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Original Studies |
INSERM U-457, Hôpital R. Debré (D.J., J.L., P.C., C.L.-M.), 75019 Paris; and Centre du Bilan de Santé de l’Enfant (M.D.T.), Paris, France
Address all correspondence and requests for reprints to: Delphine Jaquet, M.D., INSERM U-457, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France. E-mail: djacquet{at}infobiogen.fr
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Abstract |
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Introduction |
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The first 2 yr of life are critical for ponderal growth, with a 3- to 4-fold increase in body weight. A unique pattern of body mass index (BMI) is observed during the same period, with a dramatic increase over the first year followed by a slight decrease during the second year of life (12). Children born with intrauterine growth retardation (IUGR) demonstrate a postnatal catch-up for weight and height growth, especially during the first year of life. This catch-up results in a correction of weight and height deficit in about 90% of children born with IUGR (13).
The aim of our study was to describe the postnatal time course of serum leptin concentrations in children between birth and 2 yr of age, over this critical period of positive energy needs. We have also investigated how leptin is involved in the catch-up growth of children born with IUGR.
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Subjects and Methods |
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Neonates and children born with IUGR. Seventy children born with IUGR and previously recruited for a prospective survey of growth and growth factors during the first 2 yr of life were included in the present study (14, 15). IUGR was defined as birth weight below the third percentile for gestational age according to the French growth standard curves reported by Leroy (16). Malformations and/or chromosomal abnormalities or maternal short stature were not considered as exclusion criteria. Other causes for IUGR included pregnancy-induced hypertension, multiple pregnancies, smoking, and heavy alcohol consumption. Children were studied at birth, 3 days of life, and 3, 6, 12 and 24 months of life. Blood samples were taken from the cord at birth and at each visit thereafter.
Control population. The control population was made up of cross-sectional samples of healthy children born with a birth weight above the 25th percentile according to the French growth standard curves reported by Leroy (16). This population included 35 newborns, 32 infants aged 3 days, and 66 and 61 children aged 12 and 24 months, respectively. Blood samples were obtained at birth from the cord and from venous puncture thereafter during a free health examination.
Blood samples were collected after informed parental consent, and the study protocol was approved by the local university ethical committee.
Protocol
Auxologic data. Auxologic data were recorded in all subjects of the two populations. Weight was expressed as crude values in both groups. In the IUGR group, weight was also expressed as SD scores corrected for gestational age and sex according to the extrauterine growth standard curves reported by Largo et al. (17) from birth to 3 months of age. From 6–24 months of age, growth standard curves, as reported by Sempe, were used (18). Weight for height was expressed as the BMI (kilograms per m2).
Serum leptin measurement. All sera were stored at -80 C until assayed. Serum leptin concentrations were measured using a specific RIA (Linco Research, Inc., St. Charles, MO) as previously described by Maffei et al. (19). The sensitivity of the assay was 0.5 ng/mL, with intra- and interassay coefficients of variation of 5.2% and 8.7%, respectively, at 2.3 ng/mL.
Statistical analysis
All data were entered and analyzed on the SAS statistical package. (SAS Institute, Inc., Cary, NC). Results are expressed as means (SD). Serum leptin values were log transformed for the statistical analysis.
The statistical significance of differences between IUGR and control groups and between gender in each group were tested by unpaired t test. For the longitudinal analysis in the IUGR group, comparisons of mean values were made using a paired t test. Correlations between variables were assessed using linear regression analysis.
Multivariate models (general linear model procedure) were fitted with log-transformed leptin values as the dependent variable and group (IUGR vs. control), gender, and BMI as explanatory variables at each time point. A P value of 0.05 was regarded as significant.
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Results |
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Clinical characteristics of the two populations are
summarized in Table 1
. There was no
significant difference in gestational age between the two groups of
newborns (39.48 ± 1.65 vs. 38.92 ± 1.95 weeks).
As expected, body weight was higher in the control group than in the
IUGR group (3.42 ± 0.56 vs. 2.03 ± 0.30 kg;
P < 0.0001) at birth. The IUGR group showed a dramatic
catch-up growth for weight during the first year of life (mean weight,
-2.58 ± 0.52 SD score at birth vs.
