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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1344
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1372-1378
Copyright © 2007 by The Endocrine Society

Increased Oxidative Stress in Prepubertal Children Born Small for Gestational Age

Angelika Mohn, Valentina Chiavaroli, Marina Cerruto, Annalisa Blasetti, Cosimo Giannini, Tonino Bucciarelli and Francesco Chiarelli

Departments of Pediatrics (A.M., V.C., M.C., A.B., C.G., F.C.) and Biochemistry (T.B.), University of Chieti, 66100 Chieti, Italy

Address all correspondence and requests for reprints to: Angelika Mohn, Department of Pediatrics, University of Chieti, Via Dei Vestini 15, 66100 Chieti, Italy. E-mail: amohn{at}unich.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Low birth weight is associated with an increased risk of metabolic and cardiovascular diseases in adulthood. The development of insulin resistance (IR) seems to play a pivotal role; no data on the oxidant-antioxidant status are available in this risk group.

Objective: This study is an assessment of oxidant-antioxidant status in prepubertal children born small for gestational age (SGA) in comparison to healthy controls and the relationship to IR.

Design: This cross-sectional study compares indexes of IR and oxidant-antioxidant status in three different groups (SGA+, SGA–, controls), with analysis by post hoc and Pearson correlation.

Setting: The study was conducted in the Academic Department of Pediatrics.

Participants: A total of 19 SGA+ and 16 SGA– children were compared with 13 controls.

Intervention: No intervention was used.

Main Outcome Measures: Indexes of IR (glucose to insulin ratio, homeostasis model assessment of IR) were evaluated, and markers of oxidative stress (lag phase, malonildialdehyde, vitamin E) were measured.

Results: Homeostasis model assessment of IR was significantly higher in SGA+ than SGA– children (1.32 ± 0.9 vs. 0.69 ± 0.47; P = 0.03) and controls (0.71 ± 0.37; P = 0.04). Glucose to insulin ratio was significantly lower in SGA+ than SGA– children (12.41 ± 5.01 vs. 26.54 ± 17.18; P = 0.02) and controls (26.96 ± 20.70; P = 0.04). Lag phase was significantly shorter in SGA+ than SGA– children (24.3 ± 4.38 vs. 35.59 ± 11.29 min; P = 0.003) and controls (45.28 ± 7.69 min; P = 0.0001) and in SGA– than controls (P = 0.01). Malonildialdehyde was significantly higher in SGA+ than SGA– children (0.79 ± 0.3 vs. 0.6 ± 0.1 nmol/mg; P = 0.03) and controls (0.36 ± 0.04 nmol/mg; P = 0.0001) and in SGA– children than controls (P = 0.02). Vitamin E was significantly reduced in SGA+ children than controls (27.54 ± 7.9 vs. 43.23 ± 11.32 µmol/liter; P = 0.002).

Conclusion: Oxidative stress is present in both SGA+ and SGA– children, with a continuous alteration in relation to IR. Therefore, catch-up growth might exert the greatest influence in the development of future diseases.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INFANTS BORN SMALL for gestational age (SGA) are known to be at increased risk of adult degenerative disease, such as cardiovascular dysfunction and the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity (1, 2, 3, 4, 5, 6, 7, 8).

Insulin resistance (IR) is a common feature of these pathogenic conditions and represents an early and constant alteration found in SGA children, suggesting that this metabolic abnormality plays, with compensatory hyperinsulinemia, a pivotal role in linking low birth weight (BW) to long-term consequences (9, 10, 11, 12). Most of these dysfunctions are related to rapid postnatal catch-up growth (13, 14, 15, 16). This phenomenon, described in nearly 90% of subjects born SGA, determines changes in body proportions due to enhanced central fat deposition (15) and leading thereby to a relevant increase of the body mass index (BMI) (17, 18, 19, 20). This determines changes in insulin sensitivity and is associated with a higher predisposition to develop IR (2, 21, 22, 23). Oxidative stress, occurring as a consequence of imbalance between the formation of oxygen free radicals and inactivation of these species by antioxidant defense system (24), seems to be tightly linked to significantly decreased insulin sensitivity. In fact, it has been suggested that IR per se or via an increased plasma concentration of free fatty acids seems to increase reactive oxygen species production through nicotinamide adenine dinucleotide phosphate oxidase activation (25). Furthermore, the major source of oxygen free radical production is adipose tissue, which seems to play also a key role for the development of IR and even the metabolic syndrome (26, 27). Despite the well-described IR status in SGA children, the oxidant-antioxidant status has not been completely explored as up to now only data on antioxidant vitamin levels are available (28). We have chosen malonildialdehyde (MDA) and lag phase as oxidative markers because recent data clearly demonstrate that these indexes are a valid tool for estimating oxidant-antioxidant status in humans (29). Therefore, the aim of this study was to evaluate possible alterations in the oxidant-antioxidant status in SGA children compared with children born appropriate for gestational age (AGA) and to determine whether significantly reduced insulin sensitivity might be associated.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

