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Endocrinology Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; Medical Research Council Epidemiology Unit (K.O.), Cambridge CB2 2QQ, United Kingdom; Department of Paediatrics (K.O., D.B.D.), University of Cambridge, Cambridge CB2 1TN, United Kingdom; and Department of Pediatrics (F.d.Z.), University of Leuven, B-3000 Leuven, Belgium
Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.
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Abstract |
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Setting, Design, and Patients: This was a longitudinal cohort study in low birth weight (SGA; birth weight < –2 SD; n = 29) and normal birth weight (AGA; n = 22) children from Barcelona.
Main Outcome Measures: Body composition, by dual-energy x-ray absorptiometry scan, and insulin sensitivity, assessed longitudinally at ages 2, 3, and 4 yr, were measured.
Results: Mean height, weight, and body mass index at ages 2, 3, and 4 yr were not different between SGA and AGA children. At age 2 yr, SGA children had similar body composition but were more insulin sensitive than AGA children and had lower serum IGF-I levels and lower neutrophil counts. Between ages 2 and 4 yr, despite similar gains in weight and body mass index, SGA children gained more abdominal fat and body adiposity and less lean mass than AGA children; by age 4 yr, SGA children had greater adiposity, insulin resistance, and higher neutrophil counts than AGA children (P = 0.01–0.0004). In SGA children, total and abdominal fat mass at 4 yr was more closely related to rate of weight gain between 0 and 2 yr (P = 0.002–0.0003) than between 2 and 4 yr (P = 0.04–0.1).
Conclusion: Consequent to catch-up weight gain between birth and 2 yr, SGA children showed a dramatic transition toward central adiposity and insulin resistance between ages 2 and 4 yr. Understanding the mechanisms underlying this predisposition to adverse future health could lead to specific preventive interventions during early childhood.
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Introduction |
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However, the exact timing of the rapid weight gain that contributes to these long-term risks continues to be debated. On the one hand, several contemporary birth cohort studies show that very early infant weight gains between birth and age 1–2 yr old (4), or even as early as birth to 1 wk of age (5), are positively associated with subsequent obesity risks. In support of these findings, insulin sensitivity is already reduced by the age of 1 yr in infants who were born small for gestational age (SGA) and who showed a rapid catch-up in infancy, especially in weight (6). This trend shows a steady progression up to age 3 yr, particularly in those SGA children with postnatal upward weight centile crossing (7), and is accompanied by a parallel increase in circulating IGF-I levels (8). Furthermore, in most SGA children, catch-up is largely completed by age 2 yr; by this age height and weight are similar to children born appropriate for gestational age (AGA) (9). On the other hand, other mainly historical studies of adults with cardiovascular disease and type 2 diabetes have reported that gain in weight and body mass index (BMI) during early childhood, but after infancy, is an important factor, both for body fat mass and the disease consequences (10). For example, in the Finnish birth cohort, rapid weight gains in weight and BMI between ages 2 and 11 yr predicted increased risk for cardiovascular disease (11).
Studies that try to distinguish between the effects of infant weight gain vs. postinfancy weight gain on body composition will valuably inform the nature and timing of future preventative strategies. We recently reported that both infancy and early childhood weights contributed independently to increased body fat mass at age 17 yr (12). However, to date, no study has reported longitudinal data on the development of total and central body fat mass in SGA children who show spontaneous postnatal catch-up weight gain and growth and on its relationship to measures of insulin sensitivity, circulating IGF-I levels, and markers of inflammation.
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Subjects and Methods |
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The study population consisted of 51 girls and boys who were born either AGA (n = 22) or SGA (n = 29). Most of these children (AGA, n = 17; SGA, n = 29) had been previously recruited for an observational study of FSH and inhibin B levels in early infancy (13) and were subsequently followed up longitudinally at the Barcelona Hospital from 2 to 4 yr. The additional AGA children (n = 5) were recruited for longitudinal study between 2 and 4 yr from patients attending the General Pediatric Clinic, Barcelona Hospital, for minor elective surgery (such as inguinal herniography or circumcision) or screening purposes (blood group determination or confirmation of normal nutritional status). All children were in good general health.
Inclusion criteria were birth after a term pregnancy (37–42 wk) and birth weight for gestational age either AGA (–1 to +1 SD) or SGA (<–2 SD).
Exclusion criteria were evidence for syndromatic, chromosomal, or infectious etiology of low birth weight; hypothyroidism; urogenital tract abnormalities; systemic disease; or acute illness.
Height, weight, BMI, body composition, fasting serum glucose and insulin, serum IGF-I levels, and leukocyte count were assessed in all subjects yearly from age 2 to 4 yr. Fasting insulin resistance was estimated from fasting insulin and glucose levels using the homeostasis model assessment (HOMA) (14).
The study protocol was approved by the Institutional Review Board of Barcelona Hospital. Informed consent was obtained from the parents before inclusion.
Auxology
Birth weight and gestational age data were obtained from hospital records and transformed into SD scores (SDS), as previously described (15).
