediatr Neonatol 2008;49:13-8.
OKeeffe MJ, OCallaghan M, Williams GM, Najman JM, Bor W.
Learning, cognitive, and attentional problems in adolescents born small
for gestational age. Pediatrics 2003;112:301-7.
Padilla N, Perapoch J, Carrascosa A, Acosta-Rojas R, Botet F, Gratacos E.
Twelve-month neurodevelopmental outcome in preterm infants with
and without intrauterine growth restriction. Acta Paediatr 2010;99:
1498-503.
Brennan TL, Funk SG, Frothingham TE. Disproportionate intra-uterine
head growth and developmental outcome. Dev Med Child Neurol 1985;
27:746-50.
Kan E, Roberts G, Anderson PJ, Doyle LW. The association of growth
impairment with neurodevelopmental outcome at eight years of age in
very preterm children. Early Hum Dev 2008;84:409-16.

Guellec et al

- 2015
30. Cheong JL, Hunt RW, Anderson PJ, Howard K, Thompson DK,
Wang HX, et al. Head growth in preterm infants: correlation with magnetic resonance imaging and neurodevelopmental outcome. Pediatrics
2008;121:e1534-40.
31. Businelli C, de Wit C, Visser GH, Pistorius LR. Ultrasound evaluation of
cortical brain development in fetuses with intrauterine growth restriction. J Matern Fetal Neonatal Med 2014 Sep 10;1-6. [Epub ahead of
print].
32. Bocca-Tjeertes I, Bos A, Kerstjens J, de Winter A, Reijneveld S.
Symmetrical and asymmetrical growth restriction in preterm-born children. Pediatrics 2014;133:e650-6.
33. Tolsa CB, Zimine S, Warfield SK, Freschi M, Sancho Rossignol A,
Lazeyras F, et al. Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction.
Pediatr Res 2004;56:132-8.
34. Batalle D, Eixarch E, Figueras F, Munoz-Moreno E, Bargallo N, Illa M,
et al. Altered small-world topology of structural brain networks in
infants with intrauterine growth restriction and its association with later
neurodevelopmental outcome. Neuroimage 2012;60:1352-66.

ORIGINAL ARTICLES
35. Schober ME, McKnight RA, Yu X, Callaway CW, Ke X, Lane RH. Intrauterine growth restriction due to uteroplacental insufficiency
decreased white matter and altered NMDAR subunit composition
in juvenile rat hippocampi. Am J Physiol Regul Integr Comp Physiol
2009;296:R681-92.
36. Jegou S, El Ghazi F, de Lendeu PK, Marret S, Laudenbach V, Uguen A,
et al. Prenatal alcohol exposure affects vasculature development in the
neonatal brain. Ann Neurol 2012;72:952-60.
37. Montiel JF, Kaune H, Maliqueo M. Maternal-fetal unit interactions and
eutherian neocortical development and evolution. Front Neuroanat
2013;7:22.
38. Ester WA, van Meurs JB, Arends NJ, Uitterlinden AG, de Ridder MA,
Hokken-Koelega AC. The -G1245A IGF1 polymorphism is related
with small head size and less brain sparing in small for gestational age
born children. Eur J Endocrinol 2009;160:549-55.
39. Charkaluk ML, Marchand-Martin L, Ego A, Zeitlin J, Arnaud C,
Burguet A, et al. The influence of fetal growth reference standards on
assessment of cognitive and academic outcomes of very preterm
children. J Pediatr 2012;161:1053-8.

Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants

THE JOURNAL OF PEDIATRICS

www.jpeds.com

Vol. -, No. -

Figure 1. Study population. MPC, mental processing composite; SDQ, Strengths and difficulties Questionnaire.

7.e1

Guellec et al

- 2015

ORIGINAL ARTICLES

Table I. Maternal and obstetric characteristics according to growth restriction category

n
Family SES
Professional, manager
Intermediate white-collar
Administrative/public service, selfemployed, student
Sales and service workers
Manual worker or unemployed
French nationality
Maternal age at birth (y)
<25
25-34
$35
Parity
0
1-2
$3
Type of pregnancy
Singleton
Antenatal corticosteroids
Sex of child (male)
Congenital abnormalities

SGR, n (%)

HGR, n (%)

WGR, n (%)

AGA, n (%)

309
533
521

27 (14.0)
45 (23.3)
50 (25.9)

19 (9.9)
55 (28.7)
37 (19.3)

32 (16.9)
37 (19.6)
42 (22.2)

231 (13.6)
396 (23.2)
392 (23.0)

.481

357
558
1968

29 (15.0)
42 (21.8)
171 (91.0)

31 (16.2)
50 (26.0)
169 (92.4)

25 (13.2)
53 (24.2)
169 (89.0)

272 (16.0)
413 (24.2)
1459 (87.4)

570
1467
391

45 (21.4)
121 (57.6)
44 (21.0)

54 (26.2)
118 (57.3)
34 (16.5)

38 (19.1)
121 (60.8)
40 (20.1)

433 (23.9)
1107 (61.1)
273 (15.1)

.133

1272
890
266

124 (59.1)
70 (33.3)
16 (7.6)

116 (56.6)
66 (32.2)
23 (11.2)

118 (59.0)
67 (33.5)
15 (7.5)

914 (50.4)
687 (37.9)
212 (11.7)

.032

1678
1782
1298
229

165 (77.5)
169 (82.8)
121 (56.8)
26/212 (12.3)

155 (74.2)
154 (75.9)
109 (52.2)
22/208 (10.6)

145 (72.1)
156 (80.0)
111 (55.2)
21/199 (10.6)

1213 (66.7)
1303 (75.5)
957 (52.6)
160/1813 (8.8)

.002
.008
.620
.302

.145

SES, socioeconomic status.

Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants

7.e2