Short SGA children (SGA–). We recruited 16 Caucasian prepubertal SGA children, defined as neonates whose BW or birth crown-heel length is at least 2 SD below the mean (≤–2 SD) for the infant’s gestational age (five boys and 11 girls; mean age, 4.1 ± 2.59 yr; mean BW, 2368.4 ± 442.09 g), who had been referred to the Department of Pediatrics of the University of Chieti, Italy, and had been admitted for short stature, between June 2004 and October 2006. All children included in this study were born full term (≥37 wk complete of gestation). SGA children were assigned into this group according to the absence of catch-up growth, defined on the clinical basis of a current length less than 10th percentile. None of the children presented congenital anomalies (including Silver-Russel Syndrome), psychomotor delay, other chronic disorders, and/or autoimmune disease. Subjects born from multiple gestation were excluded.

Normal-stature SGA children (SGA+). Nineteen Caucasian prepubertal SGA children, defined as neonates whose BW or birth crown-heel length is at least 2 SD below the mean (≤–2 SD) for the infant’s gestational age (eight boys and 11 girls; mean age, 4.33 ± 1.88 yr; mean BW, 2496.31 ± 135.65 g), were recruited. SGA children were assigned into this group according to the presence of catch-up growth, defined on the clinical basis of a current length greater than 10th percentile. All children were recruited to the study after having been admitted to the Department of Pediatrics for minor diseases.

Controls. As control group, 13 healthy Caucasian prepubertal AGA children, defined as BW and length at or above 10th percentile for gestational age, comparable for sex, age (seven boys and six girls; mean age, 3.43 ± 1.34 yr; mean BW, 3.387 ± 373.56 g), were recruited to the study after having been admitted to the Department of Pediatrics for minor diseases.

After complete recovery of the disease, all children underwent a medical visit to assess general health status, including anthropometric parameters [height, SD score (SDS) height, weight, BMI (the weight in kilograms divided by the square of the height in meters), SDS BMI, waist-to-hip ratio (WHR)], bio-impedentiometry to determine fat mass, and staging of puberty on the basis of breast development in girls and genital development in boys according to the criteria of Tanner (all patients had preadolescent characteristics corresponding to stage 1). Blood samples were taken to evaluate lipid profile (total cholesterol and triglyceride), hormonal pattern [fasting insulin and glucose, C-peptide, IGF-I, IGF binding protein 3 (IGFBP-3)], as well as of markers of oxidant-antioxidant status (lag phase, MDA, vitamin E).

The study was approved by the Ethical Committee of the University of Chieti. Written informed consent was obtained from all parents, and oral consent was obtained from all children.

Anthropometric measurements

Body weight was determined to the nearest 0.1 kg, and height was measured with Harpenden stadiometer to the nearest 0.1 cm. As fatness indexes, we used WHR and BMI. To calculate WHR, the waist circumference was measured at its smallest point between iliac crest and rib cage, and the hip circumference was measured at its largest width over the greater trochanters. As further fatness index, we used fat mass (percent), estimated from four skin-fold thicknesses (made over the triceps and biceps, at the tip of the scapula, and over the iliac crest, of the left side of the body) with Holtain plicometer according to Brook’s equation (30).

Bioelectrical impedance analysis

The impedance signal (Z, in ohms) into resistance (R, in ohms) and reactance (Xc, in ohms) was estimated to calculate fat mass. Measurements were conducted in all subjects with the same single frequency phase-sensitive impedance analyzer [STA (Soft Tissue Analyzer)/BIA; Akern Sistem Srl, Florence, Italy]. The instrument applied a 50-kHz alternative current of 800 µA and was connected to surface electrodes (5400 Q-Trace Kendall); two electrodes were placed on the dorsal surface of the right hand and foot, next to the metacarpal-phalangeal, and metatarsal-phalangeal joints; two other electrodes were placed proximally on the right forearm and leg, leaving 5.5 cm of free skin around the outer electrodes (standard to tetrapolar placement). Before each testing session, the external calibration of the instrument was checked with a calibration circuit of a known impedance value (R = 380 {Omega} and Xc = 47 {Omega}, 1% error). The subjects lay recumbent on a nonconductive surface. Clothing was removed except for dry underwear. No direct contact was made with the infant’s skin during the measurement, which was done before feeding and when the child was quiet.

