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Original Studies |
U-457, INSERM, Hôpital R. Debré, 75019 Paris, France
Address all correspondence and requests for reprints to: Dr. D. Jaquet, U-457, INSERM, Hôpital R. 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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mechanisms underlying the relation between body size at birth and impaired glucose tolerance or type 2 diabetes are unclear. IUGR is known to severely alter the fetal development of adipose tissue (8, 9), which in adults plays a key role in the development of insulin resistance (10, 11). It was recently reported in 70-yr-old men that the relation between low birth weight and glucose intolerance is mediated through insulin resistance (12). It would therefore be hypothesized that this association could involve a prior step of insulin resistance, as observed in the common form of type 2 diabetes. However, Hales et al. previously postulated that undernutrition in utero could impair insulin secretion later in life and contribute to the risk of type 2 diabetes (1).
The aim of the present study was to measure insulin sensitivity in 25-yr-old adults born with IUGR compared with that in adults born under normal conditions. An additional aim was to test for a possible decreased insulin secretion relative to insulin sensitivity in subjects born with IUGR. To achieve these goals, insulin sensitivity was assessed by the measurement of insulin-stimulated glucose uptake and the monitoring of free fatty acids (FFA) under insulin stimulation. Insulin secretion was assessed by first phase insulin release (FPIR) following iv glucose stimulation.
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Subjects and Methods |
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The study was a case-control study in which all subjects were
selected according to their birth data from the cohort of the previous
study (12). Briefly, subjects were identified from a population-based
registry of the metropolitan area of the city of Haguenau in France.
This registry recorded information on all pregnancies, deliveries, and
perinatal events in the area from 1971–1985 (11). Local standard
growth curves by gestational age and gender were derived from all live
births registered. Our baseline cohort was of singleton subjects born
full term (
37 weeks) during 1971–1978, with IUGR (weight and/or
height below the third percentile for gestational age and gender,
according to the local standard growth curve; n = 236). Control
subjects were the next fullterm singleton birth of same gender in the
registry, with weight and height between the 25th and 75th percentiles
(n = 281).
Nondiabetic subjects aged 21 yr or more were selected for the purpose
of the present study. IUGR was defined as birth weight below the third
percentile. From the baseline cohort, 77 subjects born with IUGR, who
were not lost for follow-up, were declared eligible. The eligible
controls were 80 randomly selected from the group of control subjects.
The rates of participation in this study were 34% and 31% in the IUGR
and control groups, respectively, and 26 subjects born with IUGR and 25
controls were included in the present study between June 1997 and June
1998. In the IUGR and control groups, there were no significant
differences between the participants and nonparticipants in terms of
parental history of type 2 diabetes, cardiovascular disease and/or
hypertension, dyslipidemia, and birth weight (Table 1
). The etiology of IUGR was gestational
hypertension (50%), smoking (30%), congenital abnormalities (7%),
maternal short stature (7%), and unknown reason (6%). Three subjects
had more than one factor. The study protocol was reviewed and approved
by the Paris/St. Louis ethical committees.
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All subjects underwent a first medical visit at which clinical data were recorded, and a 75-g OGTT was performed. Plasma glucose and insulin were measured at 0, 30 and 120 min. The percentage of body fat mass was derived from bioelectrical impedance analysis (RJL Systems, Clinton Township, NJ). Blood pressure was measured on the right arm of seated subjects after 5 min of rest, using an automated device (Dinamap, Critikon, Neuilly-Plaisance, France) and a cuff of recommended size for the mid-upper arm circumference. Three measurements were made at a 1-min interval, and the average of the last two measurements was used for calculating the mean arterial blood pressure [(systolic blood pressure + 2 x diastolic blood pressure)/3].
