the study group consisted of 64 singleton caucasian children , born at term : 31 ( 10 female , 21 male ) were lga ( birth weight 95th percentile for gestational age ) , and 33 ( 12 female , 21 male ) appropriate for gestational age ( aga ) ( birth weight 10th90th percentile ) . no mother was obese ( pregestational bmi 30 kg / m ) , and all had a normal glucose challenge test during pregnancy . the children were examined at 67 years of age , at which time all were prepubertal . the data compared were : obesity indexes [ waist circumference , body weight , and bmi ] ; arterial blood pressure ( bp ) expressed as z scores ; blood levels of fibrinogen , antithrombin iii , protein c and s , lipoprotein(a ) [ lp(a ) ] , adiponectin , leptin , visfatin , igf-1 , igf - binding protein ( igfbp)-1 , igfbp-3 , fasting insulin ( if ) and glucose ( gf ) levels , the homeostasis assessment model of insulin resistance ( homa - ir ) index , the lipid profile , and the genetic factors v leiden g1691a mutation , prothrombin 20210a / g polymorphism , and mutation in the enzyme 5,10-methylenetetrahydrofolate - reductase gene ( mthfr - c677 t ) . venous blood samples were drawn from the children after a 12-h overnight fast . written informed parental consent was obtained for the participation of each child , and the study was approved by the local research ethics committee . components of the igfs - axis , leptin , and adiponectin levels were measured by elisa . serum visfatin cooh - terminal levels were determined by a competitive enzyme immunoassay ( phoenix pharmaceuticals ) . genomic dna was isolated from the leukocytes of peripheral whole - blood samples collected in edta - anticoagulant according to standard methods ( 5 ) . lipids and if and gf levels were determined with techniques previously described ( 1 ) . data were analyzed by anova and multiple regression analysis using the statview software package of sas institute ( cary , nc ) . the significant differences in leptin , if , and homa - ir between lga and aga children persisted after controlling for age , sex , and bmi . characteristics , anthropometric indices , and indices of the prothrombotic state and insulin resistance , components of the igfs - axis , lipid profile , and adipocytokines ( means  sd ) at prepuberty of children born lga ( birth weight 95th percentile ) or aga ( birth weight 10th90th percentile ) aptt , activated partial thromboplastin time ; fgir , fasting glucose - to - insulin ratio ; ns , not significant ( p > 0.05 ) . homozygocity for the mthfr - c677 t mutation was detected in 12 lga and 2 aga children ( p = 0.002 ) and heterozygocity in 19 lga and 8 aga children ( p = 0.003 ) . three lga and none of the aga children were heterozygous for the pt g20210a mutation ( p = 0.06 ) . one lga but no aga child was heterozygous for the factor v leiden ( fvl ) g1691a mutation . no child was homozygous for the prothrombin ( pt ) g20210a mutation or fvl polymorphism . on pooled data for lga and aga children , multiple regression analysis revealed negative correlation between birth weight z score and fibrinogen level ( t = 3.8 , p < 0.01 ) , lp(a ) level ( t = 3.4 , p < 0.01 ) , and igfbp-3 level ( t = 2.5 , p = 0.01 ) , and positive correlation between birth weight z score and if level ( t = 2.8 , p = 0.01 ) and homa - ir ( t = 2.9 , p < 0.001 ) , independent of bmi or waist circumference z score . of the lga group , 9.7% fulfilled the criteria for mets ( 3 components : waist circumference 90th percentile for age and sex for greek children ; bp 95th percentile for age , sex , and height ; gf > 100 mg / dl ; triglycerides > 95th percentile ; and hdl < 5th percentile ) ( 6,7 ) , while no aga child presented three components . in the aga group , 54.5% of the children were completely free of components of mets or risk factors for cvd ( bp 90th percentile , if > 15 u / ml , fasting glucose - to - insulin ratio < 7 , homa - ir > 2.83 , or bmi > 85th percentile ) ( 6,8 ) , while only 22.6% of the lga children were free of components or risk factors ( p = 0.008 ) . on pooled data for lga and aga children , multiple regression analysis revealed negative correlation between birth weight z score and fibrinogen level ( t = 3.8 , p < 0.01 ) , lp(a ) level ( t = 3.4 , p < 0.01 ) , and igfbp-3 level ( t = 2.5 , p = 0.01 ) , and positive correlation between birth weight z score and if level ( t = 2.8 , p = 0.01 ) and homa - ir ( t = 2.9 , p < 0.001 ) , independent of bmi or waist circumference z score . of the lga group , 9.7% fulfilled the criteria for mets ( 3 components : waist circumference 90th percentile for age and sex for greek children ; bp 95th percentile for age , sex , and height ; gf > 100 mg / dl ; triglycerides > 95th percentile ; and hdl < 5th percentile ) ( 6,7 ) , while no aga child presented three components . in the aga group , 54.5% of the children were completely free of components of mets or risk factors for cvd ( bp 90th percentile , if > 15 u / ml , fasting glucose - to - insulin ratio < 7 , homa - ir > 2.83 , or bmi > 85th percentile ) ( 6,8 ) , while only 22.6% of the lga children were free of components or risk factors ( p = 0.008 ) . children born lga at term to nondiabetic , nonobese mothers are at significant risk of developing mets . lga children had significantly higher indexes of insulin resistance ( if and homa - ir ) , independent of bmi or waist circumference z scores . the higher indexes of obesity , such as bmi and waist circumference found in this group may be attributed to earlier adiposity rebound ( 4,9 ) . increase in fibrinogen level is associated with both chronic inflammation and insulin resistance in adults with mets . the negative association between fibrinogen level and birth weight suggests that excess intrauterine growth may significantly affect this factor in a direction different from the other factors contributing to cvd and mets , and there is evidence that genetic factors may account for the negative association ( 10,11 ) . a genetic influence may also be responsible for the lower levels of lp(a ) found in the lga group . the nature of the association found between lga and mutation c677 t in the mthfr gene is unexplained and of unknown significance . this mutation is associated in the homozygous state with decreased specific mthfr activity and elevation in homocysteine levels , which has been identified as an independent risk factor for myocardial infarction and mortality in patients with confirmed cvd ( 12 ) . the significantly higher rate of homozygosity for the mthfr - c677 t mutation in the lga group indicates a possible risk for hyperhomocysteinemia , which warrants further investigation . the independent negative relationship observed between igfbp-3 and birth weight may imply a possible influence of excess intrauterine growth on igfbp-3 level at prepuberty . reduced plasma igf-1 level is considered to reflect a higher risk for insulin resistance and cvd ( 13 ) . in the present study , although lga children had higher insulin resistance indexes , they also showed a trend toward higher igf-1 levels . this may indicate a possible protective mechanism against development of insulin resistance ( 13 ) . in summary , they had higher insulin resistance indexes and anthropometric obesity markers , but lower fibrinogen and lp(a ) levels than matched aga children . lga offspring of nondiabetic , nonobese mothers warrant careful monitoring for evidence of mets precursors throughout childhood and beyond .
objectiveto evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age ( lga ) to nondiabetic , nonobese mothers.research design and methodsat 67 years of age , the comparison of various factors was made between 31 lga and 34 appropriate - for - gestational - age ( aga ) children : fibrinogen , antithrombin iii , protein c and s , fasting insulin , glucose , homeostasis assessment model of insulin resistance ( homa - ir ) index , adiponectin , leptin , visfatin , igf-1 , igf - binding protein ( igfbp)-1 , igfbp-3 , lipids , and the genetic factors v leiden g1691a mutation , prothrombin 20210a / g polymorphism , and mutation in the enzyme 5,10-methylenetetrahydrofolate - reductase gene ( mthfr - c677t).resultslga children had higher levels of leptin ( p < 0.01 ) , fasting insulin ( p < 0.01 ) , and homa - ir ( p < 0.01 ) , but lower igfbp-3 ( p = 0.0001 ) , fibrinogen ( p = 0.0001 ) , and lipoprotein(a ) ( p 
 < 0.001 ) than aga children . 
 significantly more lga children were homozygous for the mthfr - c677 t mutation ( p = 0.0016).conclusionsbeing born lga to nondiabetic , nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty .