Nutrition in infancy and long-term risk of obesity: evidence from 2
randomized controlled trials1–3
Atul Singhal, Kathy Kennedy, Julie Lanigan, Mary Fewtrell, Tim J Cole, Terence Stephenson, Alun Elias-Jones,
Lawrence T Weaver, Samuel Ibhanesebhor, Peter D MacDonald, Jacques Bindels, and Alan Lucas
ABSTRACT
Background: Growth acceleration as a consequence of relative
overnutrition in infancy has been suggested to increase the risk of
later obesity. However, few studies have investigated this associa-
tion by using an experimental study design.
Objective: We investigated the effect of early growth promotion on later
body composition in 2 studies of infants born small for gestational age
(weight ,10th percentile in study 1 and ,20th percentile in study 2).
Design: We reviewed a subset of children (n = 153 of 299 in study 1
and 90 of 246 in study 2) randomly assigned at birth to receive either
a control formula or a nutrient-enriched formula (which contained
28–43% more protein and 6–12% more energy than the control for-
mula) at 5–8 y of age. Fat mass was measured by using bioelectric
impedance analysis in study 1 and deuterium dilution in study 2.
Results: Fat mass was lower in children assigned to receive the
control formula than in children assigned to receive the nutrient-
enriched formula in both trials [mean (95% CI) difference for fat
mass after adjustment for sex: study 1: 238% (267%, 210%), P =
0.009; study 2: 218% (236%, 20.3%), P = 0.04]. In nonrandom-
ized analyses, faster weight gain in infancy was associated with
greater fat mass in childhood.
Conclusions: In 2 prospective randomized trials, we showed that
a nutrient-enriched diet in infancy increased fat mass later in child-
hood. These experimental data support a causal link between faster
early weight gain and a later risk of obesity, have important impli-
cations for the management of infants born small for gestational
age, and suggest that the primary prevention of obesity could begin
in infancy. Am J Clin Nutr 2010;92:1133–44.
INTRODUCTION
Obesity is a global problem with major public-health con-
sequences (1, 2). Although ultimately the increase in obesity is
a consequence of secular changes in cultural, behavioral, and
lifestyle factors that promote a positive-energy balance, factors in
early life are suggested to influence or program the long-term
propensity to obesity (3, 4). Growth and nutrition in infancy and
childhood are thought to be particularly influential and are one
focus of much recent research (3–6).
Previously, on the basis of a long-term follow-up of subjects
from experimental intervention studies (7, 8) and prior obser-
vational data (9, 10), it was proposed that faster growth (or growth
acceleration defined as the upward percentile crossing for weight
or length) in infancy increased the risk of later obesity and
cardiovascular disease (CVD) (7, 8). More than 25 studies now
Am J Clin Nutr 2010;92:1133–44. Printed in USA. Ó 2010 American Society for Nutrition
support this hypothesis and suggest that faster weight gain (the
upward percentile crossing for weight) in infancy is associated
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with a greater risk of long-term obesity (9–21). This association
has been seen for obesity in adults and children, in high- and low-
income countries (11–13), and is consistent for cohorts over the
past 80 y (12). This association also suggests a large effect size of
the infant growth rate on later obesity risk. For instance, ’20% of
the risk of being overweight later in childhood can be attributed
to weight gain in the highest quintile in infancy (10, 16).
Theoretically, interventions aimed at modifying infant growth
could help prevent later obesity. Nevertheless, although the in-
tervention studies of Singhal and Lucas (7) and Singhal et al (8)
provided experimental evidence in humans for a causal link
between early growth and nutrition and later risk factors for CVD,
specific evidence for a causal link between early growth and
nutrition and later adiposity, which could influence public health
practice aimed at the primary prevention of obesity, has not been
established. Previous observational studies could be confounded
by genetic and environmental lifestyle factors that affect both
early growth and long-term adiposity. Most previous studies are
1
From the Medical Research Council Childhood Nutrition Research Cen-
tre (AS, KK, JL, MF, and AL), and the Medical Research Council Centre of
Epidemiology for Child Health (TJC), University College London, Institute
of Child Health, London, United Kingdom; the Academic Division of Child
Health, University Hospital, Nottingham, United Kingdom (TS); the Leices-
ter General Hospital, National Health Service Trust, Leicester, United King-
dom (AE-J); the University Department of Child Health, Royal Hospital for
Sick Children, Glasgow, United Kingdom (LTW); the Wishaw General Hos-
pital, Wishaw, United Kingdom (SI); the Southern General Hospital, Glas-
gow, United Kingdom; and the Danone Research Centre for Specialized
Nutrition, Wageningen/Amsterdam, Netherlands (JB).
2
Supported by the Medical Research Council (United Kingdom) with
a contribution toward the follow-up of children in study 2 from the Early
Nutrition Programming Long-Term Follow-Up of Efficacy and Safety Trials
and Integrated Epidemiological, Genetic, Animal, Consumer and Economic
Research as part of Sixth Framework Programme (FP6-FOOD-CT-2005-
007036). Farley’s Health Products, a division of HJ Heinz Company Ltd
(Uxbridge, United Kingdom), supplied trial formulas for study 1; and Nu-
tricia Ltd (Trowbridge, Wiltshire, United Kingdom) provided formulas for
study 2. Farley’s Health Products and Nutricia Ltd made charitable contri-
butions for the conduct of the original randomized trials.
3
Address correspondence to A Singhal, University College London, In-
stitute of Child Health, 30 Guilford Street, London WC1N 1EH, United
Kingdom. E-mail: a.singhal@ich.ucl.ac.uk.
Received January 31, 2010. Accepted for publication August 23, 2010.
First published online September 29, 2010; doi: 10.3945/ajcn.2010.29302.
1133
1134 SINGHAL ET AL