Subjects were admitted to the Clinical Investigation Unit of the Hôpital R. Debré (Paris, France) to assess insulin sensitivity by peripheral glucose uptake during a euglycemic hyperinsulinemic clamp as described by De Fronzo et al. (13). Sixty minutes after the start of the insulin infusion (40 mU/m2·min), the steady state plasma glucose concentration was targeted at 100 ± 10 mg/dL. It has previously been demonstrated that in nondiabetic subjects, hepatic glucose production is suppressed by an insulin infusion rate of 40 mU/m2·min (14). Glucose uptake was calculated as the average glucose infusion rate during two 20-min periods (60–100 min), corrected for a target glucose of 100 mg/dL and adjusted for fat-free mass (milligrams per kg fat-free mass/min). Intraindividual coefficients of variations of blood glucose during the first and second periods were 2.1 ± 0.9% and 1.9 ± 0.9%, respectively. Mean plasma glucose concentrations before correction were similar in IUGR subjects and controls (99 ± 2 and 98 ± 2 mg/dL, respectively). Plasma insulin measured at steady state did not differ significantly between IUGR subjects and controls (plasma insulin = 89.5 ± 7.2 vs. 83.6 ± 5.6 µU/mL). FFA concentrations were measured at baseline and 90 min after the start of the insulin infusion. The relative decrease in FFA concentrations during insulin stimulation was calculated as follows: (baseline FFA - insulin stimulated FFA)/baseline FFA. Insulin secretion was assessed by the FPIR, which was measured during an iv glucose stimulation test (0.3 g/kg). FPIR was defined as the differential mean value of insulin at 1 + 3 + 5 + 10 min over baseline [(insulin 1 + 3+5 + 10 min/4) - baseline insulin].
Analytical methods
Plasma glucose concentrations during the clamp were measured by the glucose oxidase method using an on-site analyzer (Beckman Coulter, Inc., instruments, Fullerton, CA). Plasma insulin concentrations were measured using a double antibody RIA (ERIA Diagnostics Pasteur, Paris, France). Cross-reactivity with proinsulin and derived metabolites was less than 1%. Assay sensitivity was 1.2 pmol/L. Glucose, cholesterol, high density lipoprotein cholesterol, FFA, and triglycerides were measured by enzymatic methods.
Statistical analysis
All data were entered and analyzed using the SAS statistical
package (SAS Institute, Inc., Cary, NC). Results are
expressed as the mean ± SD. The differences between
the IUGR and control groups were tested by 
2
test for qualitative variables and Student’s t test for
quantitative variables. Plasma insulin, triglycerides, and FFA were log
transformed before statistical analyses.
The effect of group (IUGR vs. control) on peripheral glucose
uptake and fasting insulin, adjusting for body mass index (BMI),
percentage of total body fat, or waist to hip ratio, used regression
models (general linear models procedure). The independent effect of
IUGR on insulin secretion relative to insulin sensitivity was tested
using the log-transformed variables in a general linear models
procedure (15). Interaction between the group and the log-transformed
glucose uptake on FPIR was also tested in this model. Correlations
between FFA and triglyceride concentrations and BMI, waist to hip
ratio, fasting insulin, and insulin-stimulated glucose uptake were
tested using linear regression models. P 
0.05 was
considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 2
shows clinical characteristics at birth and at the time of the study in
the two groups. As expected from the inclusion criteria, birth weight
and ponderal index were significantly lower in IUGR-born subjects
(P < 0.0001 for both comparisons). Gestational age and
gender distributions were similar in both groups. At the time of the
study, mean ages did not significantly differ between the two groups.
Body weight, BMI, and waist to hip ratio did not differ significantly
between IUGR and control groups. In contrast, the percentage of body
fat mass was significantly higher in subjects born with IUGR
(P = 0.02). As in the previous study, body height was
significantly lower in the IUGR group (P = 0.02). Mean
arterial blood pressure were similar in both groups (85.2 ± 8.8
vs. 84.2 ± 6.9 mm Hg). Smoking habits did not
significantly differ between the IUGR and control groups (7 of 26
vs. 13 of 25; P = 0.07).
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All subjects in the control group had normal glucose tolerance according to both WHO and American Diabetes Association criteria (16, 17). In the IUGR group, one woman had impaired glucose tolerance (2 h postload plasma glucose, 187 mg/dL).
