Matern Child Health J (2013) 17:1373–1381
DOI 10.1007/s10995-012-1136-2
Being Macrosomic at Birth is an Independent Predictor
of Overweight in Children: Results from the IDEFICS Study
Sonia Sparano • Wolfgang Ahrens • Stefaan De Henauw • Staffan Marild
Denes Molnar • Luis A. Moreno • Marc Suling • Michael Tornaritis •
Toomas Veidebaum • Alfonso Siani • Paola Russo
Published online: 14 September 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Fetal macrosomia is a risk factor for the
development of obesity late in childhood. We retrospec-
tively evaluated the relationship between maternal condi-
tions associated with fetal macrosomia and actual
overweight/obesity in the European cohort of children
participating in the IDEFICS study. Anthropometric vari-
ables, blood pressure and plasma lipids and glucose were
measured. Socio-demographic data, medical history and
perinatal factors, familiar and gestational history, maternal
and/or gestational diabetes were assessed by a question-
naire. Variables of interest were reported for 10,468 chil-
dren (M/F = 5,294/5,174; age 6.0 ± 1.8 years, M ± SD).
The sample was divided in four groups according to child
birth weight (BW) and maternal diabetes: (1) adequate for
gestational age offspring (BW between the 10th and 90th
percentiles for gestational age) of mothers without diabetes
(AGA-ND); (2) adequate for gestational age offspring of
S. Sparano
A. Siani (&)
P. Russo
Epidemiology and Population Genetics, Institute of Food
Sciences, National Research Council (CNR), Via Roma, 64,
83100 Avellino, Italy
e-mail: asiani@isa.cnr.it
W. Ahrens
M. Suling
BIPS-Institute for Epidemiology and Prevention Research,
Bremen, Germany
W. Ahrens
M. Suling
Institute for Statistics, University of Bremen, Bremen, Germany
S. De Henauw
Department of Public Health, Faculty of Medicine and Health
Sciences, Ghent University, Ghent, Belgium
S. Marild
Department of Paediatrics, Queen Silvia Children’s Hospital,
University of Gothenburg, Gothenburg, Sweden
•
mothers with diabetes (AGA-D); (3) macrosomic offspring
(BW [ 90th percentile for gestational age) of mothers
without diabetes (Macro-ND); (4) macrosomic offspring of
mothers with diabetes (Macro-D). Children macrosomic at
birth showed significantly higher actual values of body
mass index, waist circumference, and sum of skinfold
thickness. In both boys and girls, Macro-ND was an
independent determinant of overweight/obesity, after the
adjustment for confounders [Boys: OR = 1.7 95 % CI
(1.3;2.2); Girls: OR = 1.6 95 % CI (1.3;2.0)], while
Macro-D showed a significant association only in girls
[OR = 2.6 95 % CI (1.1;6.4)]. Fetal macrosomia, also in
the absence of maternal/gestational diabetes, is indepen-
dently associated with the development of overweight/
obesity during childhood. Improving the understanding of
fetal programming will contribute to the early prevention
of childhood overweight/obesity.
D. Molnar
Department of Paediatrics, Medical Faculty, University of Pecs,
Pecs, Hungary
L. A. Moreno
Growth, Exercise, Nutrition and Development Research Group,
University of Zaragoza, Zaragoza, Spain
M. Tornaritis
Research and Education Institute of Child Health, Strovolos,
Cyprus
T. Veidebaum
National Institute for Health Development, Tallin, Estonia
123
1374
Keywords Fetal macrosomia
Childhood obesity