Measurements obtained were analyzed by Bodygram system (qualitative and quantitative body composition analysis) (31) to calculate fat mass.

Laboratory procedures

Biochemical analysis. Plasma glucose level was determined by using the glucose oxidase method, and plasma insulin was measured with two-site immunoenzymometric assay (AIA-PACK IRI; Tosoh, Tokyo, Japan). The limit of detection was 0.5 µU/ml with intraassay and interassay coefficients of variation less than 7% for quality control. Total cholesterol and triglyceride concentrations have been performed by using calorimetric method (at 540 nm), and test sensibility was 50 and 10 mg/dl, respectively.

Low-density lipoprotein (LDL) isolation. Plasma LDL fraction was isolated by single-vertical-spin ultracentrifugation using a discontinuous NaCl/KBr density gradient. Then it was dialyzed for 22 h in the dark against three changes of PBS containing EDTA (2.7 mmol/liter) (pH 7.4) at 4 C. LDL cholesterol (LDL-C) was measured by an enzymatic reagent (CHOD-PAP, MPR1; Boehringer Mannheim, Mannheim, Germany), and protein contents of LDL were quantified by the method of Lowry et al. (32).

LDL oxidation. Oxidation of LDL (fresh preparations at a concentration of 0.05 LDL-C/ml) was obtained by the addition of 2.5 µmol/liter CuSO4 in PBS (pH 7.4) at 37 C and was continuously controlled spectrophotometrically at 234 nm to evaluate the formation of conjugated dienes. Oxidation of LDL was calculated as the measurement of the duration of the phase before the maximum oxidation (lag phase). As previously reported (33), the oxidation curve is characterized by three phases: lag phase, propagation phase, and decomposition phase. In particular, lag phase is the time required by the reaction to gain the maximum velocity (V max) during the propagation phase (34).

Peroxidation of LDL. The lipid peroxide content of LDL was evaluated spectrophotometrically by the measurement of MDA using the thiobarbituric acid-reacting substance assay (35). LDL (200 µg of proteins) was mixed with 1.5 ml of 0.67% thiobarbituric acid and with 1.5 ml of 10% trichloroacetic acid, containing 1 mg/ml EDTA. After heating at 100 C for 30 min, fluorescent reaction products were assayed on a PerkinElmer LS 45 spectrophotometer (PerkinElmer, Norwalk, CT) with an excitation wavelength of 513 nm and an emission wavelength of 553 nm. Fresh diluted tetramethoxypropane, which yields MDA, was used as a standard, and results were expressed as nanomoles of MDA per milligram of LDL-C (36).

Vitamin E determination. Plasma and LDL vitamin E, expressed in micromoles per liter and micromoles per milligram of LDL-C, respectively, were measured with high performance liquid chromatography using a Kontrol System 450 (Milan, Italy) equipped with a UV-visible spectrophotometer (Kontrol Detector 430) at different wavelengths. Procedures were performed as previously reported (37).

Calculation. We used the following indexes for determination of IR (38): baseline glucose to insulin ratio (G/I) (IR was defined as G/I < 6) (39) and homeostasis model assessment of IR (HOMA-IR) calculated with the formula: [fasting insulin (microunits per milliliter) x fasting glucose (millimoles per liter)]/22.5.

Statistical analysis

All values were expressed as means and SD. We analyzed differences in variables between the three groups by one-way ANOVA with Tukey’s test for post hoc comparison of means between each pair of groups. Pearson correlation coefficient was used for testing variables of interest. Statistical significance level was P < 0.05. Differences in sex variable were analyzed by Fisher’s exact test. All calculations were made with the computer program SPSS (Statistical Package for the Social Science) version 10.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics

Baseline clinical characteristics, anthropometric measurements, and laboratory investigation of all subjects are reported in Table 1Go. The three groups (SGA+, SGA–, controls) were similar for age, sex, WHR. BW was significantly lower in SGA+ and SGA– children when compared with the control group (P = 0.0001 and P = 0.0001, respectively). A significant difference was found in terms of BMI and SDS BMI between the three groups: both parameters were significantly higher in SGA+ children when compared with the SGA– group (P = 0.04 and P = 0.04, respectively), whereas no difference was found between SGA+ children and controls (P = 0.99 and P = 0.98). Furthermore, a significant difference was found in terms of fat mass; this parameter was significantly lower in the SGA– group when compared with SGA+ and control children (P = 0.004 and P = 0.006, respectively), whereas no significant difference was found between the SGA+ and the control group (P = 0.99). No significant difference was found between the three groups in terms of fasting glucose, total cholesterol, and triglyceride concentrations, as well as IGF-I and IGFBP-3 levels.


