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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
AGA
BW
HC
HGR
SGR
WGR
www.jpeds.com
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 Libertes
(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
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-
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
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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.
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,
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
Guellec et al
- 2015
ORIGINAL ARTICLES
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
Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants
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.
20.
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Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants
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Figure 1. Study population. MPC, mental processing composite; SDQ, Strengths and difficulties Questionnaire.
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Guellec et al
- 2015
ORIGINAL ARTICLES
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
Intrauterine Growth Restriction, Head Size at Birth, and Outcome in Very Preterm Infants
7.e2