-0.94 ± 0.64 SD score at 12 months;
P < 0.0001). Weight growth velocity decreased
thereafter. As a result, mean weights at 12 and 24 months did not
significantly differ (-0.94 ± 0.64 vs. -1.12 ±
0.92 SD score; Table 1). However, body weight
remained significantly lower in children born with IUGR than in normal
children at 12 and 24 months (P < 0.0001 at the two
time points).
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shows the postnatal
pattern of BMI in both groups. BMI was higher in normal newborns than
in IUGR (13.9 ± 1.3 vs. 9.9 ± 0.9
kg/m2; P < 0.0001) at birth. In IUGR,
BMI significantly decreased during the first 3 days (P
= 0.006). No such variation was observed in normal newborns. As
expected in normal children, BMI was maximal at 12 months of life and
significantly decreased during the second year of life
(P < 0.0001). Children born with IUGR demonstrated a
similar postnatal pattern of BMI. However, BMI remained significantly
lower in the IUGR group at 12 and 24 months compared with that in the
control group (P = 0.0001 and P =
0.008, respectively; Fig. 1). In our study, at 1 yr of age, body
weight, height, and BMI did not significantly differ between children
born with symmetric or asymmetric IUGR (ponderal index below the third
percentile).
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Figure 2 shows the postnatal
pattern of serum leptin concentrations in both groups. The highest
serum leptin levels were observed at birth in the control and IUGR
groups (7.96 ± 8.3 and 4.48 ± 6.7 ng/mL). IUGR newborns had
significantly lower levels (P < 0.0001). During the
first 3 days of life, serum leptin values dramatically decreased in the
two groups and remained significantly lower in the IUGR group
(1.86 ± 0.84 vs. 1.30 ± 0.48 ng/mL;
P < 0.0001; Fig. 2).
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This model also indicates that differences between IUGR and control groups were not statistically significant after correction for BMI at birth and 3 days.
Serum leptin concentrations increased during the first year of life in normal children (P < 0.0001) as well as in children born with IUGR (P < 0.0001) and decreased significantly thereafter in the two groups (P < 0.02 and P < 0.0001, respectively). Serum leptin concentrations at 12 months were significantly higher in the IUGR group than in the control group (P < 0.0001), and this difference remained significant after adjustment for gender and BMI (P = 0.03).
At 1 yr of age, body weight, height, and BMI did not significantly differ between children born with symmetric or asymmetric IUGR (ponderal index below the third percentile). We did not observe any influence of body proportionality at birth (estimated by ponderal index) on serum leptin levels at 1 yr of age in children born with IUGR after adjustment for gender and BMI.
At 2 yr of age, no significant difference in leptin concentrations was
observed between the two groups (P = 0.75; Fig. 2
).
Usual determinants of serum leptin concentrations
At birth, serum leptin values were significantly correlated with body weight (r = 0.54, P = 0.0008 and r = 0.30, P = 0.01, respectively) and with BMI (r = 0.57, P = 0.0005 and r = 0.22, P = 0.05, respectively) in both control and IUGR groups. No significant correlation was observed between serum leptin values and body weight after birth and until 24 months of age in both groups. As expected, leptin was significantly correlated with BMI in normal children at 12 (r = 0.44, P = 0.0002) and 24 months of age (r = 0.30, P = 0.02). In contrast, no such association was observed in children born with IUGR after 3 days of life and during the first 2 yr thereafter (r = 0.06, P = 0.66 at 12 months and r = 0.14, P = 0.44 at 24 months).
In children born with IUGR, serum leptin levels peaked at 6 months,
whereas BMI increased significantly between 6 and 12 months
(P = 0.008; Figs. 1 and 2). However, the longitudinal
study did not show any significant correlation between baseline serum
leptin concentrations and changes in BMI over the subsequent time
interval at each time point of follow-up. Therefore, in this
population, serum leptin levels were not predictive for variation in
BMI. Conversely, variations in BMI did not predict serum leptin levels.
Likewise, in IUGR, no correlation was found between serum leptin
concentrations and weight gain, expressed as SD score,
during this period.