Gestational diabetes
Gestational weight gain
IDEFICS
Introduction
Fetal macrosomia is defined, according to the Medical
Subject Headings of the National Library of Medicine
(http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi) [1], as
birth weight of a newborn above the 90th percentile for
gestational age after adjustment for sex- and ethnicity, and
occurs in roughly 1–10 % of all deliveries with 1–2 % of
the newborns having birth weight C4,500 g or more [2].
The prenatal diagnosis of macrosomia by ultrasonography
is often inaccurate, and this condition is usually diagnosed
by measuring birth weight after delivery. Male babies are
more likely to be macrosomic compared to females [3].
Fetal macrosomia is a heterogeneous condition in terms
of definition and etiologic factors [4]. A number of pre-
disposing conditions have been identified: maternal dia-
betes or glucose intolerance, maternal overweight prior to
pregnancy, gestational weight gain [20 kg, gestational age
[41 weeks, previous history of macrosomic birth, mater-
nal age[30 years at birth, high parity, ethnicity, etc. [4, 5].
Other factors, such as parental height and weight, might
also play a role in determining newborn birth weight.
Despite the identification and characterization of these risk
factors, many cases of macrosomia remain unexplained.
Maternal overweight and associated metabolic changes,
including type 2 and gestational diabetes, play a central
role in the delivery of overweight newborns [3]. In par-
ticular, macrosomia is considered the most frequent unfa-
vorable outcome of a diabetes mellitus-complicated
pregnancy, i.e. a condition characterized by elevated blood
glucose that is the main substrate for fetal growth [6]. The
transportation of glucose across the placenta may result in
fetal hyperinsulinemia and stimulation of insulin-like
growth factors, growth hormone and other growth factors
which, in turn, stimulate growth process and deposition of
fat and glycogen. However, not only maternal glucose
intolerance [7, 8], but also other prenatal factors may alter
the intrauterine environment and influence fetal growth.
Besides short term complications such as stillbirth,
shoulder dystocia, birth trauma, and higher risk of delivery
by caesarean section [3, 9], macrosomia at birth is asso-
ciated with an increased risk of long term adverse out-
comes in the child, such as insulin resistance, diabetes,
obesity and hypertension [10].
The prevalence of overweight and obesity among chil-
dren rapidly increased over the last decades [11], leading to
increased adult obesity and its short- and long-term adverse
health outcomes [12]. Maternal and neonatal obesity might
represent a vicious cycle whereby obese mothers have
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Matern Child Health J (2013) 17:1373–1381
obese infants who in turn give birth to obese generations to
come [13]. It is therefore very important to investigate
early-life determinants of obesity that could lead to inno-
vative prevention strategies.
Existing studies focused on the long-term impacts of
macrosomia at birth in general, often without a clear dis-
tinction between the relative weight of the predictors of
neonatal macrosomia. The different maternal conditions
associated with neonatal macrosomia could differentially
impact the development of overweight and of related
metabolic abnormalities during childhood and adolescence
[14].
The present study aimed to investigate in a large sample
of European schoolchildren the association between mac-
rosomia at birth and obesity during childhood, taking into
account the possible role of one of the main causes of
macrosomia, that is diabetes during pregnancy.
Materials and Methods
Study Population
The IDEFICS (Identification and prevention of Dietary-
and lifestyle-induced health EFfects In Children and
infants) project is a large-scale European study funded by
the European Commission within the 6th Framework
Program aiming to evaluate the role of dietary, lifestyle,
social and genetic factors on the onset of diet- and lifestyle-
related disorders including overweight and obesity in
young children [15].
From September 2007 to May 2008, 16,224 preschool-
primary school children aged 2–8 years from Belgium,
Cyprus, Estonia, Germany, Hungary, Italy, Spain, and
Sweden were examined and their parents were interviewed.
Birth weight was not reported for 874 children, 3,891 were
born preterm, 554 from twin gestations and 437 were small
for gestational age newborns (SGA: birth weight \ 10th
percentile for gestational age). After the exclusion of these
5,756 children, the analysis was performed in 10,468
children (Boys = 5,294; Girls = 5,174; age = 6.0 ± 1.8
years, M ± SD).
The study was conducted according to the standards of
the Declaration of Helsinki. All applicable institutional and
governmental regulations pertaining to the ethical use of
human volunteers were followed during this research.
Approval by the appropriate ethical committees was
obtained by each of the eight centers engaged in the
fieldwork. Participants were not subjected to any study
procedure before both the children and their parents gave
their oral (children) and written (parents) informed consent
for examinations, collection of samples, subsequent anal-
ysis and storage of personal data and collected samples.
Matern Child Health J (2013) 17:1373–1381 1375