Plasma glucose at baseline and after the glucose load did not differ
significantly between IUGR and controls at any time point (Fig. 1). Fasting plasma insulin was
significantly higher in subjects born with IUGR (7.3 ± 3.8
vs. 5.3 ± 2.3 µU/mL; P = 0.03). The
difference between mean fasting plasma insulin levels remained
significant after adjusting for BMI (P = 0.03). When
the insulin response was analyzed with respect to the glucose response
using the ratio of the areas under the curves, this ratio was
significantly higher in the IUGR group than in the control group
(43.6 ± 19.7 vs. 33.6 ± 10.6 mU/g;
P = 0.03).
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Insulin-stimulated glucose uptake was lower in the IUGR group than
in controls (6.7 ± 2.9 vs. 8.0 ± 1.9 mg/kg
fat-free mass·min; P = 0.05; Fig. 2). Being born with IUGR showed an
independent effect on insulin-stimulated glucose uptake after adjusting
for BMI in comparison to controls (adjusted means, 6.8 vs.
7.8 mg/kg fat-free mass·min; P = 0.05), and as
expected, BMI had a strong independent effect (P <
0.0001). A similar result followed after adjustment for the percentage
of total body fat (adjusted means, 6.8 vs. 7.7 mg/kg
fat-free mass·min; P = 0.05) or for the waist to hip ratio
(adjusted means, 6.6 vs. 8.0 mg/kg fat-free mass·min;
P = 0.04). Eight subjects born with IUGR (31%) showed
an insulin-stimulated glucose uptake out of the control distribution
and were regarded as insulin resistant (Fig. 2). These
insulin-resistant IUGR subjects did not significantly differ from the
insulin-sensitive IUGR subjects in terms of BMI (27.0 ± 5.7
vs. 22.8 ± 4.1 kg/m2;
P = 0.07), body fat mass (28.7 ± 7 vs.
26.6 ± 8.1%; P = 0.54), birth weight (2350
± 230 vs. 2443 ± 251 g; P =
0.23), and ponderal index (22.9 ± 1.3 vs. 22.7 ±
3.3 kg/m3). In IUGR subjects, no significant
relation was found between insulin-stimulated glucose uptake and
etiology of IUGR.
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Mean values of FPIR were higher in subjects born with IUGR than in controls (76 ± 47 vs. 65 ± 35 µU/mL). IUGR had no effect on FPIR (P = 0.86) after adjustment for insulin-stimulated glucose uptake. As expected, insulin-stimulated glucose uptake had a strong effect on FPIR (P = 0.0002), but there was no interaction between the group and insulin-stimulated glucose uptake (P = 0.65).
Serum lipids profile
At baseline, cholesterol and high density lipoprotein cholesterol did not differ between the IUGR and control groups [4.41 ± 0.99 vs. 4.25 ± 0.71 mmol/L (P = 0.52) and 1.50 ± 0.45 vs. 1.40 ± 0.32 mmol/L (P = 0.34), respectively]. Neither fasting triglycerides (1.04 ± 0.44 vs. 0.83 ± 0.14 mmol/L; P = 0.08) nor mean FFA values at baseline (555 ± 182 vs. 475 ± 272 µmol/L; P = 0.13) or the relative decrease in FFA concentrations during insulin stimulation (0.72 ± 0.17 vs. 0.76 ± 0.14; P = 0.24) significantly differed between the two groups.
In both groups no significant correlation was found among fasting
triglycerides, insulin-stimulated FFA suppression, and BMI or
waist to hip ratio (Table 3). In the IUGR group, triglyceride
concentrations were positively correlated with fasting insulin
and inversely correlated with insulin-stimulated glucose uptake. The
relative decrease in FFA concentrations during insulin stimulation was
significantly correlated with insulin-stimulated glucose uptake and was
marginally and inversely correlated with fasting insulin. These
correlations were not observed in the control group (Table 3).
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Discussion |
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At 25 yr of age, our study population already showed decreased insulin sensitivity. This feature seems isolated, as we could not demonstrate any statistically significant difference between IUGR subjects and controls in BMI, blood pressure, triglycerides, or cholesterol, which all contribute to syndrome X. The absence of the complete syndrome could be attributed to the young age of our study population compared with that in previous studies in the literature (4, 5). Therefore, isolated decreased insulin sensitivity in early adulthood would indicate that insulin resistance and hyperinsulinemia are early defects in the development of syndrome X (20, 21). It should be noted that although nonsignificant, IUGR subjects had higher mean BMI and triglyceride concentrations, which strengthens the above-mentioned hypothesis.
