Catch-up growth in girls born small for gestational age

precedes childhood progression to high adiposity

Lourdes Ib
a~nez, Ph.D.,a Abel Lopez-Bermejo, Ph.D.,b Marta Diaz, Ph.D.,a and Francis de Zegher, Ph.D.c
a
Endocrinology, Hospital Sant Joan de D
eu, University of Barcelona, and CIBER de Diabetes y Enfermedades Metab
olicas
Asociadas (CIBERDEM), Barcelona, Spain; b Pediatric Endocrinology, Dr. Josep Trueta Hospital and Girona Institute for
Biomedical Research, Girona, Spain; and c Department of Woman and Child, University of Leuven, Leuven, Belgium

Objective: To study across childhood the features of small for gestational age (SGA) girls with spontaneous catch-
up growth.
Design: Longitudinal study (age 2–8 years).
Setting: University hospital.
Patient(s): Post-catch-up SGA girls (n ¼ 18) versus healthy control girls born appropriate for gestational age
(AGA; n ¼ 13).
Intervention(s): None.
Main Outcome Measure(s): Height, weight, fasting glucose, insulin, IGF-I, high-molecular-weight (HMW)
adiponectin, LDL and HDL cholesterol, triglycerides, body composition by absorptiometry (2–8 years); visceral
fat by magnetic resonance imaging (6–8 years); bone age (by automated reading), sex hormone–binding
globulin, DHEAS, and leptin (8 years).
Result(s): At age 2 years, AGA and SGA girls were comparable for all study markers. Between 2 and 8 years, girls
were prepubertal; AGA and SGA girls gained height, lean mass, and bone mineral content similarly; other out-
comes diverged so that, at age 8, SGA girls had markedly higher levels of circulating insulin, IGF-I, DHEAS,
LDL cholesterol, and leptin; lower HMW adiponectin and SHBG levels; more total and visceral fat (without
being obese); and an older bone age.
Conclusion(s): After completing catch-up growth and before starting puberty, SGA girls develop an ensemble that
includes not only central adiposity, hyperinsulinemia, and hypoadiponectinemia but also hyperleptinemia,
dyslipidemia, lower SHBG and higher DHEAS levels, and faster bone maturation. (Fertil Steril
2011;96:
220–3. 2011 by American Society for Reproductive Medicine.)
Key Words: Fetal growth, adiposity, bone maturation, abdominal fat, visceral fat, body composition, insulin, IGF-I,
high-molecular-weight adiponectin, leptin, DHEAS, SHBG, LDL cholesterol, HDL cholesterol, polycystic ovary
syndrome, PCOS