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  		TABLE 1. Clinical characteristics and biochemical evaluation of the study population

 
IR indexes

IR indexes of the study population are reported in Fig. 1Go. Insulin was significantly higher in the SGA+ group when compared with controls (P = 0.04), whereas no difference was observed between the SGA+ and the SGA– groups (P = 0.06), and between SGA– children and the control group (P = 0.92). C-peptide was significantly higher in the SGA+ group in comparison to controls (P = 0.03), and between the SGA+ and the SGA– groups (P = 0.03); no difference was observed between SGA– children and controls (P = 0.98). HOMA-IR was significantly higher in SGA+ children when compared with controls (P = 0.04), and a significant difference was also detected between SGA+ and SGA– children (P = 0.03); no difference was observed between the SGA– and the control group (P = 0.99). Furthermore, G/I was significantly lower in SGA+ children when compared with the control group (P = 0.04), and a significant difference was also found between SGA+ and SGA– children (P = 0.02); no significant difference was detected when SGA– children when compared with the control group (P = 0.99).


Figure 1
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  		FIG. 1. IR indices of the study population. Significant values by post hoc analysis: *, SGA+ vs. controls; {dagger}, SGA+ vs. SGA–; {ddagger}, SGA– vs. controls. P by one-way ANOVA: insulin, P = 0.02; C-peptide, P = 0.01; HOMA-IR, P = 0.01; G/I, P = 0.01.

 
Oxidant-antioxidant status

Oxidant-antioxidant status of the study population is reported in Fig. 2Go. Lag phase was significantly shorter in SGA+ children when compared with the control group and to the SGA– children (24.3 ± 4.38 vs. 45.28 ± 7.69, and vs. 35.59 ± 11.29 min; P = 0.0001 and P = 0.003, respectively); a significant difference was also found between the SGA– and the control group (P = 0.01). MDA was significantly higher in SGA+ when compared with controls and to SGA– children (0.79 ± 0.3 vs. 0.36 ± 0.04, and vs. 0.6 ± 0.1 nmol/mg; P = 0.0001 and P = 0.03, respectively); a significant difference was also observed between the SGA– and the control groups (P = 0.02). Vitamin E was significantly lower in the SGA+ group when compared with controls (27.54 ± 7.9 vs. 43.23 ± 11.32 µmol/liter; P = 0.002), and in the SGA– group when compared with control children (31.34 ± 8.84 vs. 43.23 ± 11.32 µmol/liter; P = 0.02), whereas no significant difference was observed between SGA+ and SGA– children (P = 0.57). No difference was found in terms of LDL vitamin E. In the SGA group, the following correlations were found between IR indexes and markers of oxidative stress. A direct correlation was found between HOMA-IR and MDA (r = 0.39; P = 0.01), whereas an inverse correlation was detected between HOMA-IR and lag phase (r = –0.33; P = 0.04). A direct correlation was found between G/I and lag phase (r = 0.36; P = 0.02); an inverse correlation was detected between G/I and MDA (r = –0.38; P = 0.02). No significant correlations were found between markers of oxidative stress and fatness indexes (Table 2Go).


Figure 2
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  		FIG. 2. Oxidant-antioxidant status of the study population. Significant values by post hoc analysis: *, SGA+ vs. controls; {dagger}, SGA+ vs. SGA–; {ddagger}, SGA– vs. controls. P by one-way ANOVA: lag phase, P = 0.0001; MDA, P = 0.0001; vitamin E, P = 0.003.

 

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  		TABLE 2. Multivariate correlates of lag phase, MDA, and vitamin E

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is well known that low BW is tightly linked to an increased rate in adulthood of hypertension (40), artery disease, abnormalities in lipid metabolism and blood coagulation (6, 7), all predictive of a greater risk of ischemic heart disease (41, 42). This increased risk of adult-onset cardiovascular and metabolic dysfunctions has been attributed to a reduced insulin sensitivity, already evident during the prepubertal period (2, 5).