In subjects born with IUGR, the relative decrease in FFA concentrations during insulin stimulation correlated significantly with insulin-stimulated glucose uptake. We regarded this observation as indirect evidence for insulin resistance in adipose tissue associated with low glucose uptake. Insulin resistance in adipose tissue is usually observed at a late stage of insulin resistance along with impaired glucose tolerance and type 2 diabetes (10, 11, 22). However, our data suggest that insulin resistance in adipose tissue appears early in IUGR subjects. These observations would thus argue in favor of a role of adipose tissue in the development of IUGR-associated metabolic disorders. IUGR is known to severely alter adipose tissue development in utero, resulting in a 5- to 6-fold decrease in body fat mass at birth (8, 9). Likewise, we have previously shown that serum leptin concentrations are decreased in fetuses and newborns with IUGR, in keeping with the decreased body fat mass (23). Babies born with IUGR demonstrate a postnatal weight catch-up growth characterized by an increased growth velocity during the first 2 yr of life (24). The increased percentage of body fat mass observed in adults with IUGR could be interpreted as abnormalities persisting in the growth of adipose tissue in adulthood, due to the special time course of adipose tissue development during the fetal and neonatal periods. Therefore, we propose that the adipose tissue of subjects born with IUGR is functionally and/or constitutively altered, with long term metabolic consequences on glucose homeostasis.
Using parameters derived from the OGTT, Barker’s group reported that insulin secretion was decreased in subjects with low birth weight, and they hypothesized that undernutrition during fetal life could impair the development of ß-cell function (1, 25). In our previous study we did not find any difference in insulin secretion indexes derived from OGTT between IUGR and controls (7). In the present study we hypothesized that in young adults born with IUGR, impaired insulin secretion, if any, would be related to insulin sensitivity. Using iv glucose tolerance testing, we did not observe either a crude or a relative defect in acute insulin secretion. Therefore, impaired ß-cell function does not appear to be the primary defect leading to abnormal glucose tolerance and type 2 diabetes in humans born with IUGR.
In our study population we could not find any relationship between insulin sensitivity and birth data in the IUGR group. However, caution should be used in the interpretation of these results due to the small size of our study group. Furthermore, attention should be paid to the greater variability in all clinical and biological variables studied in the IUGR group compared with that in our control group. This points to the likely heterogeneity of the IUGR group. We propose that this variability could depend on interactions between environmental factors and the genotype of the fetus (26). Such interactions make it difficult to determine the mechanisms underlying the long term metabolic changes associated with intrauterine growth retardation.
In summary, we have demonstrated decreased insulin-stimulated glucose uptake in young adults born with IUGR, with no evidence of major impairment of ß-cell function. In addition, our data suggest that insulin resistance in adipose tissue appears early in the course of insulin resistance in these subjects. Considering the key role of adipose tissue and lipid metabolism in the pathophysiology of insulin resistance and type 2 diabetes, it could be hypothesized that the time course of adipose tissue development in IUGR subjects is involved in the long term metabolic changes observed in IUGR adults. However, further exploration is required to investigate the pathophysiological mechanism underlying the development of insulin resistance in this population in the light of the known developmental abnormalities during fetal life, especially those occurring in adipose tissue of small for gestational age fetuses.
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Acknowledgments |
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Footnotes |
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2 Supported by a fellowship from Guigoz (France).
Received September 9, 1999.
Revised December 15, 1999.
Accepted December 30, 1999.