Table 1 Characteristics of the study subjects by group and sex

AGA-ND AGA-D Macro-ND Macro-D

Boys
N 4,501 109 650 34
Age (years) 6.0 (5.9;6.0) 6.0 (5.6;6.3) 5.9 (5.8;6.0) 5.2 (5.6;6.8)
Birth weight (kg) 3.5 (3.5;3.5) 3.5 (3.3;3.5) 4.3a,b (4.3;4.3) 4.4a,b (4.3;4.5)
3 a,b
Ponderal index (kg/m ) 25.8 (25.7;25.9) 26.4 (24.8;28.0) 28.2 (27.8;28.5) 27.8c (26.5;29.1)
Girls
N 4,415 103 628 28
Age (years) 6.0 (6.0;6.1) 6.0 (5.8;6.2) 6.1 (6.0;6.2) 6.2 (5.5;7.0)
Birth weight (kg) 3.3 (3.3;3.3) 3.3 (3.3;3.4) 4.1a,b (4.1;4.2) 4.2a,b (4.1;4.3)
3 a,b
Ponderal index (kg/m ) 25.8 (25.7;26.0) 25.5 (24.7;26.2) 27.9 (27.7;28.2) 27.8d,e (26.1;29.5)
Data are mean (95 % confidence interval)
AGA-ND adequate for gestational age offspring of mothers without diabetes, AGA-D adequate for gestational age offspring of mothers with
diabetes, Macro-ND macrosomic offspring of mothers without diabetes, Macro-D macrosomic offspring of mothers with diabetes
P for multiple comparisons: a \0.001 vs AGA-ND, b \0.001 vs AGA-D, c
0.016 vs AGA-ND, d
0.020 vs AGA-D, e
0.035 vs AGA-ND

Anthropometry and Blood Pressure
Children underwent a standardized physical examination.
Anthropometric data included body weight and height,
waist and hip circumferences and the measurement of
skinfold thickness. A detailed description of the anthro-
pometric measurements in the IDEFICS study, including
intra- and inter-observer reliability, has been recently
published [16].
The measurement of weight was carried out using an
electronic scale (Tanita BC 420 SMA, Tanita Europe
GmbH, Sindelfingen, Germany) to the nearest 0.1 kg
with children wearing light clothes, without shoes.
Height was measured using a telescopic height-measur-
ing instrument (Seca 225 stadiometer, Birmingham, UK)
to the nearest 0.1 cm. The body mass index (BMI) was
calculated as weight (in kg) divided by height squared
(in m).
Waist circumference was measured using an inelastic
tape (Seca 200), precision 0.1 cm, range 0 ± 150 cm at the
midpoint between the iliac crest and the lower coastal
border or 10th rib with the subject in a standing position
and recorded at the nearest 0.1 cm. Both triceps and sub-
scapular skinfold thickness were measured by means of a
caliper (Holtain, Holtain Ltd, Pembrokeshire, UK, range
0 ± 40 mm). Measures were taken twice on the right hand
side of the body and the mean was calculated.
For the definition of overweight/obesity, we used the
International Obesity Task Force (IOTF) reference and cut-
offs as defined by Cole et al. [17, 18], that classified the
children as thin (grade 1–3), normal weight, overweight
and obese. We operationally grouped the children into two
categories: (1) underweight (thinness grade 1–3) plus
normal weight and (2) overweight plus obese.
Systolic and diastolic blood pressure were measured
after 5 min rest in the seated position, at the child right arm
with a cuff of appropriate size for arm circumference using
an automatic sphygmomanometer (Welch Allyn 4200B-E2
Inc., Skaneateles Falls, NY, USA). Two measurements
were made and the average of the measurements was used
for analysis.
Blood Samples
Children were asked to participate, on a voluntary basis, in
blood drawing. A detailed description of sample collection
and analytical procedures in the IDEFICS survey has been
recently published [19, 20]. Blood glucose, total- and
HDL-cholesterol, and triglycerides were assessed, in fast-
ing status, in 8,304 children by the portable Cholestech
LDX analyzer at each point-of-care centre [21]. LDL-
cholesterol was calculated according to the formula of
Friedwald [22]. Serum insulin and glycated hemoglobin
(HbA1c) were measured in a central laboratory through
enzyme-linked immunosorbent assay kit and by high-
pressure liquid chromatography with an automated HLC-
723G7 analyzer respectively. The homeostatic model
assessment (HOMA) index was calculated according to the
formula: HOMA = [serum insulin (lU/mL) 9 blood glu-
cose (mmol/L)]/22.5 [23].
Questionnaire
Dietary habits and lifestyles of children were described
by parents by filling in a specific questionnaire that
also included data on child birth events and information
about socio-demographic characteristics such as parental
ethnicity, education, occupation and income. Parental

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Table 2 Maternal characteristics by study group