Recent data indicate that enlarged adipocytes, hyperinsulinemia, elsewhere (6). In brief, inclusion criteria were [1] birth at Hospital Sant
and hypoadiponectinemia are key pathogenic features of polycystic Joan de D
eu, Barcelona, after a term pregnancy (37–42 weeks); [2] birth
ovary syndrome (PCOS) (1–4). Girls born small for gestational age weight Z-score for gestational age either strictly AGA (between 1 and
(SGA) have a reduced number of subcutaneous adipocytes (5) and þ1) or SGA (below 2). The main exclusion criteria were gestational diabe-
tes; evidence for syndromatic, chromosomal, or infectious etiology of low
are thus at risk for these features, even in the absence of obesity.
birth weight; and urogenital tract anomalies or systemic disease in the girls.
We performed a longitudinal, observational study (age 2–8 years) None of the girls received a potentially confounding medication such as
comparing SGA girls with spontaneous catch-up growth to healthy metformin.
control girls born appropriate for gestational age (AGA). Prelimi- In the present report, we compare the courses (2–8 years) of AGA girls
nary reports on this cohort disclosed the early development of insu- (n ¼ 13) to those of SGA girls who normalized their height through sponta-
lin resistance and body adiposity (age 2, 3, and 4 years) (6) and the neous catch-up growth (n ¼ 18 of the 22 originally enrolled SGA girls). The
appearance of visceral adiposity and hypoadiponectinemia (age 2, present analysis was restricted to girls because the endocrine-metabolic
4, and 6 years) (7, 8). profile and the body composition of SGA children become gender-specific
at age 6 years (9, 10) and because the number of enrolled boys was too
PATIENTS AND METHODS low for meaningful AGA versus SGA comparisons. The additional
criterion of catch-up growth in height was prompted by the recent insight
The study population was recruited between 2000 (at birth) and 2003 (at age
that SGA children with a persistently short stature have an endocrine-
2 years). Study inclusion and exclusion criteria have been described
metabolic profile and body composition differing from those in SGA children
with spontaneous catch-up growth (11).
Received November 27, 2010; revised February 21, 2011; accepted
Consecutive study protocols were approved by the Institutional Review
March 30, 2011; published online May 5, 2011.
L.I. and M.D. are Clinical Investigators of CIBERDEM CB07/08/0044 (Insti- Board, Barcelona University Hospital. Written informed consent was given
tuto de Salud Carlos III, Madrid, Spain). A.L.-B. is an Investigator of the by the parents.
Fund for Scientific Research I3 (Ministry of Science and Innovation, Bone age (Greulich-Pyle) was first assessed at age 8 and was calculated in
Spain). F.d.Z. is an Investigator of the Clinical Research Fund, Leuven an automated fashion (BoneXpert, Visiana) (12). Other methods have been
University Hospital, Belgium. described (6–11). In brief, birth weight and gestational age were obtained
Reprint requests: Lourdes Iba
n~ez, Ph.D., Hospital Sant Joan de Deu, from hospital records. Height and weight between 2 and 8 years were
University of Barcelona, Endocrinology, Passeig de Sant Joan de Deu, measured by a single investigator (LI), and body mass index was derived.
2, Esplugues, Barcelona 08950, Spain (E-mail: [email protected]). Body composition was assessed by absorptiometry (Lunar Prodigy and

220 Fertility and Sterility Vol. 96, No. 1, July 2011 0015-0282/$36.00
Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.03.107
 TABLE 1
Longitudinal courses (age 2-8 years) in girls born AGA or SGA.

AGA (n [ 13) SGA (n [ 18)

2y 8y D 2–8 y 2y 8y D 2–8 y

Bone age, y — 7.5  0.2 — — 8.8  0.3a —

Height, cm 88  2 125  1 37  1 87  2 128  1 41  2
Weight, kg 12.5  0.5 25.4  0.8 12.9  0.6 12.0  0.7 30.0  1.4a 18.0  1.2b
BMI, kg/m2 16.3  0.3 16.1  0.4 0.2  0.5 15.9  0.4 18.3  0.8b 2.4  0.8
BMI Z-score 0.2  0.2 0.5  0.2 0.3  0.3 0.5  0.3 0.5  0.4b 1.0  0.4
Glucose, mg/dL 82  3 84  1 23 78  1 89  2 11  2a
Insulin, mU/L 3.6  0.5 3.5  0.5 0.1  0.7 2.7  0.3 7.7  0.7c 5.0  0.7c
HOMA-IR 0.7  0.1 0.7  0.1 0.0  0.2 0.5  0.1 1.7  0.2c 1.2  0.2c
IGF-I, mg/L 84  5 173  5 89  8 74  6 245  16c 171  15a
HMW adiponectin, mg/L 13.9  1.7 20.5  0.9 6.6  1.9 15.1  1.4 10.9  1.6c 4.2  1.5c
LDL cholesterol, mg/dL — 81  3 — — 106  4c —
HDL cholesterol, mg/dL — 57  1 — — 52  2b —
LDL-to-HDL ratio — 1.4  0.1 — — 2.1  0.1c —
Triglycerides, mg/dL — 54  4 — — 65  5b —
Leptin, ng/mL — 1.4  0.2 — — 4.8  0.8a —
SHBG, mg/dL — 2.9  0.2 — — 1.7  0.1c —
DHEAS, mg/dL — 37  3 — — 57  5a —
Bone mineral content, kg 0.37  0.04 0.86  0.04 0.49  0.03 0.35  0.03 0.87  0.05 0.53  0.03
Lean mass, kg 9.7  0.3 18.7  0.4 9.0  0.5 9.4  0.4 18.2  0.7 8.8  0.5
Fat mass, kg 2.4  0.2 5.7  0.4 3.3  0.3 2.3  0.3 9.7  0.9c 7.4  0.8a
Fat mass, % 19.5  1.4 23.0  1.1 3.5  1.1 19.2  1.7 33.8  1.8c 14.6  1.7a
Abdominal fat mass, kg 0.6  0.1 1.7  0.1 1.1  0.1 0.6  0.1 3.2  0.2c 2.6  0.2c
Visceral fat, cm2 — 22  2 — — 47  4c —
Note: Birth weight was 3.3  0.1 kg in AGA girls, and 2.2  0.1 kg in post-catch-up SGA girls. Values are mean  SEM.
a
P%.01 for AGA versus SGA differences either at 8 years or in changes (D) between 2 and 8 years.
b
P%.05 for AGA versus SGA differences either at 8 years or in changes (D) between 2 and 8 years.
c
P%.0001 for AGA versus SGA differences either at 8 years or in changes (D) between 2 and 8 years.