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J. C. Jimenez-Chillaron, M. Hernandez-Valencia, C. Reamer, S. Fisher, A. Joszi, M. Hirshman, A. Oge, S. Walrond, R. Przybyla, C. Boozer, et al. {beta}-Cell Secretory Dysfunction in the Pathogenesis of Low Birth Weight-Associated Diabetes: A Murine Model Diabetes, March 1, 2005; 54(3): 702 - 711. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]
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X. Wang, Y. Cui, X. Tong, H. Ye, and S. Li Effects of the Trp64Arg Polymorphism in the {beta}3-Adrenergic Receptor Gene on Insulin Sensitivity in Small for Gestational Age Neonates J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4981 - 4985. [Abstract] [Full Text] [PDF]
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K. L. Gatford, M. J. De Blasio, P. Thavaneswaran, J. S. Robinson, I. C. McMillen, and J. A. Owens Postnatal ontogeny of glucose homeostasis and insulin action in sheep Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E1050 - E1059. [Abstract] [Full Text] [PDF]
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T. S. Hermann, C. Rask-Madsen, N. Ihlemann, H. Dominguez, C. B. Jensen, H. Storgaard, A. A. Vaag, L. Kober, and C. Torp-Pedersen Normal Insulin-Stimulated Endothelial Function and Impaired Insulin-Stimulated Muscle Glucose Uptake in Young Adults with Low Birth Weight J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1252 - 1257. [Abstract] [Full Text] [PDF]
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D. A. Stoffers, B. M. Desai, D. D. DeLeon, and R. A. Simmons Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat Diabetes, March 1, 2003; 52(3): 734 - 740. [Abstract] [Full Text] [PDF]
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Y. van Pareren, P. Mulder, M. Houdijk, M. Jansen, M. Reeser, and A. Hokken-Koelega Effect of Discontinuation of Growth Hormone Treatment on Risk Factors for Cardiovascular Disease in Adolescents Born Small for Gestational Age J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 347 - 353. [Abstract] [Full Text] [PDF]
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M. A. Murtaugh, D. R. Jacobs Jr., A. Moran, J. Steinberger, and A. R. Sinaiko Relation of Birth Weight to Fasting Insulin, Insulin Resistance, and Body Size in Adolescence Diabetes Care, January 1, 2003; 26(1): 187 - 192. [Abstract] [Full Text] [PDF]
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K. L. Kind, P. M. Clifton, P. A. Grant, P. C. Owens, A. Sohlstrom, C. T. Roberts, J. S. Robinson, and J. A. Owens Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R140 - R152. [Abstract] [Full Text] [PDF]
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D. Jaquet, D. A. Tregouet, T. Godefroy, V. Nicaud, D. Chevenne, L. Tiret, P. Czernichow, and C. Levy-Marchal Combined Effects of Genetic and Environmental Factors on Insulin Resistance Associated With Reduced Fetal Growth Diabetes, December 1, 2002; 51(12): 3473 - 3478. [Abstract] [Full Text] [PDF]
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M. A. Veening, M. M. van Weissenbruch, and H. A. Delemarre-van de Waal Glucose Tolerance, Insulin Sensitivity, and Insulin Secretion in Children Born Small for Gestational Age J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4657 - 4661. [Abstract] [Full Text] [PDF]
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C. B. Jensen, H. Storgaard, F. Dela, J. J. Holst, S. Madsbad, and A. A. Vaag Early Differential Defects of Insulin Secretion and Action in 19-Year-Old Caucasian Men Who Had Low Birth Weight Diabetes, April 1, 2002; 51(4): 1271 - 1280. [Abstract] [Full Text] [PDF]
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F. Beringue, B. Blondeau, M. C. Castellotti, B. Breant, P. Czernichow, and M. Polak Endocrine Pancreas Development in Growth-Retarded Human Fetuses Diabetes, February 1, 2002; 51(2): 385 - 391. [Abstract] [Full Text] [PDF]
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R. Bajoria, S. R. Sooranna, S. Ward, and M. Hancock Placenta as a Link between Amino Acids, Insulin-IGF Axis, and Low Birth Weight: Evidence from Twin Studies J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 308 - 315. [Abstract] [Full Text] [PDF]
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D. Jaquet, H. Vidal, R. Hankard, P. Czernichow, and C. Levy-Marchal Impaired Regulation of Glucose Transporter 4 Gene Expression in Insulin Resistance Associated with in UteroUndernutrition J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3266 - 3271. [Abstract] [Full Text] [PDF]
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S. E. Oberfield Metabolic Lessons from the Study of Young Adolescents with Polycystic Ovary Syndrome--Is Insulin, Indeed, the Culprit? J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3520 - 3525. [Full Text]
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, control group.
, control group; 
, IUGR group). The
P value is given for the mean comparison adjusted for
BMI.