At ages 2, 3, and 4 yr, weight was measured to the nearest 0.5 kg using a hospital balance beam scale; height was measured to the nearest 0.5 cm with a Harpenden stadiometer; the absolute values for both parameters were transformed into SDS according to British references (16), which are applicable to Catalan children (17). BMI was calculated as the ratio of weight (kilograms) to height squared (meters).
Body composition
Body composition was assessed by dual-energy x-ray absorptiometry, with a Lunar Prodigy coupled to Lunar software (version 3.4/3.5; Lunar Corp., Madison, WI) (18), appropriately adapted for measurements in babies and young children. Absolute (kilograms) whole-body fat and lean mass as well as fat content in the abdominal region, which was defined as the area between the dome of the diaphragm (cephalad limit) and the top of the great trochanter (caudal limit), were assessed (19). Total irradiation dose per assessment was 0.1 milli-Sievert (about one tenth of the usual radiation received with a regular x-ray of the thorax). Coefficients of variation (CVs) for scanning precision are 2.0 and 2.6% for fat and lean body mass (20), with an intraindividual CV for abdominal fat of 0.7%.
Fat mass, lean mass, and abdominal fat were assessed; body composition data were corrected for differences in height, as recommended by Wells and Cole (21).
Assays
A differential leukocyte count was determined within 2 h after blood sampling by an automatic cell counter (ABX Pentra 120; ABX Diagnostics, Montpellier, France), as described (22); the intraassay CV determined on five replicates of each leukocyte measurement was 1% or less.
Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin and IGF-I were measured by immunochemiluminescence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA). The lower detection limit for insulin was 2.0 µU/ml; all values below this limit were considered to be 1.9 µU/ml. The lower detection limit for IGF-I was 25 ng/ml; the intra- and interassay CVs for both insulin and IGF-I were less than 10%.
Statistics
Differences in rate of change in body size and composition from 2 to 4 yr between SGA and AGA groups were tested by analysis of covariance (general linear models) by coentering the interactive term between age and birth weight group.
Subsequently for significant outcomes, cross-sectional differences between SGA and AGA groups at each age point were tested using unpaired t tests. Univariate correlations were tested by Pearson’s method; multiple regression models were used to adjust body composition analyses for height, sex, and age and were also used to identify independent contributions of weight gain 0 to 2 yr and 2 to 4 yr to body composition at age 4 yr. We had sufficient power to detect a difference of at least 0.8 multiples of an SD between SGA and AGA children. Within SGA children we had 80% power at the 5% level to detect a correlation coefficient (r) of 0.46 or less. Skewed data were transformed to normal distributions by calculating the natural logarithms.
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Results |
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By definition, SGA children were lighter at birth than AGA children, but they gained weight faster between birth and 2 yr (median, IQ range, for SD change in weight SD in SGA vs. AGA: 1.25, 0.7, to 2.02 vs. –0.39, –1.18, to 0.04; P < 0.0001).
Mean height, weight, and BMI data did not differ significantly between AGA and SGA children at ages 2, 3, and 4 yr (Table 1
); the gains in height, weight, and BMI during 2–4 yr were also similar between the two groups (P = 0.4 to 0.7; data not shown).
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At baseline (age 2 yr), there were no differences in body composition between SGA and AGA children (abdominal fat mass, SGA: 0.61 ± 0.05 kg; AGA: 0.51 ± 0.05 kg; lean body mass, SGA: 9.14 ± 0.13 kg; AGA: 9.44 ± 0.15 kg). However, between ages 2 and 4 yr, the gains in abdominal fat and body adiposity were strikingly higher in SGA than AGA children; and the SGA children also showed lower gains in lean body mass [abdominal fat mass at age 4 yr, SGA: 1.17 ± 0.1 kg; AGA: 0.80 ± 0.04 kg; P = 0.0003; lean body mass at age 4 yr, SGA: 11.16 ± 0.33 kg; AGA: 12.36 ± 0.28 kg; P = 0.02 (Fig. 1)]. Therefore, by ages 3–4 yr, SGA children had greater total and abdominal fat and lower lean body mass than AGA children (Fig. 1).
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Insulin sensitivity, IGF-I levels, and leukocyte count
At baseline (age 2 yr), SGA children had lower fasting insulin levels and insulin resistance scores (HOMA) than AGA children (Table 2). SGA children also had lower levels of IGF-I and a lower neutrophil to lymphocyte ratio (Fig. 1
), reflecting a lower absolute neutrophil count and a higher lymphocyte count (Table 2).
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and Fig. 1). Associations with weight gain in SGA children
Among SGA children, as expected, rate of weight gain between 0 and 2 yr was inversely related to weight gain between 2 and 4 yr (r = –0.40, P = 0.03). By age 4 yr, total and abdominal body fat mass showed strong independent correlations with weight gain between 0 and 2 yr (P = 0.0005–0.0007), with much weaker effects seen for weight gain between 2 and 4 yr (P = 0.006–0.2; Table 3).