also based on anthropometric measures of adiposity [eg, body
mass index (BMI)] rather than more direct measures of lean mass
and fat mass (20), and few studies have assessed, prospectively,
the programming effects of infant linear growth rather than
weight gain on later body composition (11–13).
Therefore, in the current study, we investigated the role of
early growth and nutrition on later body composition by using an
experimental approach (8). We studied term infants born small
for gestational age (SGA) who participated in 2 randomized
controlled trials and in whom it was ethical at the time to assign
randomly to a nutrient-enriched formula that promoted growth
(which was thought to be beneficial) or to a standard formula (8,
22). Our study outcome was childhood adiposity, which was
suggested to be programmed by nutrition (3–7) and to track
strongly into adult life (23).
tween 1993 and 1995 (study 1) (22) and from 5 hospitals in the
Glasgow (United Kingdom) region between 2003 and 2005
(study 2). Infants who met the eligibility criteria (37 wk
gestation, free of congenital abnormalities, and with birth weight
,10th percentile for gestation and sex according to UK growth
charts (24) for study 1 and ,20th percentile for study 2) were
enrolled as soon as possible after birth (22). An arbitrary defi-
nition of birth weight ,20th percentile was chosen for study 2
because it was felt that this was the heaviest cutoff for infants in
whom it was still ethical to randomly assign them to a nutrient-
enriched formula. Gestational age was determined from the last
menstrual period or first trimester ultrasound scan. Infants of
mothers who had unequivocally decided to formula feed
were randomly assigned to receive a standard-term formula or
a nutrient-enriched formula (Table 1). The mean age at ran-
domization was 4 d in study 1 (n = 299) and 5 d in study 2 (n =

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SUBJECTS AND METHODS
Participants
Research nurses recruited infants from 5 hospitals in Cam-
bridge, Nottingham, and Leicester in the United Kingdom be-
246). The randomization schedule, which was generated by
random permuted blocks and prepared by a member of the team
who was not involved in data collection, was assigned by using
sealed, numbered, and opaque envelopes (22). Informed written
consent was obtained from parents.

TABLE 1
Composition of trial diets (per 100 mL)
Study 1 Study 2

Nutrient-enriched Nutrient-enriched
Term formula formula Term formula formula

Energy (kJ) 284 301 280 310

Energy (kcal) 68 72 66 74
Protein (g) 1.4 1.8 1.4 2.0
Casein 0.6 0.7 0.6 0.8
Whey 0.9 1.1 0.8 1.2
Carbohydrate (g) 7.0 7.2 7.5 7.5
Lactose 7.0 6.2 7.5 7.5
Maltodextrin 0.0 1.0 — —
Fat (g) 3.8 4.0 3.5 4.0
Minerals
Calcium (mg) 39 70 54 90
Phosphorus (mg) 27 35 27 45
Chloride (mg) 45 45 43 46
Sodium (mg) 17 22 19 24
Potassium (mg) 57 78 68 73
Zinc (mg) 0.3 0.6 0.5 0.7
Iron (mg) 0.6 0.6 0.5 1.1
Copper (lg) 42 57 40 60
Iodine (lg) 4.5 4.5 10 20
Manganese (lg) 3.4 5.0 0 9
Vitamins
Retinol (lg) 100 100 84 107
Thiamine (lg) 42 95 40 90
Riboflavin (lg) 55 100 120 120
Vitamin B-6 (lg) 35 80 40 80
Vitamin B-12 (lg) 0.1 0.2 0.2 0.2
Folate (lg) 3.4 25 10 20
Vitamin C (mg) 6.9 15 8 16
Vitamin D (lg) 1.0 1.3 1.4 1.6
Vitamin E (mg) 0.5 1.5 1.1 2.0
Vitamin K (lg) 2.7 6.0 5.0 5.9
Pantothenic acid (mg) 0.2 0.4 0.3 0.6
Taurine (mg) 5.0 5.1 5.3 4.9
Choline (mg) 4.8 5.1 9.7 33.0
 EARLY NUTRITION AND LATER BODY FATNESS
A reference group of breastfed infants (37 wk gestation and
birth weight ,10th percentile) was also recruited in study 1 (n =
175) (22). If a mother changed to formula feeding in 2 wk of
delivery, their infant was withdrawn from the study. The median
duration of exclusive breastfeeding was 12 wk (interquartile
range: 8–16 wk) and the total duration of breastfeeding was
29 wk (interquartile range: 16–52 wk).
Study design
Formulas were assigned until 9 mo of age in study 1 and until
6 mo of age in study 2. Anthropometric and demographic in-
formation was obtained as described (22). Social class was based
on the occupation of the parent who provided the main financial
support for the family. Both trials were double blind (ie, neither
1135
mothers nor researchers were aware of the participant’s formula
assignment).
Composition of formulas
The nutrient-enriched formulas were designed to promote
growth and were closer to preterm formula with predominantly
higher protein content than to standard-term formula. The
nutrient-enriched formula in study 1 (Farley’s PremCare;
Farley’s Health Products, a division of HJ Heinz Company Ltd,
Stockley Park, Uxbridge, United Kingdom) contained 28% more
protein and 6% more energy than standard (control) formula
(Farley’s Ostermilk; Farley’s Health Products) (22) (Table 1).
The nutrient-enriched formula in study 2 (specifically manu-
factured for the study by Nutricia Ltd, a part of the Danone

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FIGURE 1. Derivation of sample for study 1 (A) and study 2 (B). 1Withdrawn from the study by the mothers for reasons considered by research nurse to be
related to formula (eg, constipation, vomiting, or feeling unsettled or not satisfied with formula). 2Not traced or did not reply to initial letter. 3Withdrawn by
family doctor (reasons not given).
1136 SINGHAL ET AL

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FIGURE 1. (Continued ).