AGA-ND AGA-D Macro-ND Macro-D
n = 8,916 n = 212 n = 1,278 n = 62

Age at time of child examination (years) 35.0 (34.9;35.1) 36.4c (35.6;37.1) 35.7a (35.4;36.0) 36.7b (35.2;38.2)
2 a a,d
BMI at time of child examination (kg/m ) 23.8 (23.7;23.9) 25.5 (24.8;26.1) 24.8 (24.6;25.0) 27.7a,e,f (26.3;29.1)
Graduated (%) 29.6 25.0 27.5 16.71
a a
Age during pregnancy (years) 29.0 (28.9;29.1) 30.4 (29.7;31.1) 29.8 (29.5;30.0) 30.7 (29.3;32.0)
g
Number of previous pregnancies 1.1 (1.1;1.1) 1.1 (1.0;1.2) 1.0 (1.0;1.1) 0.9 (0.7;1.1)
m
Gestational weight gain (Kg) 14.0 (13.9;14.2) 12.9 (12.0;13.7) 15.8a,h (15.4;16.1) 15.3i (13.3;17.2)
C-section (%) 20.1 20.7 27.3 29.02
Alcohol consumption during pregnancy (%) 25.6 14.7 25.3 11.33
Smoking during pregnancy (%) 13.7 13.7 9.4 17.74
Data are mean (95 % confidence interval)
BMI body mass index, C-section caesarean section, AGA-ND adequate for gestational age offspring of mothers without diabetes, AGA-
D adequate for gestational age offspring of mothers with diabetes, Macro-ND macrosomic offspring of mothers without diabetes, Macro-
D macrosomic offspring of mothers with diabetes
P for multiple comparisons: a \0.001 vs AGA-ND, b 0.054 vs AGA-ND, c 0.001vs AGA-ND, d \0.001 vs Macro-D, e \0.001 vs Macro-ND,
f
0.002 vs AGA-D, g 0.013 vs AGA-ND, h \0.001 vs AGA-D, i 0.022 vs AGA-D, m 0.015 vs AGA-ND
1
P by Chi-square test: 0.048, 2 \0.001, 3 \0.001, 4 \0.001

overweight/obesity (at least one parent with BMI [25 kg/
m2) was diagnosed based on self- reported weight and
height at the moment of the visit. Maternal parity was
defined as the number of live births before the pregnancy
under consideration, while attained parental education was
defined according to the International Standard Classifica-
tion of Education (ISCED) [24]. Physical activity of chil-
dren was investigated by questionnaire. Parents were asked
to approximately indicate the number of minutes the child
used to spend in outdoor activities (weekdays and week-
end) and whether or not the child regularly practiced
physical exercise in a sport club. Another section of the
questionnaire investigated perinatal factors, either prenatal
factors (gestational weight gain, parity), and early postnatal
factors (child birth weight and height, gestational age,
length of gestation, type of delivery, duration and type of
feeding). Children’s weight (Kg) and height (cm) at birth
were used to calculate the ponderal index, an indicator of
fetal growth status, according to the formula: (child birth
weight)/(child birth height)3. Mothers were asked if the
child was born at term or not; in the latter case, they were
asked to report how many weeks earlier the delivery
occurred. Other data extracted from this section of the
questionnaire were maternal age at the birth of the child,
maternal smoking and alcohol consumption during preg-
nancy (yes/no) and gestational weight gain (Kg).
The medical history of the child and his family was
reported by parents in an interview including questions about
the biological relatives of the child. For each biological
relative, it was asked whether or not hypertension, dyslipi-
demia, diabetes mellitus, cardiovascular, cerebrovascular
and neoplastic diseases had been diagnosed and, if so, the age
of onset or of the first diagnosis.
Besides the medical history of the family, parents were
asked to provide details about adverse effects during the
index pregnancy (complications, drug use or hospitaliza-
tion). Furthermore, it was asked whether the biological
mother had a diagnosis of gestational diabetes, gestosis,
glycosuria or proteinuria during the index pregnancy.
Statistical Analysis
Data were analyzed using PASW (Predictive Analytics
SoftWare) Statistics (version 18; SPSS Inc., Chicago, IL,
USA). Statistical tests were performed at a significance
level of a = 0.05. Data are expressed as mean and 95 %
confidence intervals (CI) for continuous variables and as
percentages for categorical variables. Macrosomia was
defined according to the Medical Subject Headings of the
National Library of Medicine (http://www.nlm.nih.gov/
cgi/mesh/2012/MB_cgi) [1], that is birth weight [4,000 g
or above the sex-specific 90th percentile for a given
population.
Children born at term were classified as adequate for
gestational age (AGA: birth weight between the 10th and
90th of the sex- and country-specific percentile) and mac-
rosomic children (Macro: birth weight [90th sex- and
country-specific percentile). According to the occurrence
of macrosomia and of maternal diabetes (as either pre-
gestational or gestational diabetes), children were divided
into four groups: (1) AGA of mothers without diabetes
(AGA-ND, n = 8,916); (2) AGA of mothers with diabetes

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Table 3 Anthropometric characteristics and blood pressure by study group and sex
AGA-ND AGA-D Macro-ND Macro-D