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Discussion |
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The main limitation of dual-energy x-ray absorptiometry assessment of body composition is the inability to distinguish sc from intraabdominal fat mass. Our analyses were therefore based on total body fat and the subsection of fat mass within the abdominal area of the scan. Furthermore, our sample size was not large, and it is possible that true differences in central fat and lean mass were already evident at the baseline assessment at age 2 yr. However, it is not easy to collect body composition data in this young age group, and the current study provides unique longitudinal data on body composition in SGA and AGA groups. The majority of both the SGA and AGA groups was female; however, there was no significant difference in the proportion of males in each group; sex differences in body size and composition were adjusted for, and similar trends in changes in body fat and lean mass were seen in both SGA boys and girls (data not shown).
The changes in body composition between 2 and 4 yr in these SGA children were accompanied by a shift from insulin sensitivity to insulin resistance and also by rises in neutrophil count and IGF-I levels. Other detailed studies in SGA subjects with spontaneous postnatal catch-up show that some infants have already developed insulin resistance by age 1 yr (6), and this progresses rapidly in many infants by age 3 yr (7). Accumulation of central and specifically visceral fat will lead to insulin resistance, possibly due to increased lipolysis and release of free fatty acids (23). Alternatively, the early development hyperinsulinemia resulting from a ß-cell compensatory response to muscle-specific insulin resistance could positively feed back to promote further peripheral and central fat deposition. In support of this concept, experimental studies in low-birth-weight children and adolescents with insulin resistance, show that insulin sensitization with metformin leads to a gradual reduction of total and central fat mass (24, 25). In those studies, metformin also increased lean body mass while reducing circulating IGF-I levels, possibly indicating increased IGF-I sensitivity (24, 25). The opposite changes that we have now observed in 2- to 4-yr-old SGA infants (i.e. decreasing lean body mass despite increasing IGF-I levels) might therefore indicate that they have a relative IGF-I resistance. Indeed, defects in insulin and/or IGF-I signaling that are specific to muscle tissue could explain why SGA infants show lesser gains in lean mass but rather divert nutrients toward fat accumulation (26). Such metabolic abnormalities may be more marked in those SGA infants who showed rapid catch-up between 0 and 2 yr (7), and this might explain the link between earlier weight gain and subsequent gains in adiposity.
Changes in leukocyte and specifically neutrophil counts have recently been observed to accompany insulin resistance and other markers of chronic inflammation (27, 28, 29). Girls with a history of low birth weight and precocious pubarche, a population characterized by a fast childhood growth and weight acceleration, already show a cluster of cardiovascular risk factors by age 8 yr, including insulin resistance, central adiposity, dyslipidemia, and proinflammatory changes, such as raised leukocyte counts and neutrophil to lymphocyte ratios (22, 28). Furthermore, in SGA children neutrophil decreased after insulin sensitization therapy with metformin and increased with GH therapy (22). Its relevance to endothelial function and long-term cardiovascular health is yet unknown. However, the absolute neutrophil count, or neutrophil to lymphocyte ratio could represent a future simple marker to monitor changes in insulin resistance and the associated chronic inflammatory process.
It has been suggested that interventions to limit excess postnatal weight gain could prevent the development of central obesity, insulin resistance, and the associated type 2 diabetes and cardiovascular disease risks linked to low birth weight. However, the timing of such intervention is debated. Several SGA infants in our study showed very large weight gains, from below –2 SD at birth (less than the centile) to above +2 SD (greater than the 98th centile) by age 2 yr, possibly demonstrating an overshoot of appetite-driven catch-up weight gain (30, 31). Fifty-five percent of SGA infants continued to gain in weight SDS between 2 and 4 yr; however, the risk of adiposity at age 4 yr was much more related to their earlier weight gain from birth to 2 yr. Infant weight gain appears to be a more important factor for obesity risk among more contemporary cohorts, compared with older cohorts that relied on historical growth records (4); these differences in findings could reflect the secular trends to increasing childhood overweight and obesity as young as 2–3 yr old (32), in contrast to older populations who often grew up during the peri- and postworld war years (11).
In conclusion, SGA children showed greater accumulation of total body and abdominal fat than AGA children between ages 2 and 4 yr, despite having already completed their catch-up growth and weight gains between birth and age 2 yr. This was accompanied by a shift from insulin sensitivity to insulin resistance. Our novel findings suggest there may be two separate opportunities for early intervention against the development of future disease risks in low-birth-weight subjects: first, general measures to prevent excessive rates of weight gain during infancy; second, understanding the mechanisms by which SGA infants who have caught up in weight are subsequently prone to develop more adipose tissue and insulin resistance leading to potential, more specific interventions during early childhood. However, such observational data do not prove causation. For example, more rapid weight gain between 0 and 2 yr could just be a proxy marker for other etiological mechanisms such as a greater degree of fetal growth restraint or some other propensity to future adiposity. Future intervention studies are needed before translating such observations into public health messages.
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Acknowledgments |
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Footnotes |
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First Published Online March 14, 2006
Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; CV, coefficient of variation; HOMA, homeostasis model assessment; SDS, SD score; SGA, small for gestational age.
Received December 20, 2005.
Accepted March 7, 2006.
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