At birth, serum leptin concentrations in the two groups were higher in girls than in boys, and this gender difference was significant [10.81 ± 9.3 vs. 6.28 ± 6.5 ng/mL (P = 0.04) in the control group and 4.88 ± 8.6 vs. 3.97 ± 2.95 ng/mL (P = 0.03) in the IUGR group]. This gender difference persisted throughout the first 2 yr of life in normal children, but disappeared in children born with IUGR as early as 3 days of age. Therefore, in contrast with normal children, we did not observe any effect of determinants usually known to regulate serum leptin concentrations in children born with IUGR during postnatal catch-up growth.
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Discussion |
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Serum leptin concentrations are higher in prepubertal children than in adults with respect to body fat mass. Consequently, Hassink et al. hypothesized that children would develop a relative leptin resistance beneficial for their positive energy needs (6). The first year of life is characterized by maximal weight growth velocity. Mean BMI values in prepubertal children reported by Rolland-Cachera et al. are lower than those in 12-month-old children (16.2 ± 1.4 vs. 17.4 ± 1.4) (12). However, in our study, serum leptin values observed at 12 months in normal children are lower than those reported in prepubertal children (2.89 ± 1.16 vs. 4–8 ng/mL) (6, 7). Consequently, we cannot suggest that normal children develop leptin resistance early in life. Higher leptin values observed in older children could be explained, rather, by the onset of puberty, as suggested by previous studies (20, 21).
Newborns consistently demonstrate high serum leptin values that dramatically decrease during the first days of life. Unlike Manchini et al., who explained this decrease by variations in BMI (22), we demonstrate that the variation in serum leptin concentrations during this period is independent of intrauterine growth status and variations in BMI. However, serum leptin correlated with BMI at birth and 3 days of age in both groups. It is tempting to speculate that the high serum leptin concentrations observed at birth are an adaptative pathway to prepare for the drastic changes in feeding status and energy balance that occur after birth. The decrease in serum leptin between birth and 3 days of life would reflect the return to expected values with respect to body fat mass. Taken together, these results suggest that the loop by which leptin regulates energy homeostasis is already effective at birth and is able to contribute to the metabolic adaptations for extrauterine life. This regulatory loop would remain effective even if adipose tissue development is defective, as in IUGR.
Children born with IUGR have significantly higher serum leptin values than normal children at the end of the first year of life regardless of BMI and gender, and this difference tends to disappear during the second year of life. Moreover, the relationships observed at birth between serum leptin values and its usual determinants, such as BMI and gender, disappear in these children during this period. It has been reported that low leptin values relative to body weight would be predictive of weight gain (23, 24). We did not observe such a correlation in children born with IUGR during the first 2 yr of life, although it was a critical period for children born with IUGR, who demonstrate a dramatic catch-up growth for weight and height. Therefore, we could speculate that these children develop leptin resistance to increase their energy balance. Thus, leptin resistance could mask the association between serum leptin and its usual determinants, making them less efficient to regulate serum leptin concentrations.
Leptin resistance in this population could be an adaptative pathway beneficial for catch-up growth. However, an alternative hypothesis is that high serum leptin concentrations would reflect a defect in adipose tissue functions. The special time course of adipose tissue development in IUGR is characterized by a dramatically reduced body fat mass at birth (25) followed by a drastic increase in weight growth velocity during the first year of life. We cannot exclude that this postponed growth of adipose tissue could affect the sensitivity of regulatory systems of leptin synthesis and secretion in adipose tissue. The increased risk of obesity in adults born with IUGR described by Ravelli et al. (26) also supports this hypothesis. It would be of considerable interest to investigate serum leptin concentrations with respect to body fat mass in adults born with IUGR to further document this hypothesis.
In summary, serum leptin is present and appears to be effective and regulated during the first years of life in healthy children under the same conditions as it is in older children. Leptin could be one of the hormonal components involved in metabolic and energetic adaptations at birth. Children born with IUGR consistently demonstrate high serum leptin values with respect to BMI during the first year of life. We suggest two hypotheses to explain this observation: 1) these children could develop an adaptative leptin resistance beneficial for their catch-up growth; and 2) high serum leptin concentrations could reflect an adipocyte defect, consequence of the special time course of adipose tissue development in fetuses and children born with IUGR. Both hypotheses should be tested in animal models and in humans.
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Acknowledgments |
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Footnotes |
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Received November 16, 1998.
Revised February 17, 1999.
Accepted February 4, 1999.
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, P = 0.0008).