Boys
N 4,501 109 650 34
Weight (kg) 23.3 (23.1;23.4) 23.6 (22.6;24.5) 25.1a,b (24.7;25.5) 25.3 (23.6;27.0)
a,f
Height (cm) 117.5 (117.4;117.7) 117.3 (116.4;118.3) 119.7 (119.3;120.1) 112.0c (118.2;121.7)
a
WC (cm) 54.8 (54.6;55.0) 55.2 (54.0;56.3) 56.5 (56.1;57.0) 56.6 (54.5;58.7)
BMI (kg/m2) 16.5 (16.4;16.6) 16.7 (16.3;17.2) 17.2a (17.0;17.3) 17.1 (16.3;18.0)
h
SS (mm) 17.2 (16.1;17.5) 18.3 (16.9;19.7) 18.3 (17.7;18.9) 18.7 (16.1;21.2)
OW/OB (%)* 18.3 21.1 24.6 29.4
SBP (mmHg) 100.6 (100.3;100.9) 100.0 (98.4;101.7) 100.4 (99.7;101.1) 103.7 (100.7;106.6)
DBP (mmHg) 62.6 (62.4;62.8) 63.2 (61.9;64.4) 62.7 (62.1;63.2) 65.5 (63.3;67.7)
Girls
N 4,415 103 628 28
Weight (kg) 22.9 (22.7;23.0) 23.4 (22.4;24.3) 24.8a,d (24.4;25.2) 25.7e (23.9;27.4)
a,f
Height (cm) 116.8 (116.7;117.0) 116.4 (115.4;117.4) 119.3 (118.9;119.7) 118.1 (117.1;120.8)
a
WC (cm) 54.2 (54.0;54.4) 54.6 (53.4;55.8) 55.7 (55.2;56.2) 57.4 l (55.2;59.7)
2 a g
BMI (kg/m ) 16.4 (16.3;16.5) 16.8 (16.3;17.3) 17.0 (16.8;17.2) 17.8 (16.9;18.7)
i
SS (mm) 19.7 (19.5;20.0) 21.0 (19.5;22.6) 21.1 (20.5;21.8) 22.7 (19.7;25.7)
OW/OB (%)* 21.3 30.1 28.0 46.4
SBP (mmHg) 100.4 (100.1;100.7) 98.7 (97.0;100.4) 100.7 (100.0;101.4) 99.8 (96.4;103.1)
DBP (mmHg) 63.7 (63.5;63.9) 63.6 (62.3;65.0) 63.8 (63.3;64.4) 63.6 (61.1;66.1)
Data are mean (95 % confidence interval). Statistical analysis was adjusted by child age and practice of sports
WC waist circumference, BMI body mass index, SS sum of skinfolds, OW/OB overweight/obesity, SBP systolic blood pressure, DBP diastolic
blood pressure, AGA-ND adequate for gestational age offspring of mothers without diabetes, AGA-D adequate for gestational age offspring of
mothers with diabetes, Macro-ND macrosomic offspring of mothers without diabetes, Macro-D macrosomic offspring of mothers with diabetes
P for multiple comparisons: a \0.001 vs AGA-ND, b 0.024 vs AGA-D, c 0.041 vs AGA-ND, d 0.036 vs AGA-D, e 0.012 vs AGA-ND, f \0.001 vs
AGA-D; g 0.023 vs AGA-ND, h 0.004 vs AGA-ND, i 0.001 vs AGA-ND, l 0.032 vs AGA-ND
*
P for linear trend: \0.001

(AGA-D, n = 212); (3) Macro of mothers without diabetes
(Macro-ND, n = 1,278); (4) Macro of mothers with dia-
betes (Macro-D, n = 62).
Differences in continuous variables between groups
were tested using analysis of variance (ANOVA) and
analysis of co-variance (ANCOVA), with Bonferroni’s
correction for multiple comparisons, separately in boys and
girls. Frequencies were compared by the Chi-square test or
Chi-square for linear trend as appropriate.
The odds ratio of overweight/obesity across the four
study groups was estimated by logistic regression analysis,
separately in boys and girls. To evaluate the possible effect
of known determinants of body mass in children available
in the IDEFICS database, we modeled different regression
equations adding step-by-step the selected covariables.
Model 1 included as covariates child age (years) and
practice of sports (minutes/day); Model 2 included the
same variables in Model 1 plus parental overweight/obesity
(at least one parent with BMI [25 kg/m2 and education
(ISCED categories); Model 3 included the same covariates
of Model 2 plus country, maternal age at child birth (years),
weight gain in pregnancy (kg), smoking and alcohol con-
sumption during pregnancy (yes/no).
Results
Table 1 shows the characteristics of the population under
investigation. Both, macrosomic boys and girls, showed a
significantly higher ponderal index in comparison to the
other two groups.
Table 2 illustrates maternal risk factors across catego-
ries of birth weight and maternal diabetes. Mothers with
diabetes reported a lower alcohol consumption during
pregnancy. Mothers of macrosomic infants reported a more
frequent occurrence of caesarean section and gained more
weight during pregnancy. At the time of the screening,
Macro-D mothers had the highest BMI and were less
educated than those in the other groups.
Table 3 shows the anthropometric variables and the
prevalence of overweight/obesity at the time of the survey
by study groups and sex. In both sexes, macrosomic

