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APPLIED NUTRITIONAL INVESTIGATION

Relation of Cord Serum Levels of GrowthHormone, Insulin-like Growth Factors, Insulin-like

Growth Factor Binding Proteins, Leptin, and

Interleukin-6 With Birth Weight, Birth Length,and Head Circumference in Termand Preterm Neonates

Hui-Chen Lo, PhD, Lon-Yen Tsao, MS, Wen-Yin Hsu, MS, Hsia-Nan Chen, MD,Wai-Kit Yu, MD, and Chiu-Yen Chi, BS

From the Departments of Medical Education and Research, and Pediatrics, and the Teamof Clinical Nutrition Support Service, Changhua Christian Hospital, Changhua, Taiwan,

Republic of China

OBJECTIVES: Fetal growth process is governed by multiple factors. We investigated the relation of

insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), leptin, and interleukin-6 (IL-6) withintrauterine growth in preterm and term neonates.

METHODS: Thirty-eight preterm and 43 term neonates were recruited. Anthropometric measures were

recorded and umbilical cord blood samples were collected at birth.

RESULTS: Birth weight (BW), birth length (BL), ponderal index, head circumference (HC), and cord

serum levels of albumin, prealbumin, retinol-binding protein (RBP), total and free IGF-I, IGF-II,

IGFBP-3, acid-labile subunit (ALS), and leptin were significantly lower, whereas levels of IGFBP-1,

IGFBP-2, and IL-6 were significantly higher in preterm than in term neonates (P 0.05). Total and free

IGF-I, ALS, and leptin had significantly positive correlations, whereas IGFBP-2 had a significantly

negative correlation, with BW and BL in preterm plus term neonates. Forward stepwise multivariate

regression analysis showed that gestational age (GA), IGFBP-2, leptin, and free IGF-I are significant

predictors of BW; GA, IGFBP-2, ALS, transferrin, and leptin are significant predictors of BL; and GA and

free IGF-I are significant predictors of HC in preterm and term neonates.

CONCLUSIONS: Our results suggest that IGF-I, IGF-II, IGFBP-2, ALS, and leptin play important roles in

intrauterine growth. Nutrition 2002;18:604 608. Elsevier Science Inc. 2002

KEY WORDS: intrauterine growth, insulin-like growth factors, leptin, cytokine

INTRODUCTION

Fetal growth process is governed by interactions between multiplefactors, such as the genetic, nutritional, hormonal, and other envi-ronmental factors.1 The preterm neonates born with low birthweights are at much greater risk of medical problems requiringintensive medical management, which may be a consequence ofdisturbances in this interaction. Understanding the relation be-tween hormones and intrauterine growth may help us to predict the

mortality and morbidity of preterm and term neonates.Birth weight (BW), birth length (BL), weight:length ratio suchas body mass index and ponderal index (PI), and head circumfer-ence (HC) have been used as conventional indices for evaluatingnutrition status and predicting the metabolic complications ofintrauterine growth retardation.2 However, these anthropometric

measurements are not sensitive enough to reflect mild or moderategrowth and metabolic abnormality. Therefore, several serum pro-teins, e.g., albumin, prealbumin, transferrin, and retinol-bindingprotein (RBP), have been suggested as sensitive indicators ofnutrition status and have been used as clinical indices of intrauter-ine growth.36 However, the clinical experience is controversialwith the use of these conventional nutrition-related serum proteinsto assess intrauterine growth in preterm neonates.

In the past two decades, several serum proteins and hormones

have been strongly related to fetal growth. For example, insulin-like growth factors (IGFs), the peptides structurally homologouswith proinsulin,710 and leptin, the ob gene product,11,12 have beenshown to play important roles in mediating fetal and postnatalgrowth and development. In addition, IGF binding proteins (IG-FBPs), such as IGFBP-1, -2 and -3 that regulate the bioactivity ofIGF-I, and acid-labile subunit (ALS), a high-molecular-weightprotein bound with IGFBP-3 and IGF-I, are involved in the processof fetal growth.710 Evidence also shows that insulin has a centralrole in regulating growth in the fetus1 and is related mainly to fetalovergrowth.13 In contrast, fetally derived interleukin-6 (IL-6) playsa role in the pathophysiology of abnormal pregnancy and pretermlabor.14

To our knowledge, several studies have focused on the inter-

This work was supported by funds from the GSK Foundation Corporation

and grant NSC 89-2320-B-371-002 from the National Science Council of

ROC.