Group, Trowbridge, Wiltshire, United Kingdom) contained 43%
more protein and 12% more energy than standard formula (Cow
and Gate, Premium; Nutricia Ltd). Both nutrient-enriched for-
mulas contained more minerals, trace elements, and vitamins to
support the projected increases in growth (Table 1). All formulas
fulfilled the European Community directive for the composition
of formulas for term infants.
Follow-up
Participants in both studies were followed to test the hy-
pothesis that children randomly assigned to receive the standard
and lower-nutrient formula compared with children randomly
assigned to receive the nutrient-enriched formula would have
advantages for later health as suggested previously (7). All
children who were alive, traceable, and willing to participate were
reviewed in their homes between 1999 and 2002 (8) (study 1) or
in a research center between 2008 and 2009 (study 2). The
derivation of the sample followed in childhood for both studies is
given in Figure 1.
Heights and weights of participating children and their
mothers were measured by using a portable stadiometer accurate
to 1 mm (Holtain Instruments Ltd, Crymmych, United Kingdom)
and electronic scales accurate to 0.1 kg (Seca; CMS Weight
Equipment Ltd, London, United Kingdom) respectively. Triceps,
biceps, and subscapular and suprailiac skinfold thicknesses were
measured in duplicate with skinfold calipers (Holtain Instruments
Ltd, Crymmych, United Kingdom), and mean values were
 EARLY NUTRITION AND LATER BODY FATNESS
obtained. All measurements were made by trained observers who
were blind to the subject’s birth weight, gestation, and original
dietary assignment. Equipment was calibrated before each field
site visit, and the measuring techniques of observers were
monitored throughout.
Ethical considerations
Both studies were initiated in the 1990s to test the hypothesis
that a nutrient-enriched formula would promote catch-up growth
in infants born SGA and, as suggested by the fetal origins of
adult-disease hypothesis, would benefit long-term risk factors for
CVD (7). Promoting growth in infants born SGA by using nu-
trient-enriched formulas was ethical because this was accepted
pediatric clinical practice at the time and because of expected
benefits for long-term growth and cardiovascular health. Both
initial trials and subsequent follow-ups were approved by a na-
tional ethics committee and the ethics committee of each par-
ticipating center. However, after informing the ethics committee,
recruitment for study 2 was stopped prematurely when adverse
effects of nutrient-enriched formula became evident at follow-up
of children in study 1.
Body composition
Body composition was assessed in study 1 by using bioelectric
impedance analysis (BIA), which is a simple, validated technique
widely used to investigate the programming of body composition
(25, 26). Measurements were conducted by the research nurse in
the participant’s home by using a single-frequency (50 kHz)
bioelectric impedance analyzer (Model BIM4, impedance range
10–2000 ; SEAC, Queensland, Australia). Participants wore light
indoor clothing, were measured lying supine, and care was taken
to ensure that the limbs were not in skin contact with the body.
Electrodes were attached, in 2 pairs, to the right hand and foot of
each participant in a tetrapolar arrangement in accordance with
the manufacturer’s instructions. The raw impedance value was
determined in duplicate, and the mean value was obtained.
Fat and fat-free (lean) body mass were calculated from the raw
impedance value according to the equations of Houtkooper et al
(27) as validated previously in children. An estimate of adiposity
was also obtained by adjusting BMI for the reciprocal of im-
pedance (1/R) (28), which thereby allowed for the assessment of
differences in body composition between groups measured by
using BIA but without the use of population-specific equations
(28).
Deuterium dilution
Fat mass was determined in study 2 by measurement of total
body water by using 2H-labeled water dilution with a dose
equivalent to 0.05 g 2H20 (99.9%)/kg body weight. Urine sam-
ples were obtained before and 4 h after the dose was given,
stored at 280°C, and analyzed in duplicate by using the
equilibration method and isotope ratio-mass spectrometry (Iso-
Analytic Limited, Crewe, United Kingdom). For calculating
total body water, the 2H20 dilution space was assumed to be
overestimated by a factor of 1.044. A correction was made for
the dilution of the dose by water intake during the 4-h equili-
bration period. To estimate the fat-free mass, total body water
was divided by a sex- and age-specific hydration factor. Fat mass
1137
was estimated as body weight (in kg) minus fat-free mass (in
kg). In both studies, fat mass was also estimated from the sum
of 4 skinfold thicknesses and from fat mass calculated from
skinfold thicknesses by using the equations of Deurenberg et al
(29).
Statistical analyses
The sample size was chosen to detect a one-half SD difference
in outcome variables between randomized groups with 80%
power and P , 0.05 (which required ’128 subjects). A subset
of 153 of 299 formula-fed children from study 1 (8) and 90 of
246 children from study 2 agreed to participate at our initial
attempt at follow-up. Therefore, study 2 was powered to detect
a 0.6-SD difference in outcome between randomized groups
with 80% power and P , 0.05.
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We chose fat mass rather than BMI as our principal outcome
because, despite a lack of longitudinal data predicting adult
cardiovascular risk from childhood fat mass, faster weight gain in
infancy has been shown to have greater programming effects on
fat rather than lean mass (14, 19–21), and BMI is a poor estimator
of body fat in young children of normal weight.
To exclude an effect of a randomized diet on overall body size
rather than specifically fat mass, total body fat and fat-free mass
were divided by height squared as advocated by VanItallie et al
(30) to give a fat mass index (fat divided by height squared) and
fat-free mass index (fat-free mass divided by height squared),
which are terms that provide indexes of fat and lean masses
relative to height and expressed in the same units as BMI (28).
This analysis was checked by using log-log regression to de-
termine the correct power to fully adjust fat for height and then by
using regression analysis to adjust fat mass for height raised to the
correct power.
Comparisons between groups were made with Student’s t test
for continuous variables and chi-square analysis for categorical
variables. Initial analyses were on an intention-to-treat basis.
Subsequent analyses were adjusted for sex by using multiple
linear regression because a greater proportion of male children
were followed up in the nutrient-enriched group than in the
standard formula-fed group in study 1. In secondary analyses,
comparisons between randomized groups were adjusted for sex
together with other potential confounding factors (ie, birth-
weight z score, gestation, and manual compared with nonmanual
social class).
The distributions of fat mass, fat mass index, and the sum of
skinfold thickness in study 1 and the sum of skinfold thickness in
study 2 were right skewed and, therefore, were loge transformed
and then multiplied by 100 before analysis. The SD for 100 loge-
transformed data represented the CV of the original data (31),
whereas regression coefficients represented the percentage dif-
ference in fat mass indexes per unit change in the independent
variable (31).
Linear regression analyses were used to assess the influence of
infant growth rate on later body composition. Growth in infancy
was expressed as the change in SD score (z score) for length and
weight between randomization and the end of the dietary in-
tervention (9 mo for study 1 and 6 mo for study 2). z scores were
calculated by using percentiles for British infants (24). As-
sumptions of linearity were checked by using visual inspection
of scatter plots. All analyses were conducted with SPSS for
1138 SINGHAL ET AL
TABLE 2
Characteristics of children who were and were not followed up1
Study 1 Study 2