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Table 4 Metabolic variables by study group and sex

AGA-ND AGA-D Macro-ND Macro-D

Boys
N 3,423 93 486 32
Glucose (mg/dl) 85.6 (85.2;85.9) 86.6 (84.6;88.6) 85.5 (84.6;86.3) 86.4 (83.0;89.8)
Insulin (lU/mL) 4.1 (4.0;4.2) 4.9 (4.1;5.7) 4.4 (4.1;4.8) 4.2 (2.8;5.6)
HOMA index (unit) 0.9 (0.9;0.9) 1.1 (0.9;1.2) 0.9 (0.8;1.0) 0.9 (0.6;1.2)
HbA 1c (%) 4.6 (4.6;4.7) 4.8 (4.7;5.0) 4.6 (4.6;4.7) 4.7 (4.5;4.9)
Total cholesterol (mg/dl) 156.3 (155.3;157.3) 153.1 (147.1;159.2) 156.2 (153.5;158.8) 149.9 (139.6;160.2)
HDL cholesterol (mg/dl) 52.6 (52.2;53.1) 51.6 (48.8;54.3) 51.4 (50.1;52.6) 52.6 (47.8;57.4)
LDL cholesterol (mg/dl) 94.5 (93.6;95.5) 93.0 (87.3;98.6) 95.6 (93.1;98.0) 89.2 (79.6;98.8)
Triglycerides (mg/dl) 60.6 (59.2;62.1) 56.1 (47.3;64.9) 60.9 (57.0;64.7) 51.7 (36.6;66.8)
Girls
N 3,376 86 477 24
Glucose (mg/dl) 83.2 (82.9;83.5) 83.2 (81.3;85.2) 83.3 (82.4;84.1) 84.2 (80.5;87.9)
Insulin (lU/mL) 4.7 (4.6;4.9) 4.4 (3.4;5.4) 4.8 (4.3;5.2) 5.6 (3.4;7.8)
HOMA index (unit) 1.0 (0.9;1.0) 0.9 (0.7;1.1) 1.0 (0.9;1.1) 1.2 (0.7;1.6)
HbA 1c (%) 4.6 (4.6;4.6) 4.6 (4.5;4.8) 4.6 (4.5;4.6) 4.8a (4.5;5.0)
Total cholesterol (mg/dl) 160.6 (159.6;161.7) 157.9 (151.2;164.6) 162.8 (159.9;165.6) 164.6 (152.0;177.3)
HDL cholesterol (mg/dl) 51.2 (50.7;51.6) 52.0 (49.1;54.9) 50.6 (49.4;51.8) 52.5 (47.0;57.9)
LDL cholesterol (mg/dl) 100.1 (99.1;101.1) 96.4 (90.2;102.7) 102.6 (100.0;105.3) 102.7 (90.8;114.5)
Triglycerides (mg/dl) 61.9 (60.6;63.3) 57.8 (49.6;66.0) 63.9 (60.2;67.6) 56.4 (40.4;71.4)
Data are mean (95 % confidence interval). Statistical analysis was adjusted by child age
HOMA Homeostatic model assessment, HbA1c Hemoglobin A 1c, HDL high density lipoprotein, LDL low density lipoprotein, AGA-ND
adequate for gestational age offspring of mothers without diabetes, AGA-D adequate for gestational age offspring of mothers with diabetes,
Macro-ND macrosomic offspring of mothers without diabetes, Macro-D macrosomic offspring of mothers with diabetes
a
P for multiple comparisons: 0.06 vs AGA-ND