~ez. SGA girls: from low to high adiposity. Fertil Steril 2011.
Ib
an

Lunar software v3.4/3.5; Lunar Corp.); the instrument underwent daily SGA girls between ages 2 and 8 years (including ages 4 and 6 years
quality control and weekly calibration. Visceral fat in the abdominal in Fig. 1) and cross-sectional results at age 8 (Fig. 2).
region was assessed at ages 6 and 8 years by magnetic resonance imaging At age 2 years, AGA and SGA girls were comparable for all study
(MRI) using a multiple-slice MRI 1.5 Tesla scan (Signa LX Echo Speed markers. Between 2 and 8 years, all girls remained prepubertal.
Plus Excite, General Electric). Blood samples were obtained in the fasting
AGA and SGA girls gained height, lean mass, and bone mineral con-
state for measurement of glycemia (by glucose oxidase method) and, after
centrifugation and freezing (80 C), for assaying of serum insulin and
tent similarly; other outcomes diverged between subgroups so that,
IGF-I (both by immunochemiluminiscence; Immulite 2000, Diagnostic at age 8, SGA girls had markedly higher levels of circulating insulin,
Products), sex hormone–binding globulin (SHBG), DHEAS, leptin (by ra- IGF-I, DHEAS, LDL cholesterol, and leptin; lower HMW adiponec-
dioimmunoassay; Linco Research), high-molecular-weight (HMW) adipo- tin and SHBG levels; more total and visceral fat; and an older bone
nectin (by ELISA; Linco Research), HDL and LDL cholesterol, and age (all P%.001).
triglycerides. Insulin resistance was estimated from fasting insulin and glu-
cose levels using the homeostasis model assessment (HOMA-IR); HOMA-
IR is calculated as the product of fasting insulin (mU/L) and plasma glucose DISCUSSION
(mmol/L) divided by 22.5. Circulating T was not studied. Measurements in
samples from AGA and SGA girls were performed concomitantly at each
After completing catch-up growth and before starting puberty, SGA
age. girls were found to develop an ensemble consisting of total and vis-
Statistical analyses were performed with SPSS version 12.0 (SPSS Inc.). ceral adiposity (without obesity), hyperinsulinemia, hypoadiponec-
AGA versus SGA comparisons at age 8 years were made by two-sided tinemia, hyperleptinemia, dyslipidemia, lower SHBG and higher
t-test, after log transformation when appropriate. AGA versus SGA differ- DHEAS levels, and a faster bone maturation.
ences in rate of change between 2 and 8 years were assessed by repeated- The mechanisms underpinning the development of this ensemble
measures general linear model. Statistical significance was set at P<.05. are likely to be multiple. Supranormal enlargement of subcutaneous
adipocytes may be a prime mechanism for at least two reasons. First,
studies in monozygotic girls discordant for prenatal weight gain dis-
RESULTS closed in 1981 that prenatal growth restraint is followed by a reduced
None of the 31 enrolled girls dropped out of the study (100% study number of subcutaneous adipocytes in childhood and adolescence
completion over 6 years), and none developed precocious pubarche (5). More recently, SGA girls were shown to underexpand their ad-
or precocious puberty. Table 1 shows longitudinal data in AGA and ipose tissue not only before birth (13, 14) but also during the