Standard formula vs Standard formula vs

Breastfed nutrient-enriched formula nutrient-enriched formula

Followed up Not followed up Followed up Not followed up Followed up Not followed up

(n = 97) (n = 78) (n = 153) (n = 146) (n = 90) (n = 156)

Growth2
At birth
Gestation (wk) 39.3 6 1.53 39.1 6 1.3 39.2 6 1.3 39.2 6 1.4 39.4 6 1.4 39.6 6 1.2
Birth weight (kg) 2.6 6 0.3 2.5 6 0.3 2.6 6 0.3 2.6 6 0.3 2.7 6 0.3 2.7 6 0.3
Birth-weight z score 21.7 6 0.5 21.7 6 0.5 21.7 6 0.5 21.7 6 0.5 21.5 6 0.5 21.4 6 0.5
At enrollment
Weight (kg) 2.5 6 0.3 2.5 6 0.3 2.5 6 0.3 2.5 6 0.3 2.7 6 0.4 2.8 6 0.4
Weight z score 21.8 6 0.5 21.8 6 0.5 21.8 6 0.6 21.8 6 0.6 21.8 6 0.6 21.7 6 0.5

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Length (cm) 47.9 6 1.8 47.2 6 1.84 47.2 6 1.9 47.1 6 2.2 48.0 6 2.5 48.3 6 2.9
Length z score 21.1 6 0.8 21.4 6 0.95 21.4 6 0.9 21.5 6 1.0 21.4 6 1.0 21.4 6 0.9
Growth from randomization to study end: change in
Weight z score 0.90 6 0.9 0.70 6 1.0 0.94 6 1.0 0.80 6 1.0 1.4 6 0.9 1.2 6 0.9
Length z score 0.45 6 1.0 0.40 6 0.9 0.82 6 1.0 0.79 6 1.1 0.9 6 1.1 1.1 6 1.1
Demographic
Male [% (n)]6 54 (52) 52 (41) 44 (68) 47 (68) 46 (41) 58 (90)
Maternal age (y)2 30.0 6 4.4 28.8 6 5.0 26.8 6 4.9 26.4 6 5.4 28.8 6 6.5 26.4 6 6.3
Social class: nonmanual [% (n)]6 64 (62) 68 (53) 20 (31) 24 (35) 23 (21) 12 (19)7
Maternal educational qualifications [% (n)]6,8
No qualifications 3 (3) 4 (3) 30 (46) 39 (57) 11 (10) 32 (50)5
University degree or higher 34 (33) 37 (29) 3 (5) 7 (10) 24 (22) 13 (20)5
1
There was a small loss of n (,10%) for some variables.
2
Comparisons of children who were and were not followed up were made by using Student’s t test.
3
Mean 6 SD (all such values).
4,5
Significant difference between children who were and were not followed up: 4P = 0.01; 5P = 0.02.
6
For dichotomous variables, comparisons of children who were and were not followed up were made by using the chi-square test.
7
Significant difference between children who were and were not followed up: P = 0.03.
8
Highest level of educational qualifications of mothers (only data for mothers with no qualifications or those with a university degree or higher are
shown).

Windows (version 12.0; SPSS Inc, Chicago, IL), and statistical
significance was taken as P , 0.05.
RESULTS
Comparison of groups randomly assigned to receive
different formulas
Children followed up were representative of the original study
population in both studies; demographic or anthropometric
factors in infancy did not differ between children who were or
were not followed up (Table 2) or between randomized formula-
fed groups in children lost to follow-up (data not shown). There
were no significant differences between randomized formula-fed
groups at randomization (baseline) (Table 3). Infants assigned to
receive nutrient-enriched formula were significantly heavier and
longer than were control infants at the end of the intervention in
study 1 but not in study 2 (Table 3). Relatively more boys were
followed up in the nutrient-enriched formula group than in the
standard-formula group in study 1 (Table 3), but there were
no other differences in anthropometric, socioeconomic, or de-
mographic factors between dietary groups at follow-up (Table 3)
or in maternal age, anthropometric measures, BMI, education,
and incidence of smoking during pregnancy (data not shown).
There were no adverse events reported in both studies, and the
commonest reason for withdrawing from formula feeding was
the mother changing formula for nonmedical reasons such as
moving on to a follow-on formula. Reasons for participants
withdrawing from the trial are given in Figure 1. The volume of
formula-milk intake (available in study 2) did not differ between
randomized formula-fed groups (Table 3).
At follow-up, children randomly assigned to receive a standard
formula in infancy had lower fat mass than those assigned to
receive a nutrient-enriched formula [mean (95% CI) difference:
study 1: 230% (258%, 21.7%) (P = 0.04); study 2: 21.2 kg
(22.4, 0.0 kg) (P = 0.05), or 18% lower]. The fat mass index in
infants randomly assigned to receive the standard- compared
with the nutrient-enriched formula was lower in study 1 but not
in study 2 (Table 4). There were no significant group differences
in the fat-free mass or fat-free mass index (Table 4). The sum of
skinfold thickness or fat mass derived from skinfold thickness
did not differ between randomized dietary groups (Table 4).
In secondary analyses, fat mass was lower in infants randomly
assigned to receive the standard rather than the nutrient-enriched
formula after adjustment for sex (Table 4) [for study 2, the mean
(95% CI) difference expressed as a percentage of fat mass in
the nutrient-enriched formula-fed group was 218% (236%,
20.3%) (P = 0.04)]. Similar findings were obtained after
 EARLY NUTRITION AND LATER BODY FATNESS 1139
TABLE 3
Anthropometric and demographic characteristics of children1
Study 1 Study 2