children (either Macro-ND and Macro-D) showed higher Discussion

weight, height, waist circumference, BMI, and sum of
skinfolds than AGA groups, after controlling for age and
practice of sport. The prevalence of overweight/obesity
linearly increased from the AGA-ND to the Macro-D
group.
No differences were found across groups in the blood
pressure levels (Table 3), lipid profile, glucose and insulin
plasma levels and HOMA index (Table 4). A trend toward
higher levels of HbA1c was observed in Macro-D girls as
compared to AGA-ND girls (P = 0.06) (Table 4).
The relative impact of macrosomia and maternal diabetes
on childhood obesity was evaluated by logistic regression
analyses, stratified by sex, having AGA-ND as reference
group (Table 5). The unadjusted analysis showed that the risk
of obesity was significantly higher in Macro-ND boys
[OR = 1.4, 95 % CI: 1.2;1.8] and girls [OR = 1.4, 95 % CI:
1.2;1.7] and Macro-D girls [OR = 3.2, 95 % CI: 1.5;6.7].
Similar results were found in the fully adjusted model, con-
firming that the condition of Macro-ND was significantly
associated with an increased risk of overweight/obesity in
both boys and girls, while Macro-D presents a weaker but still
significant association with overweight/obesity only in girls.
Increasing evidence supports the hypothesis that fetal devel-
opment is influenced by maternal and fetal factors that
determine the intrauterine environment; the adaptation of the
fetus to this environment results in fetal ‘‘programming’’ [25].
Several epidemiological studies suggested prenatal pro-
gramming of childhood overweight and obesity [26], gesta-
tional weight gain [27] and maternal diabetes [28] being
among the involved factors. Excessive gestational weight gain
may induce during childhood (and later during adulthood) a
persisting susceptibility to obesogenic environment [27].
Hyperglycemia during pregnancy determines an exces-
sive fat deposition in the fetus [28] that might continue
later in life. Birth weight may be considered a proxy of in
utero exposure, such as to excessive maternal weight gain
or to altered maternal glucose metabolism. The prenatal
period may therefore be a critical window for intervention
aimed to reduce adverse fetal programming and in turn its
consequences, like childhood obesity and associated met-
abolic and cardiovascular disorders [29].
Our findings show that macrosomia at birth is associated
with higher body mass and prevalence of overweight/

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Matern Child Health J (2013) 17:1373–1381 1379

Table 5 Odds ratio for overweight/obesity by study group

OR (95 % CI) P OR (95 % CI) P
Boys Girls

Unadjusted
AGA-ND 1 – – 1 – –
AGA-D 1.2 (0.7;1.9) 0.46 1.6 (1.0;2.4) 0.03
Macro-ND 1.4 (1.2;1.8) 0.0001 1.4 (1.2;1.7) 0.0002
Macro-D 1.8 (0.9;3.9) 0.10 3.2 (1.5;6.7) 0.002
MODEL 1a
AGA-ND 1 – – 1 – –
AGA-D 1.2 (0.7;1.9) 0.49 1.6 (1.0;2.5) 0.04
Macro-ND 1.5 (1.2;1.9) \0.0001 1.4 (1.2;1.8) 0.0002
Macro-D 1.6 (0.7;3.6) 0.22 3.1 (1.5;6.7) 0.003
MODEL 2b
AGA-ND 1 – – 1 – –
AGA-D 1.1 (0.7;1.9) 0.62 1.4 (0.8;2.2) 0.21
Macro-ND 1.5 (1.2;1.9) 0.0002 1.5 (1.2;1.8) 0.0002
Macro-D 1.4 (0.6;3.1) 0.41 2.4 (1.0;5.5) 0.04
c
MODEL 3
AGA-ND 1 – – 1 – –
AGA-D 1.4 (0.8;2.5) 0.18 1.4 (0.8;2.3) 0.19
Macro-ND 1.7 (1.3;2.2) \0.0001 1.6 (1.3;2.0) \0.0001
Macro-D 1.8 (0.7;4.3) 0.21 2.6 (1.1;6.4) 0.04
Data are odds ratio (OR) (95 % confidence interval)
Overweight/obesity defined according to international obesity taskforce age- and sex-specific cut-off
a
Adjusted by age and practice of sports
b
Same factors of model 1 plus additional adjustment by parental overweight and education
c
Same factors of model 2 plus additional adjustment by country, maternal age at child birth, weight gain, smoking and alcohol consumption in
pregnancy
AGA-ND adequate for gestational age offspring of mothers without diabetes, AGA-D adequate for gestational age offspring of mothers with
diabetes, Macro-ND macrosomic offspring of mothers without diabetes, Macro-D macrosomic offspring of mothers with diabetes