Fertility and Sterility 221

 FIGURE 1
Longitudinal courses between 2-8 y in girls born appropriate-for-gestational age (AGA; n¼13; white dots) or small-for-gestational-age (SGA;
n¼18; blue dots). While lean mass remains similar between AGA and SGA girls, fat mass diverges, particularly abdominal fat, apparently due
to visceral fat. While BMI remains within normal limits, fasting hyperinsulinemia develops along with hypoadiponectinemia and elevated levels
of circulating IGF-I. Plots represent mean and 95% CI. *P%0.01, yP%0.005, zP%0.0001 for AGA vs. SGA differences in rate of change.

25 12 4 60

Abdominal fat (Kg)

Visceral Fat (cm2)

Lean Mass (Kg)

20

Fat mass (Kg)

9 3
† 40
15 ‡
6 2
*
10
20
3 1
5

0 0 0 0

HMW Adiponectin (mg/L)

2 10 300 25

8 20
Insulin (mIU/L).
BMI Z-score

IGF-I (ng/mL)
†
200
6 ‡ 15 ‡
0
4 10
100
-1 2 5

-2 0 0 0
2 4 6 8 2 4 6 8 2 4 6 8 2 4 6 8
Age (yr) Age (yr) Age (yr) Age (yr)

Ib
a~nez. SGA girls: from low to high adiposity. Fertil Steril 2011.

FIGURE 2
Endocrine-metabolic markers and bone maturation in 8 year-old girls, born appropriate-for-gestational age (AGA; n¼13; white bars) or
small-for-gestational-age (SGA; n¼18; blue bars), who were enrolled at age 2 y and followed until age 8 y. Plots represent mean and 95% CI.
*P%0.05, yP%0.01, zP%0.001 for differences between AGA and post-catchup SGA girls.

‡ † ‡
90
DHEA-S (mcg/dL)

120 12
SHBG (nmol/L)

Bone Age (yr)

80 60 8

40 30 4

0 0 0
Triglycerides (mg/dL)

‡ 90 ‡
3 * 6
LDL-to-HDL ratio

Leptin (ng/mL)

2 60 4

1 30 2

0 0 0
AGA SGA AGA SGA AGA SGA
Ib
a~nez. SGA girls: from low to high adiposity. Fertil Steril 2011.

222 Ib
an~ez et al. SGA girls: from low to high adiposity Vol. 96, No. 1, July 2011
postnatal phase of catch-up growth, when they prioritize the recov- androgen excess. The strengths of our study include [1] the presence
ery of fat-free mass (15). Second, although they are hypoadipose, of healthy, parallel AGA controls over 6 years; [2] the time window
SGA infants have elevated leptin levels (15, 16) that may induce and the consistency of the longitudinal follow-up (age 2–8 years; no
leptin resistance in the hypothalamic regulation of appetite and AGA or SGA dropouts; no changes in methods); [3] the concomitant
thus generate an early tendency to fat excess (17–19). We and detailed assessments of endocrine-metabolic state (including
speculate that the combination of a reduced adipocyte number and leptin and HMW adiponectin) and body composition (absorptiome-
an augmented fat storage leads to adipocyte enlargement and to try and abdominal MRI).
complications of adipose tissue hyperexpansion (20). In conclusion, SGA girls tend to follow an altered developmental
The limitations of our study include [1] the absence of ethnic het- trajectory that may lead to an abnormal fat storage in puberty and
erogeneity in the study population, implying that the present find- adulthood and thus to PCOS (1). The recognition of such a trajectory
ings remain to be confirmed in populations with other genetic is becoming clinically relevant, as evidence is emerging that early
backgrounds; [2] the absence of epigenetic substudies that may metformin intervention can slow down the pubertal maturation to
have pointed to molecular mechanisms governing the phenotypic di- menarche, can reduce the pubertal and postmenarcheal gain of total,
vergences between AGA and post-catch-up SGA girls; [3] the ab- visceral, and hepatic fat, and can thus presumably delay the progres-
sence of T measurements that may have pointed to prepubertal sion to PCOS (21–25).

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