Randomly assigned formula-fed groups Randomly assigned formula-fed groups

Breastfed group Standard formula Nutrient-enriched Standard formula Nutrient-enriched

(n = 97) (n = 83) formula (n = 70) (n = 49) formula (n = 41)

At follow-up
Children followed [% (proportion)] 55 (97/175) 56 (83/147) 46 (70/152) 40 (49/124) 34 (41/122)
Male [% (n)] 54 (52) 33 (27) 59 (41)2 43 (21) 49 (20)
Age (y) 7.0 6 0.83 6.8 6 0.6 6.7 6 0.4 6.3 6 0.8 6.3 6 0.7
In infancy
Gestation (wk) 39.3 6 1.5 39.3 6 1.4 39.1 6 1.2 39.3 6 1.5 39.4 6 1.3
Birth weight (kg) 2.6 6 0.3 2.6 6 0.3 2.5 6 0.3 2.7 6 0.4 2.7 6 0.3
Birth-weight z score 21.7 6 0.5 21.7 6 0.5 21.8 6 0.6 21.5 6 0.6 21.5 6 0.5
Apgar score at 5 min 9.0 6 1.1 9.5 6 0.7 9.7 6 0.6 9.1 6 1.0 9.1 6 0.8

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At enrollment
Weight (kg) 2.5 6 0.3 2.5 6 0.3 2.5 6 0.3 2.7 6 0.4 2.7 6 0.3
Weight z score 21.8 6 0.5 21.8 6 0.5 21.8 6 0.6 21.9 6 0.6 21.7 6 0.5
Length (cm) 47.9 6 1.8 47.3 6 1.7 47.1 6 2.1 47.9 6 2.4 48.1 6 2.6
Length z score 21.1 6 0.8 21.4 6 0.8 21.5 6 1.0 21.4 6 1.0 21.3 6 1.0
Social class: nonmanual [% (n)] 64 (62) 22 (18) 19 (13) 26 (13) 20 (8)
End of intervention
Completed trial diet [% (n)] 93 (90) 88 (73) 91 (64) 82 (37/45) 79 (27/34)
Volume of milk intake (mL) — — — 809 6 257 719 6 189
Weight (kg) 8.3 6 0.8 8.2 6 1.0 8.5 6 0.94 7.3 6 0.9 7.5 6 0.6
Weight z score 20.9 6 0.9 20.9 6 1.1 20.7 6 1.0 20.5 6 1.0 20.3 6 0.8
Length (cm) 70.1 6 2.1 69.6 6 2.8 70.6 6 2.74 65.3 6 2.6 66.0 6 2.4
Length z score 20.6 6 0.8 20.7 6 1.1 20.5 6 1.1 20.5 6 1.1 20.2 6 1.0
Growth from random assignment to
study end
Change in weight z score 0.9 6 0.9 0.8 6 1.1 1.2 6 0.94 1.3 6 1.0 1.4 6 0.7
Change in length z score 0.4 6 0.9 0.7 6 1.0 0.9 6 1.1 0.9 6 1.2 1.0 6 0.9
At follow-up
Weight (kg) 22.7 6 4.0 22.0 6 4.2 22.7 6 6.1 21.0 6 3.1 22.5 6 4.8
Weight z score 20.2 6 1.2 20.3 6 1.1 20.1 6 1.2 20.2 6 1.1 0.1 6 1.4
Height (cm) 119.8 6 6.6 117.3 6 6.9 118.1 6 6.4 116.0 6 8.8 116.6 6 8.2
Height z score 20.2 6 1.1 20.5 6 1.1 20.3 6 1.1 20.3 6 1.8 20.2 6 1.7
1
Comparisons of randomly assigned formula-fed groups were made by using Student’s t test for continuous variables and the chi-square test for
categorical variables; all results were not significant except where indicated. There was a small loss of n (,15%) for some variables.
2
P = 0.001.
3
Mean 6 SD (all such values).
4
P = 0.03.

adjustment for sex together with potential confounding factors
(ie, birth-weight z score, gestation, and social class) (Table 4)
and after further adjustment for maternal BMI (available in 140
mothers in study 1 only) [mean (95% CI) difference in fat mass:
233% (263%, 22.1%), P = 0.04; mean (95% CI) difference in
the fat mass index = 232% (261%, 22.1%), P = 0.04]. Similar
results were obtained when fat mass was fully adjusted for
height by raising height to the correct power [study 1: mean
(95% CI) difference in fat mass between randomly assigned
groups after adjusting for sex, potential confounding factors, and
height5: 233% (260%, 26%), P = 0.02; study 2: mean (95%
CI) difference in fat mass between randomly assigned groups
after adjusting for sex, potential confounding factors, and
height2.7: 21.0 kg (22.1, 20.0 kg), P = 0.06]. There was little
evidence that the relation between formula type and later fat
mass or fat mass index differed according to sex (P . 0.2 for
formula · sex interaction).
Nonrandomized analyses in formula-fed infants
Effect of infant growth
We tested the hypothesis that the effect of early diet on later
adiposity was mediated by an effect of the diet on infant growth.
Faster growth in infancy (expressed as the change in z score for
weight between randomization and the end of the dietary in-
tervention at age 9 mo in study 1 and age 6 mo in study 2) was
associated with later fat mass assessed by all 3 measures of body
fat (ie, bioelectric impedance analysis, deuterium dilution, and
skinfold thickness) (Table 5). The change in z score for length
between randomization and the end of the dietary intervention at
age 9 was also associated with later adiposity in study 1 but not
study 2 (Table 5). These results represent a doubling (106%
increase) of fat mass in the children with the highest compared
with the lowest z score gain for length in the first 9 mo (range:
21.8 to 4.1 z scores) and an 83% increase in fat mass in children
 1140

TABLE 4
Comparison of body fatness at follow-up1
Randomly assigned formula-fed groups

Unadjusted Adjusted for sex2 Adjusted for confounding factors3

Breastfed Standard formula Nutrient-enriched formula P4 Values P Values P

5
Study 1
BMI (kg/m2) 16.0 6 1.86 16.0 6 1.8 16.3 6 2.9 0.5 20.4 (21.2, 0.4)7 0.3 20.6 (21.4, 0.2) 0.2
Bioelectric impedance analysis
Fat mass (kg) 1.6 (97)8 2.0 (88) 2.7 (74) 0.04 238.3% (266.9%, 29.8%) 0.009 238.7% (267.8%, 29.6%) 0.01
Fat mass index (kg/m2) 1.1 (94) 1.5 (85) 1.9 (71) 0.04 236.1% (263.5%, 28.8%) 0.01 236.2% (264.1%, 28.2%) 0.01
BMI adjusted for 1/R (kg/m2) 16.3 6 0.8 15.9 6 0.9 15.9 6 0.9 0.9 20.7 (21.4, 0.03) 0.06 20.8 (21.5, 0.002) 0.05
Fat-free mass (kg) 20.8 6 3.0 19.3 6 3.0 19.8 6 3.6 0.3 20.4 (21.5, 0.7) 0.5 20.5 (21.6, 0.6) 0.3
Fat-free mass index (kg/m2) 14.4 6 1.2 14.0 6 1.3 14.1 6 1.5 0.8 0.08 (20.4, 0.5) 0.7 0.003 (20.5, 0.5) 0.9
Skinfold thickness
Sum of skinfold thicknesses (mm) 26.3 (33) 29.4 (27) 28.1 (37) 0.4 21.0% (211.4%, 9.5%) 0.9 22.1% (212.6%, 8.4%) 0.7
Fat mass (kg)9 3.7 (34) 3.9 (29) 3.8 (41) 0.5 21.9% (213.0%, 9.2%) 0.7 23.5% (214.6%, 7.6%) 0.5
Fat mass index (kg/m2)9 2.6 (30) 2.9 (23) 2.7 (36) 0.3 20.2% (29.5%, 9.0%) 0.9 21.6% (210.9%, 7.8%) 0.7
Study 2
BMI (kg/m2)10 — 15.7 6 1.9 16.4 6 1.9 0.08 20.7 (21.5, 0.09) 0.08 20.6 (21.4, 0.2) 0.1
Deuterium dilution11
Fat mass (kg) — 5.4 6 1.6 6.6 6 3.3 0.05 21.2 (22.4, 20.02) 0.04 21.2 (22.5, 20.05) 0.04
SINGHAL ET AL

Fat mass index (kg/m2) — 4.0 6 1.2 4.6 6 2.0 0.1 20.6 (21.4, 0.1) 0.1 20.6 (21.4, 0.1) 0.09
Fat-free mass — 15.9 6 2.2 16.5 6 2.6 0.2 20.7 (21.8, 0.5) 0.2 20.7 (21.8, 0.5) 0.3
Fat-free mass index — 11.8 6 1.3 11.9 6 1.0 0.6 20.1 (20.7, 0.4) 0.7 20.08 (20.6, 0.5) 0.8
Skinfold thickness10
Sum of skinfold thicknesses (mm) — 31.0 (28) 33.8 (38) 0.2 29.1% (222.6%, 4.5%) 0.2 27.6% (221.2%, 6.0%) 0.3
Fat mass (kg)9 — 4.0 6 1.3 4.6 6 1.9 0.08 20.6 (21.2, 0.02) 0.06 20.5 (21.1, 0.1) 0.1
Fat mass index (kg/m2)9 — 3.0 6 0.7 3.3 6 1.0 0.1 20.3 (20.7, 0.03) 0.07 20.3 (20.6, 0.08) 0.1
1
There was a small loss of n (,15%) in some models. 1/R, reciprocal of impedance.
2
Comparisons of randomly assigned formula-fed groups were adjusted for sex by using multiple regression analysis.
3
Comparisons of randomly assigned formula-fed groups were adjusted for sex, manual or nonmanual social code, birth-weight z score, and gestation by using multiple regression analysis.
4
Comparisons of randomly assigned formula-fed groups were made by using Student’s t test.
5
n = 97 (breastfed), 83 (standard formula), and 70 (nutrient-enriched formula).
6
Mean 6 SD (all such values).
7
Mean difference; 95% CI in parentheses (all such values).
8
Geometric mean for loge-transformed data; % CV in parentheses (all such values).
9
Derived from skinfold thickness by using the equations of Deurenberg et al (29).
10
n = 49 (standard formula) and 41 (nutrient-enriched formula).
11
n = 36 (standard formula) and 34 (nutrient-enriched formula).

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 EARLY NUTRITION AND LATER BODY FATNESS 1141
TABLE 5
Regression of body fatness at follow-up on early weight and length gain1
Weight gain Length gain

Outcome variable Regression coefficient (95% CI) P Regression coefficient (95% CI) P

Study 1 (n = 153)
BMI (kg/m2) 0.33 (20.10, 0.77) 0.1 0.52 (0.1, 1.0) 0.02
Bioelectric impedance analysis
Fat mass2 17.3 (2.5, 32.0) 0.02 18.0 (2.4, 33.6) 0.02
Fat mass index2 10.4 (24.0, 24.7) 0.1 11.2 (23.9, 26.4) 0.1
BMI adjusted for 1/R 0.25 (20.17, 0.66) 0.2 0.45 (0.04, 0.86) 0.03
Fat-free mass (kg) 1.5 (1.0, 2.1) ,0.001 1.5 (0.9, 2.0) ,0.001
Fat-free mass index (kg/m2) 0.2 (20.06, 0.4) 0.1 0.06 (20.2, 0.3) 0.6
Skinfold thickness
Sum of skinfold thicknesses (%)2 6.3 (0.9, 11.7) 0.02 6.7 (1.2, 12.3) 0.02
Fat mass (%)2,3 12.2 (6.9, 17.5) ,0.0001 12.1 (6.5, 17.7) ,0.0001
Fat mass index (%)2,3 5.7 (1.1, 10.4) 0.02 5.9 (1.0, 10.8) 0.02

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Study 2
BMI (kg/m2) (n = 90) 0.67 (0.2, 1.2) 0.006 0.13 (20.3, 0.5) 0.5
Deuterium dilution (n = 70)
Fat mass (kg) 0.8 (0.04, 1.6) 0.04 0.4 (20.2, 1.1) 0.2
Fat mass index (kg/m2) 0.5 (0.03, 1.0) 0.04 0.3 (20.1, 0.8) 0.2
Fat-free mass (kg) 0.7 (0.05, 1.4) 0.04 0.5 (20.03, 1.0) 0.06
Fat-free mass index (kg/m2) 0.2 (20.09, 0.6) 0.1 0.0 (20.3, 0.3) 0.9
Skinfold thickness (n = 90)
Sum of skinfold thicknesses (%)2 9.6 (1.4, 17.8) 0.02 4.9 (22.1, 11.9) 0.2
Fat mass (kg)3 0.5 (0.1, 0.8) 0.01 0.3 (20.1, 0.7) 0.2
Fat mass index (kg/m2)3 0.3 (0.07, 0.5) 0.009 0.08 (20.1, 0.3) 0.4
1
All values are regression coefficients; 95% CIs in parentheses. There was a small loss of n (,15%) in some models. 1/R, reciprocal of impedance.
Changes in body composition per z score change in weight or length between random assignment and age 9 mo (study 1) or 6 mo (study 2) were adjusted for
sex, manual or nonmanual social code, birth-weight z score, and gestation by using multiple regression analysis.
2
Percentage change in adiposity per z score change in weight or length.
3
Derived from skinfold thickness by using the equations of Deurenberg et al (29).