obesity at school age in both boys and girls, supporting the
previously identified association between neonatal macro-
somia and later development of overweight [30].
We tried to disentangle the possible specific effect of
gestational/maternal diabetes in the relationship between
fetal macrosomia and higher body mass during childhood.
Our data suggest a possible sex-difference in the associa-
tion, Macro-D girls showing the highest risk of overweight/
obesity during childhood, the risk being present but not
statistically significant in Macro-D boys. Although this
finding should be cautiously interpreted due to the small
number of children in the Macro-D groups, the higher
degree of insulin resistance observed in girls during
childhood by other authors [31] may offer a mechanistic
explanation for the extremely high prevalence of over-
weight/obesity in macrosomic girls born to diabetic
mothers (either preexisting or gestational). In our study we
did not observe differences in insulin resistance measures
between the different groups, probably due to the fact that
metabolic derangements may occur later during growth
[32, 33]. In our sample, girls from Macro-D group showed
a trend to higher levels of HbA1c, although it did not reach
statistical significance due to the small number of Macro-D
girls having this parameter measured (n = 24).
Other studies have explored the relation between
maternal/gestational diabetes and body mass in children.
Plagemann et al. [34] observed that infants of mothers
with gestational diabetes were predisposed to develop
overweight and obesity during childhood. Pettitt et al. [35]
suggested that gestational diabetes was the most important
single risk factor for childhood obesity, independent of
child birth weight in Pima Indians. On the other hand,
childhood obesity is the result of the concomitant effect of
a number of cofactors, including those associated to the
pregnancy (age at delivery, gestational weight gain,
smoking and alcohol consumption), to the family (parental

123
1380
overweight and education) and to the child lifestyle (e.g.
physical activity). In our study fetal macrosomia remained
a strong predictor of childhood obesity after adjustment for
many of these confounders, independently from maternal
diabetes.
Consisting evidence suggests that prenatal programming
may influence the development of metabolic syndrome
phenotypes in adult life [36]. In our study we evaluated the
effect of neonatal macrosomia and maternal gestational
diabetes on the cardio-metabolic risk profile of children.
Our analysis did not show significant differences in blood
pressure values and metabolic parameters between the four
study groups. The lack of a significant difference could be
due to the young age of the children, since blood pressure
increase and metabolic alterations might occur more likely
later with age. In fact, the International Diabetes Federation
and American Heart Association have both proposed a
definition of metabolic syndrome in children and adoles-
cents [32, 33]. In both guidelines, the cut-offs for metabolic
and blood pressure variables were defined only for children
above 10 years of age, due to the high variability of these
variables below this age. It is thus possible that the effect of
macrosomia and gestational diabetes on biochemical
parameters would be more evident during adolescence
rather than childhood. Long-term prospective studies, as
the ongoing follow-up of the IDEFICS cohort, are needed
to answer this question.
Despite the many strengths of the present study, there
are some limitations as well. First, we did not assess the
pre-pregnancy weight of the mother, which is a factor
influencing not only the gestational weight gain but also the
birth weight [37]. Unfortunately, this question was not
included in the parental questionnaire that we administered
to the mothers. In fact, the present paper reports the results
of a secondary analysis of the database of the IDEFICS
project, which remains the largest pan-European cohort of
children available at the moment. In the planned follow-up
of this cohort, which will begin in 2013, we will try to
collect more information on pre-natal factors in order to
further develop this issue. Second, data related to preg-
nancy and delivery of the index child were self-reported by
the mothers on average after 6 years. This happens in all
the studies of the association of pre- and post-natal factors
with conditions developing later in life. However, in the
IDEFICS study, this information was corroborated for a
large proportion of the children, by the availability of the
official maternity records that the mothers were asked to
present at the time of the visit.
In conclusion, the condition of macrosomia is related to
the risk of childhood overweight. In addition to the pro-
motion of a healthy lifestyle and to the screening for ges-
tational diabetes, a careful monitoring of maternal weight
and gestational weight gain, both factors influencing the
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Matern Child Health J (2013) 17:1373–1381
uterine microenvironment and fetal growth, might have
long-term benefits for the early prevention of obesity.
Acknowledgments This study was conducted as part of the IDE-
FICS study (http://www.idefics.eu). We gratefully acknowledge the
financial support of the European Community within the Sixth RTD
Framework Programme Contract no. 016181 (FOOD) and the grant
support from EU for the IDEFICS study. We are grateful for the
support provided by school boards, headmasters and communities.
We thank the IDEFICS children and their parents for participating in
this extensive examination. The information in this document reflects
the authors’ view and is provided as is.
Conflict of interest The authors declare that they have no conflict
of interest.
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