This study is, to the best of our knowledge, the first evaluating insulin sensitivity, oxidant-antioxidant status, and their mutual correlations in prepubertal children born SGA in comparison to AGA. Our data clearly show that SGA+ children have significantly lower insulin sensitivity than SGA– children and controls: in fact, HOMA-IR values were significantly higher in the SGA+ group when compared with the SGA– group and to controls, whereas G/I values were significantly lower in SGA+ children when compared with SGA– and control children. These findings are in agreement with previous data reported by Veening et al. (22) who demonstrated, in a small sample of SGA children, a significant rate of IR that was strongly associated with postnatal catch-up growth: SGA+ children, especially those with a BMI greater than 17 kg/m2, were more insulin resistant than SGA– children and controls. The clamp technique, used by these authors, is recognized as the gold standard (38) to measure IR, whereas indexes derived from fasting blood glucose and insulin levels such as HOMA-IR and G/I used in the present study are considered surrogate measures. However, recent data clearly demonstrate that these indexes are a valid tool for estimating IR in children (43, 44). The significantly decreased insulin sensitivity in our SGA+ children points out the critical role of catch-up growth which is normally associated with substantial change in body distribution: in fact, a large epidemiological study showed that children who experience significant catch-up for weight in the first 2 yr of life are taller, heavier, and fatter at 5 yr and have a lower birth weigh than those who do not. In fact, SGA children who showed an efficient catch-up growth during infancy display a dramatic adiposity increase (15, 18) with increased percentage of body fat, reflected by a greater BMI (15) and increased fat mass as also seen in our SGA+ children.

However, SGA+ children not only demonstrated a significantly decreased insulin sensitivity but also substantially altered oxidant-antioxidant status. Oxidative stress plays a fundamental role in the pathophysiology of endothelial dysfunction, inflammation, and atherosclerotic cardiovascular disease. In the present study, we used lag phase, MDA, and vitamin E to explore the oxidant system; all these compounds are recognized as being reliable markers of this system in humans (29). Our data clearly show that lag phase, an index inversely related to oxidative stress, is significantly shorter in SGA+ children when compared with control children. Likewise, a significant difference was found in MDA, an index directly related to oxidative stress, which was on average 2-fold greater in the SGA+ group the values found in the control group. This altered oxidant status was associated with decreased plasma vitamin E levels in SGA+ than in control children. The reason underlying this alteration of the oxidant-antioxidant status remains speculative. However, it might be the result of the reduced insulin sensitivity observed in this risk group supported by the suggestive correlations found between IR and oxidative stress. In fact, a recent study has shown that one major mechanism of vascular dysfunction with IR involves the increased generation, availability, and/or actions of reactive oxygen species (45). Furthermore, many studies report a strong relationship between increased IR and different risk factors for cardiovascular disease in prepubertal SGA children, such as an increase systolic blood pressure (46). This is plausible because hydrogen peroxide generation seems to be linked to action of insulin itself which might also induce the production of cytokines. The subsequent increased oxidative stress is responsible of cell membranes damage and oxidation of low-density lipoproteins, which represents a key step in the generation of foam cells and fatty streak leading to the development and progression of atherosclerosis (47).

Recently a further hypothesis has emerged to explain the fetal origin of later diseases of SGA children. This "oxidative stress hypothesis" (48) postulates that impaired redox balance during the intrauterine life might modulate gene expression (49, 50), function and proliferation of pancreatic ß-cells (51, 52), and blood pressure (53, 54). In fact, Gupta et al. (55) recently demonstrated that neonates born SGA present increased oxidative stress, suggesting that the intrauterine period is, as a matter of fact, critical for its development, most likely due to intrauterine malnutrition (55, 56). This observation is supported by our results. In fact, SGA– children presented values for lag phase and MDA in between SGA+ and control children, being significantly different from both. These results suggest a background oxidative derangement in SGA population, which is exacerbated in SGA+ children by the reduced insulin sensitivity burden induced by the effective catch-up growth.

Without any doubt, the major limitation of the present study is the relatively small sample size because this might implicate that the results are not easily applicable to the whole population of prepubertal SGA children. However, the presence of two different SGA populations compared with normal controls explores widely a possible alteration of the oxidative system. Furthermore, it needs to be acknowledged that these results might be adaptive and facilitated by improved growth.

In summary, our data show that oxidative stress is already present during the prepubertal age in both SGA+ and SGA– children, with a continuous alteration in oxidant-antioxidant status in relation to IR. These findings confirm the important role of postnatal catch-up growth, which seems to exercise the greatest influence. Because metabolic abnormalities are already evident during the prepubertal age, oxidant-antioxidant status might be a potential marker for the early identification and intervention in the development of future metabolic and cardiovascular dysfunctions.


   Footnotes
 
Conflict of Interest: None. The authors have nothing to disclose.

First Published Online January 30, 2007

Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; BW, birth weight; G/I, glucose to insulin ratio; HOMA-IR, homeostasis model assessment of IR; IGFBP-3, IGF binding protein 3; IR, insulin resistance; MDA, malonildialdehyde; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; SDS, SD score; SGA, small for gestational age; WHR, waist-to-hip ratio.

Received June 22, 2006.

Accepted January 23, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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