with the highest compared with the lowest z score gain for
weight in the first 9 mo (range: 21.7 to 3.1 z scores).
Effect of size at birth
We assessed whether the effect of a nutrient-enriched formula
on later adiposity was independent of the degree of growth re-
tardation at birth. There was no evidence of an interaction be-
tween the birth-weight z score and randomly assigned
formula-fed group for measures of later body composition (eg,
P . 0.4 for birth-weight z score · formula-group interaction
for the fat mass index and fat-free mass index in both studies).
Furthermore, after adjustment for potential confounding factors,
the birth-weight z score was not associated with fat or the fat
mass index (P . 0.8 in both studies), but as expected (25), the
birth-weight z score was associated with fat-free mass and the
fat-free mass index [eg, in study 2, the regression coefficient
(95% CI) for the fat-free mass index = 0.7 kg/m2 (0.2, 1.2
kg/m2) change per z score increase in birth weight (P = 0.005);
other data not presented].
Breastfed reference group
Exploratory analyses in breastfed children also suggested that,
after adjusting for potential confounding factors, faster weight
gain (but not length gain) in infancy was associated with greater
fat mass [regression coefficient (95% CI): 30% (4%, 55%) in-
crease in fat mass per z score increase in weight (P = 0.02)] and
fat mass index (regression coefficient (95% CI): 25% (0%, 50%)
increase per z score increase in weight (P = 0.05)] (data not
shown for length gain).
DISCUSSION
In 2 intervention studies with prospective follow-up to age 5–
8 y, we showed that a nutrient-enriched formula that promoted
faster weight gain in infancy increased body fatness later in life.
This effect was evident with 2 dietary interventions, by using 2
different methods of assessing adiposity, and was independent of
sex, height in childhood, birth-weight z score, gestational age,
socioeconomic status, and maternal BMI. These experimental
data suggest that the association between infant growth and
nutrition and the long-term risk of obesity is independent of
genetic or environmental confounding factors that influence
early growth and later adiposity. Therefore, our findings sup-
ported, for the first time to our knowledge, the hypothesis that
there is at least a partially causal link between early nutrition
and long-term adiposity. These data have important implications
for the management of infants born SGA and suggest that the
primary prevention of obesity could begin in infancy with major
benefits for CVD risk (31) and public health.
The effects of infant nutrition and growth on later adiposity
were substantial. Fat mass in childhood was 22–38% greater in
infants who were randomly assigned to receive the nutrient-
enriched formula than in infants who were randomly assigned to
1142 SINGHAL ET AL
receive the standard formula and .15% greater per z score in-
crease in infant weight gain. The effect size was greater in study
1, possibly because of a longer exposure to faster infant weight
gain (9 mo compared with 6 mo in study 2), which was sug-
gested to have a greater effect on later obesity risk (13). The
effect size was comparable with nonrandomized studies for the
long-term effects of infant growth and nutrition, which suggests
that, in a contemporary Western environment, ’20% of the
population risk of overweight in childhood can be attributed to
infant nutrition (formula feeding rather than breastfeeding) (6)
or to being in the highest quintile for weight gain in infancy (10,
16).
Our findings are consistent with the extensive observational
evidence for an association between faster weight gain in infancy
and a later risk of obesity (9–21). This association is strong and
consistent, shows a dose-response effect, is biologically plausi-
ble, and is reproducible in animal models (13, 33). Nevertheless,
a causal link between infant growth and later adiposity has not
been established because, in observational studies, genetic fac-
tors, which are a major influence on postnatal growth rate (34,
35), could influence appetite and, hence, the risk of overfeeding
in infancy and later obesity (13). Although our study cannot
separate the effects of nutrition from growth (because it is not
possible to randomize to growth alone), our findings supported
the hypothesis that infant weight gain and nutrition program
obesity independent of genetic influences. Similar findings were
obtained for BMI in a recent randomized trial, although the study
did not have measures of fat mass and had follow-up only to age
2 y (1 y beyond the intervention period) (36).
Many studies in animals support the hypothesis that over-
feeding in infancy increases later adiposity (37–39). For instance,
male infant baboons fed a formula that provided 31% more
energy had greater mesenteric and omental fat depots (but not
total body weight) after puberty (37). This observation was
consistent with our findings of programming of adiposity rather
than body weight or BMI and with recent studies that showed
a stronger association between rapid weight gain in infancy and
later body fat rather than lean mass or BMI (15, 19–21). Because
body weight and BMI are both composite measures of fat and
lean tissue and are relatively inaccurate indexes of adiposity (25,
28), data from animals and humans support the hypothesis that
faster weight gain in infancy has stronger programming effects on
body fatness than on lean tissue or total body size. This selective
programming effect on adiposity is of particular public-health
interest because of the strong link between obesity and CVD (40).
Unlike most, but not all, previous research (41), we showed
that faster length gain and faster weight gain in infancy was
associated with later adiposity in study 1, which suggested that
growth, and not simply the accumulation of fat in infancy,
programmed body fatness. However, because the randomized
study addressed infant feeding and not growth, our study could
not determine whether it was faster growth or infant nutrition
(which influences early growth) that was the causal link between
the nutrient-enriched formula and later greater adiposity. Also,
because the nutrient-enriched formula was enriched in several
nutrients designed to promote growth, we cannot determine
which component (ie, proteins, calories, or micronutrients) was
influential for later adiposity. Nonetheless, the primary pro-
gramming role of growth, rather than a unique component of the
formula, is supported by the observation that faster weight gain
was associated with greater adiposity in childhood even in those
who were breastfed (14, 16, 41, 42). Similarly, faster weight gain
has been shown to program later obesity independent of protein
intake (41) and the method of infant feeding (42).
We recognize several potential limitations of our study. First,
to study children in their own homes, we used a field technique
(ie, BIA) to assess body composition. Nevertheless, BIA has been
widely used to study programming effects (25, 26) and correlates
closely with more sophisticated measures of body composition
such as the 4-component model (28). The experimental study
design, blinded data collection, and analysis of BIA data that does
not rely on population-specific equations, all supported the hy-
pothesis that differences in adiposity between dietary groups
were unlikely to be a consequence of the technique of mea-
surement. This hypothesis was further supported by the similar
findings in a second population that used deuterium dilution to
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estimate fat mass. We cannot explain the lack of effect of nu-
trition in both randomized studies on fat mass estimated by using
skinfold thickness rather than BIA or deuterium dilution. One
possibility is that skinfold thickness directly measures only
subcutaneous fat in the torso and arm, whereas both BIA and
deuterium dilution also incorporate leg fat, which was previously
shown to be affected by nutritional supplementation in infancy
(43). Another possibility is that differences in early growth rates
might have affected body geometry, to which BIA is sensitive,
although we have no evidence to support this hypothesis. Finally,
the influence of early growth and nutrition on later adiposity may
be weaker for subcutaneous fat compared with deeper fat depots.
The measurement of body resistivity by BIA may better reflect
intramyocellular lipid, which has a strong effect on CVD risk
(44). Nevertheless, similar findings from fat mass measured by
using all 3 techniques (ie, BIA, deuterium dilution, and skinfold
thickness) strongly supported the hypothesis that infant growth
influences later adiposity independent of the technique by which
fat is measured.
Second, a follow-up rate of only 51% of infants originally
randomly assigned in study 1, and 37% of infants in study 2, is
clearly a potential source of bias (45). However, this follow-up
rate was comparable with similar studies (45) and was unlikely to
introduce systematic bias because our sample was representative
of subjects recruited at birth, and subject characteristics of
children reviewed at 5–8 y did not differ between randomized
groups at birth or at follow-up. Moreover, there is no prior reason
why the epidemiologic association between faster infant weight
gain and later adiposity should differ between children reviewed
and children not followed up. Third, we studied infants born
SGA, and whether our findings apply to infants with birth weight
appropriate for gestational age is uncertain. However, there is
extensive epidemiologic evidence to support the applicability of
our data to such infants (9–21), whereas many studies suggest that
the programming of obesity by infant growth is independent of
size at birth (13). Finally, our study did not identify mechanisms
for the observed effects. Because the nutritional intervention was
from soon after birth to ages of 6–9 mo, we could not identify the
exact timing of rapid weight gain that programs later obesity. For
instance, faster weight gain as early as the first postnatal weeks
was suggested to affect later health (7, 33), possibly via the
programming of appetite (46). We also cannot exclude differ-
ences between randomized formula-fed groups in dietary intakes
or feeding behaviors in infancy and childhood that could
 EARLY NUTRITION AND LATER BODY FATNESS
influence later adiposity. Furthermore, we could not investigate
the effects of early growth on later regional fat distributions.
However, the effect of infant diet on total body fat, but not
subcutaneous fat as assessed by skinfold thickness, was con-
sistent with the hypothesis that programming effects were most
marked for deeper fat depots, as previously shown (37, 47, 48).
In conclusion, further experimental data are required to define
the risks and benefits of promoting growth in infants born SGA
(49), especially for outcomes other than adiposity such as neu-
rodevelopment. In a study by Morley et al (50), a nutrient-
enriched diet did not improve cognitive development in children
at 18 mo of age. However, our data suggest that optimizing the
pattern of infant growth could play a key role in helping to
combat the current obesity epidemic.
We thank Wendy Jenkins, Dee Beresford, Penny Lucas, and Emma Sutton
for technical assistance.
The authors’ responsibilities were as follows—AS: was the principal in-
vestigator and main author and had final responsibility for the decision to sub-
mit the manuscript for publication; TJC provided statistical expertise; JL and
KK: supervised data collection; and all authors: contributed to the study de-
sign and preparation of the final manuscript for submission, had full access to
the data, took responsibility for data integrity, and read and agreed to the man-
uscript as written. The study sponsors had no role in the study design, col-
lection, analysis, and interpretation of data, writing of the report, or
decision to submit the manuscript for publication. None of the authors de-
clared a conflict of interest.
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