Correspondence to: Lon-Yen Tsao, MD, Department of Pediatrics, Chan-

ghua Christian Hospital, 135 Nanhsia Street, Changhua, 500, Taiwan, ROC

Nutrition 18:604 608, 2002 0899-9007/02/$22.00Elsevier Science Inc., 2002. Printed in the United States. All rights reserved. PII S0899-9007(01)00811-5

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actions between growth hormone (GH), IGFs, or IGFBPs withgestational age (GA) and BW in neonates. There is growingevidence showing the importance of leptin and cytokines on fetalgrowth. The interactions between IGFs, IGFBPs, ALS, leptin,cytokine, and intrauterine growth are still unclear. Therefore, weinvestigated the relation of cord serum levels of these hormoneswith BW, BL, and HC in term and preterm neonates and sought thedominant proteins regulating intrauterine growth.

METHODS AND MATERIALS

Subjects

Umbilical cord blood samples were collected from 43 term neo-nates and 38 preterm neonates admitted to Changhua ChristianHospital with GAs younger than 37 wk and BWs lower than1250 g and referred to the team of the Clinical Nutrition SupportService. Dating pregnancy from the first day of the last menstrualperiod was used to assess GA. All preterm and term neonates hadweights appropriate for GA, that is, BWs between the 10th and90th percentiles of the normal growth chart of infants, and werefree of major congenital anomalies, congestive heart failure, renal

disease, or major surgical procedures. In addition, the mothers ofthose neonates were free of cardiovascular disease, renal and liverdiseases, hypertension, and diabetes. All umbilical cord bloodsamples were taken by the nurses at the delivery room and weredivided into clinical and laboratory samples. Laboratory sampleswere centrifuged, divided, and stored at 80C for future assays.Ethical approval from the Institutional Review Board of ChanghuaChristian Hospital and informed parental consent were obtained.

Anthropometric Measurements

BW and BL were obtained from each preterm and term neonateimmediately after birth. Measurement of HC was done on day 2 toallow for resolution of edema and head molding. Based on BW and

BL, PI (BW/BL

3

; g

cm

3

100) was calculated and used as anindex of nutrition status for neonates.15

Biochemical Analysis

Serum concentrations of albumin, prealbumin, and transferrinwere measured with an automatic analyzer (Hitachi 747, Tokyo,Japan). Serum concentrations of RBP were determined by a sand-wich enzyme-linked immunosorbant assay (ELISA), as describedby Topping et al.16 Total and free IGF-I, IGF-II, GH, insulin,IGFBP-1, IGFBP-3, and ALS were measured with commerciallyavailable ELISA kits (Diagnostic Systems Laboratories Inc., Web-ster, TX, USA). IGFBP-2 levels were measured with a commer-cially available radioimmunoassay kit (Diagnostic Systems Labo-ratories Inc.). Leptin and IL-6 were analyzed with the DuoSetELISA Development kit (R & D Systems, Inc., Minneapolis, MN,USA). Samples were analyzed in one assay with duplication. Theinterassay and intra-assay coefficients of variation were 5% to10%.

Statistical Analysis

Values are expressed as mean standard deviation. The signifi-cant difference of each parameter between preterm and term neo-nates was determined by Students t test. A simple correlationanalysis was processed by Pearsons method to assess the relationsbetween GA, sex, and serum substrates in preterm and termneonates. Multiple regression analysis for the effect of serumsubstrates on BW, BL, PI, and HC was performed in preterm and

term neonates after adjustment by sex and GA. Forward stepwisemultivariate regression analysis assessed the influence of multiple

variables on BW, BL, PI, and HC. Statistical significance wasassumed at P 0.05.

RESULTS

Anthropometric Data

Sex, GA, BW, BL, HC, and PI of preterm and term neonates arelisted in Table I. There were 16 males and 22 females amongpreterm neonates and 24 males and 19 females among term neo-nates. The GA averages were 29.4 3.2 wk and 39.1 1.2 wk forpreterm and term neonates, respectively. BW, BL, PI, and HCwere 1165 214 g, 37.7 2.5 cm, 2.25 0.44, and 26.2 2.1cm in preterm neonates and 3213 419 g, 50.5 1.9 cm, 2.50 0.27, and 33.6 1.3 cm in term neonates, respectively. Termneonates had significantly greater BW, BL, PI, and HC than didpreterm neonates (P 0.005).

Biochemical Data

Cord serum levels of nutrition-related proteins and hormones inpreterm and term neonates are shown in Table II. Serum levels ofalbumin, prealbumin, and RBP were significantly greater in termneonates than in preterm neonates (P 0.001). There were nosignificant differences in cord serum levels of transferrin, insulin,and GH between preterm and term neonates. Cord serum levels oftotal IGF-I, free IGF-I, IGF-II, IGFBP-3, ALS, and leptin weresignificantly greater, whereas those of IGFBP-1, IGFBP-2, andIL-6 were significantly lower, in term neonates than in pretermneonates. The ratio of free to total IGF-I did not differ signi ficantlybetween preterm and term neonates.

Correlations

There were no significant correlations between sex and serumsubstrate levels in preterm, term, and preterm plus term neonates(data not shown). The correlations between GA and serum hor-mones in preterm, term, and preterm plus term neonates are shownin Table III. Cord serum levels of IGFBP-2 and leptin had signif-icantly positive correlations with GA in preterm neonates. Cordserum levels of IGF-II, IGFBP-2, and IGFBP-3 had significantlypositive correlations, whereas those of insulin and free IGF-I andthe ratio of free to total IGF-I had significantly negative correla-tions, with GA in term neonates. When combining preterm andterm neonates, most of the serum hormones we measured hadsignificantly positive correlations with GA; IGFBP-1 and IL-6 hadsignificantly negative correlations with GA and insulin; and GH,IGFBP-2, and the ratio of free to total IGF-I had no signi ficant

correlation with GA.The results of multiple regression analyses between BW, BL,

TABLE I.

SUBJECT CHARACTERISTICS OF PRETERM AND TERM

NEONATES*

Preterm Term P

Male/female 16/22 24/19

Gestational age (wk) 29.4 3.2 39.1 1.2 0.0001Birth weight (g) 1165 214 3213 419 0.0001

Birth length (cm) 37.7 2.5 50.5 1.9 0.0001

Ponderal index 5.48 6.98 4.92 4.69 0.0026

Head circumference (cm) 26.2 2.1 33.6 1.3 0.0001

* Values are means standard deviation.

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and serum hormone levels in preterm plus term neonates, adjustedby GA and sex, are shown in Table IV. Cord serum levels of totaland free IGF-I, IGFBP-3, ALS, leptin, and the ratio of free to totalIGF-I had significantly positive correlations with BW. However,cord serum levels of IGFBP-2 had a significantly negative corre-lation with BW. There was no significant correlation between BWand serum concentrations of insulin, GH, IGF-II, IGFBP-1, or IL-6in preterm plus term neonates.

Cord serum levels of total and free IGF-I, ALS, leptin, and theratio of free to total IGF-I had signi ficantly positive correlations,whereas that of IGFBP-2 had a significantly negative correlation,

with BL (Table IV). There was no significant correlation betweenBL and cord serum levels of insulin, GH, IGF-II, IGFBP-1,IGFBP-3, or IL-6 in preterm plus term neonates. Most serumhormones we measured had no significant correlation with HC;free IGF-I had a significantly positive correlation with HC (P 0.0103, R2 0.8389). In addition, cord serum levels of IGF-II hadsignificantly positive correlations with PI in preterm plus termneonates (P 0.0134, R2 0.1117).

Multiple regression analysis between total IGF-I and otherserum hormones in preterm plus term neonates was performedafter adjusting for GA and sex. Serum levels of total IGF-I hadsignificantly positive correlations with free IGF-I (P 0.0001,

TABLE II.

SERUM BIOCHEMICAL CHARACTERISTICS OF PRETERM AND

TERM NEONATES*

Preterm Term P

Albumin (g/L) 46.4 11.4 58.5 5.7 0.0001

Prealbumin (mg/L) 81.8 24.8 100.5 21.4 0.0006Transferrin (g/L) 1.26 0.53 1.42 0.32 NS

RBP (g/L) 10.5 3.8 13.7 4.3 0.0008

Insulin (mU/L) 5.48 6.98 4.92 4.69 NS

Growth hormone (g/L) 22.6 13.5 26.6 14.9 NS

Total IGF-I (g/L) 29.5 14.8 66.5 26.7 0.0001

Free IGF-I (g/L) 1.29 1.33 3.22 1.61 0.0001

Free/total IGF-I 0.055 0.090 0.048 0.021 NS

IGF-II (g/L) 302 62 332 47 0.0169

IGFBP-1 (g/L) 282 241 82 80 0.0001

IGFBP-2 (g/L) 31.3 20.7 23.4 7.33 0.0226

IGFBP-3 (g/L) 744 315 1549 686 0.0001

ALS (mg/L) 1.97 0.97 3.43 1.47 0.0001

Leptin (g/L) 0.58 0.89 5.94 3.38 0.0001

IL-6 (ng/L) 66.6 84.2 12.4 33.4 0.0004

* Values are means standard deviation.

ALS, acid-labile subunit; IGF, insulin-like growth factor; IGFBP,

insulin-like growth factor binding protein; IL-6, interleukin-6; NS, not

significant; RBP, retinol-binding protein.

TABLE III.

CORRELATION COEFFICIENTS BETWEEN GESTATIONAL AGE AND SERUM HORMONES IN PRETERM, TERM, AND PRETERM PLUS

TERM NEONATES*

Preterm Term Preterm plus term

r P r P r P

Insulin 0.1193 NS 0.3410 0.0252 0.1143 NS

Growth hormone 0.3132 NS 0.0502 NS 0.1995 NS

Total IGF-I 0.0765 NS 0.1244 NS 0.5819 0.0001

Free IGF-I 0.2634 NS 0.3248 0.0336 0.4054 0.0002

Free/Total IGF-I 0.2405 NS 0.3112 0.0422 0.1501 NS

IGF-II 0.0469 NS 0.4697 0.0015 0.2670 0.0149

IGFBP-1 0.0566 NS 0.1754 NS 0.4225 0.0001

IGFBP-2 0.4806 0.0026 0.4554 0.0022 0.0307 NS

IGFBP-3 0.1496 NS 0.3490 0.0218 0.5611 0.0001

ALS 0.1135 NS 0.0152 NS 0.4349 0.0001

Leptin 0.5619 0.0004 0.2876 NS 0.7193 0.0001

IL-6 0.3729 NS 0.1497 NS 0.4805 0.0001

* Values are means standard deviation.ALS, acid-labile subunit; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL-6, interleukin-6; NS, not significant.

TABLE IV.

REGRESSIONS OF BIRTH WEIGHT AND BIRTH LENGTH WITH

SERUM HORMONES IN PRETERM PLUS TERM NEONATES*

Birth weight Birth length

P R2 P R2

Insulin NS 0.8276 NS 0.8563

Growth hormone NS 0.8276 NS 0.8547

Total IGF-I 0.0001 0.8641 0.0052 0.8718

Free IGF-I 0.0001 0.8682 0.0005 0.8801

Free/total IGF-I 0.0422 0.8386 0.0310 0.8651

IGF-II NS 0.8298 NS 0.8562

IGFBP-1 NS 0.8343 NS 0.8560

IGFBP-2 0.0005 0.8576 0.0053 0.8717

IGFBP-3 0.0395 0.8389 NS 0.8573

ALS 0.0001 0.8687 0.0003 0.8824

Leptin 0.0002 0.8609 0.0130 0.8683

IL-6 NS 0.8082 NS 0.8577

* Values are the corresponding P and adjusted R2

values after adjust-ment by gestational age and sex.

ALS, acid-labile subunit; IGF, insulin-like growth factor; IGFBP,

insulin-like growth factor binding protein; IL-6, interleukin-6; NS, not

significant.

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R2 0.6009), IGFBP-3 (P 0.0001, R2 0.4556), ALS (P 0.0001, R2 0.5707), and leptin (P 0.0137, R2 0.3469) butsignificantly negative correlations with IGFBP-1 (P 0.0068,R2 0.3776) and IGFBP-2 (P 0.0001, R2 0.4880). Therewere no significant correlations between total IGF-I and IGF-II,GH, insulin, or IL-6 (data not shown). Serum levels of IGF-II hadsignificantly positive correlations with IGFBP-2 (P 0.0008,R2 0.1614), IGFBP-3 (P 0.0001, R2 0.2235), ALS (P 0.0069, R2 0.1074) and leptin (P 0.0031, R2 0.1275). Therewere no significant correlations between IGF-II and free IGF-I,IGFBP-1, GH, insulin, or IL-6 (data not shown).

Predictors of BW, BL, PI, and HC

The results of forward stepwise multivariate regression analysisare shown in Table V. After including all the serum substrates, ourdata showed that GA and cord serum levels of IGFBP-2, leptin,and free IGF-I are the significant predictors of BW in preterm plusterm neonates. In addition, GA and cord serum levels of IGFBP-2,ALS, transferrin, and leptin are the significant predictors of BL;GA and cord serum level of free IGF-I are the significant predic-tors of HC; and serum levels of transferrin, IGFBP-2, and IGF-IIare the significant predictors of PI.

DISCUSSION

The control of growth in the fetus and neonate is complex. Severalhormones, such as insulin, IGFs, IGFBPs, leptin, and cytokines,

have been individually shown to play important roles in regulatingthe fetal growth and nutrition status. The relations between thesehormones and intrauterine growth are still under investigation. Weinvestigated the relation of cord serum levels of GH, IGFs, IG-FBPs, ALS, insulin, leptin, and IL-6 with BW, BL, and HC inpreterm and term neonates. Our results suggested that cord serumlevels of IGF-I, IGF-II, IGFBP-2, ALS, and leptin are importantmediators in regulating the intrauterine growth.

Many fetal tissues, other than the liver, produce abundantamounts of IGF-I and IGF-II.8,17 Therefore, serum levels of IGF-Iand IGF-II should be less affected by the maturation of liverfunction than the conventional nutrition-related serum proteins. Ithas been demonstrated that IGF-I and IGF-II play important rolesin the regulation of fetal growth710 and IGF-II stimulates in uterosomatic overgrowth.14 Several studies have shown that fetalplasma IGF-I and IGF-II levels are lower in the preterm than in theterm neonates15,18 and had positive correlations with BW andGA.9,13,18 In this study, we found differences in cord serum levelsof IGF-I and IGF-II between preterm and term neonates. We alsofound that IGF-I correlates positively with BW and BL and thatIGF-II correlates positively with BW and PI but not with BL inpreterm plus term neonates. Together these findings suggest thatIGF-I and IGF-II are the useful markers in reflecting weight gain

and that IGF-I may be a useful marker in reflecting fetal lengthgain.

Most IGFs in the circulation and tissues are bound to specificcarrier proteins that extend their half-lives and inhibit or enhanceIGF bioavailability and action. In the fetal period, circulatingIGF-I binds mainly with IGFBP-1 and IGFBP-2,19 whereasIGFBP-3 is the main IGF carrier during postnatal life.20 Theaccumulation of IGFBP-1 and IGFBP-2 in fetal serum may inhibitfetal growth,7,9,10,13,15 whereas that of IGFBP-3 may stimulate fetalgrowth.20,21 Few studies have investigated the role of ALS, ahigh-molecular-weight protein bound with IGFBP-3 and IGF-I, infetal growth. In this study, we found that preterm and term neo-nates have significantly different levels of these IGF carrier pro-teins. In addition, IGFBP-1 is negatively correlated, whereasIGFBP-3 and ALS are positively correlated, with GA, suggestinga transition in the expression of binding proteins in the lategestational period. After adjustment with GA and sex, IGFBP-2and ALS correlated significantly with IGF-I, BW, and BL inpreterm plus term neonates. Based on these results, we suggest thatIGFBP-2 and ALS are better serum markers than the other IGFcarrier proteins for evaluating the intrauterine growth.

Free IGF-I, the active form of IGF-I, plays an essential role inaccelerating growth.9,22 There is a linear correlation between freeand total IGF-I. Therefore, we measured the level of free IGF-I andcalculated the ratio of free to total IGF-I to compare the bioavail-ability of IGF-I in preterm and term neonates. Our results showedthat free and total IGF-I paralleled advancing GA. After adjustingfor GA and sex, the ratio of free to total IGF-I correlated positivelywith BW, BL, and HC, which shows that free IGF-I is the major

portion of IGF-I in affecting fetal growth. In this study, free IGF-Iwas about 5% of the total IGF-I in preterm and term neonates,which is higher than the level Kawai et al. reported in infants,children, and adults.22 However, the levels of free and total IGF-Iand the ratio of free to total IGF-I in our term neonates weresimilar to those reported by Klauwer et al. in healthy newborns.23

Therefore, we believe that the high ratio of free to total IGF-Imight be due to the greater requirement of IGF-I for acceleratedfetal development.

Our findings support the concepts that neither IGF-I norIGFBP-3 synthesis is under GH control in fetal growth14,21; theGHIGF axis may be immature in the fetus and at birth; and thesignificant impact of insulin on fetal growth may not be found inpreterm and term neonates with weights appropriate for GA. It hasbeen reported that leptin derived from placenta or fetal adipose

tissue correlates positively with fetal growth11,12 with or withoutsex differences.12,24 We observed no sex difference in leptin, but

TABLE V.

FORWARD STEPWISE MULTIVARIATE REGRESSION ANALYSIS

OF PREDICTORS OF BIRTH WEIGHT, BIRTH HEIGHT, AND

HEAD CIRCUMFERENCE IN PRETERM PLUS TERM NEONATES*

Estimate Standard error P

Birth weightIntercept 2621.39 338.07 0.0001

GA 139.22 10.91 0.0001

IGFBP-2 11.19 3.10 0.0006

Leptin 63.32 15.99 0.0002

Free IGF-I 64.61 30.97 0.0405

Birth length

Intercept 10.1689 2.2393 0.0001

GA 1.0484 0.0688 0.0001

IGFBP-2 0.0589 0.0185 0.0021

ALS 0.4767 0.2281 0.0402

Transferrin 0.0199 0.0666 0.0038

Leptin 0.2391 0.1103 0.0335

Ponderal index

Intercept 1.5711 0.2305 0.0001

Transferrin 0.0044 0.0010 0.0001

IGFBP-2 0.0155 0.0047 0.0017

IGF-II 0.0019 0.0008 0.0203

Head circumference

Intercept 7.1869 1.3911 0.0001

GA 0.6426 0.0416 0.0001

Free IGF-I 0.3401 0.1259 0.0088

* All variables significantly correlated with birth weight, birth length,

ponderal index, or head circumference were included in the initial

model. The R2 values were 0.9007 for the model of birth weight, 0.9035

for the model of birth length, 0.3657 for the model of ponderal index,

and 0.8372 for the model of head circumference.

ALS, acid-labile subunit; IGF, insulin-like growth factor; IGFBP,

insulin-like growth factor binding protein; IL-6, interleukin-6.

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leptin correlated positively with GA, BW, BL, and total IGF-I.These observations may be explained by the increased expressionof leptin during the late gestational period; the increased leptinlevels may reflect more body fat in term neonates; and leptin playsan important role in regulating intrauterine growth in a sex-independent manner.

Fetally derived IL-6 was shown to play a role in the physiologyof normal pregnancy and the pathophysiology of abnormal preg-

nancy.14

Moreover, IL-6 mediated decrease in IGF-I production isthe major mechanism affecting growth in mice.25,26 For pretermand term neonates with BW appropriate for GA, we found noinverse relation between IL-6 and total IGF-I. However, pretermneonates had higher levels of IL-6 than did term neonates, whichimplicates IL-6 as a useful marker for predicting preterm labor, asreported by Dudley et al.26 The role of IL-6 in regulating intra-uterine growth needs further investigation.

To our knowledge, no study has compared the relation of theGHIGF axis, IGFBPs, insulin, leptin, and IL-6 with GA, BW, BL,HC, and PI in preterm and term neonates in one study. With theforward stepwise multivariate regression analysis, we sought themost powerful serum markers reflecting intrauterine growth. Thereis no doubt that GA is the strongest factor affecting BW, BL, PI,and HC. Among all of the serum hormones we measured,

IGFBP-2, leptin, free IGF-I, IGF-II, and ALS were the best can-didates for predicting fetal growth. In summary, our results suggestthat IGF-I, IGF-II, IGFBP-2, ALS, and leptin play important rolesin regulating intrauterine growth.

SUMMARY

The concentrations of IGFs, IGFBPs, leptin, and IL-6 in umbilicalcord blood samples were measured and their relation with BW wasinvestigated in preterm and term neonates. The data suggested thatIGF-I, IGF-II, IGFBP-2, ALS, and leptin are the most importantfactors in intrauterine growth.

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