International Journal of Pediatrics

Volume 2013 (2013), Article ID 191472, 7 pages

http://dx.doi.org/10.1155/2013/191472

Clinical Study

Maternal BMI, IGF-I Levels, and Birth Weight in African American and White Infants

Adriana C. Vidal,¹ Amy P. Murtha,² Susan K. Murphy,³ Kimberly Fortner,⁴ Francine Overcash,⁵ Nikki Henry,⁶ Joellen M. Schildkraut,⁷ Michele R. Forman,⁸ Wendy Demark-Wahnefried,⁹ Joanne Kurtzberg,¹⁰ Randy Jirtle,¹¹ and Cathrine Hoyo¹²

¹Department of Obstetrics and Gynecology and Program of Cancer Detection, Prevention and Control, Duke University School of Medicine, Durham, NC 27710, USA

²Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA

³Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA

⁴Division of Maternal Fetal Medicine, Department Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

⁵Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA

⁶Duke University School of Medicine, Durham, NC 27710, USA

⁷Department of Community and Family Medicine and Program of Cancer Detection, Prevention and Control, Duke University Medical Center, Durham, NC 27710, USA

⁸Department of Epidemiology, The University of Texas at Austin, Austin, TX 78712, USA

⁹Department of Nutrition Sciences and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

¹⁰Carolina Cord Blood Bank, Duke University Medical Center, Durham, NC 27710, USA

¹¹Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA

¹²Division of Epidemiology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA

Received 18 January 2013; Revised 9 May 2013; Accepted 9 May 2013

Academic Editor: Steven M. Donn

Copyright © 2013 Adriana C. Vidal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation) were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile), those with higher IGF-I levels (>3rd tertile) were 130 g heavier at birth, (, , ), after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30 kg/m²; the cross product term for IGF-I and maternal BMI was statistically significant (). Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity.

1. Introduction

Low birth weight (LBW) and high birth weight (HBW) are both important indicators of suboptimal intrauterine development and have been linked to risk of several chronic diseases later in life. HBW has been associated with childhood and adult obesity [1] and some cancers, including breast [2] and prostate cancer [3], whereas LBW is a consistently identified risk factor for cardiovascular disease (CVD) [4, 5] and type 2 diabetes (T2D) [6, 7].

IGF-I is a mitogenic and antiapoptotic paracrine growth factor expressed in all fetal organs [8, 9], and is essential in fetal and neonatal growth, differentiation and development [10–14]. Several lines of evidence suggest that IGF-I levels are associated with birth weight [15–26]; furthermore higher IGF-I levels are associated with higher BW, but not with lower birth weight [16, 17, 26]. In adulthood, elevated concentrations of IGF-I are associated with an increased risk of obesity and many cancers, including breast, lung, head and neck, colorectal, pancreas, synovial sarcoma, and prostate cancer [26–31]. Although concentrations of circulating IGF-I levels vary considerably by race/ethnicity and maternal prepregnancy obesity, few studies included African American women [24–26], an ethnic group that has an almost 9% higher BMI than European-American women [32]. Furthermore, studies examining both maternal obesity, an increasingly common condition, and race/ethnicity are few [33–35]. Herein, we examine associations between IGF-I levels in relation to body size at birth in a cohort of infants born to obese and non-obese African American and White women.

2. Subjects and Methods

Ethics Statement. The study protocol was approved by the Duke University Institutional Review Board (IRB). We obtained written informed consent from all participants involved in our study. We also obtained informed written consent from carers or guardians on the behalf of the minors/children participants involved in our study.

2.1. Study Participants

Pregnant women were enrolled as part of the Newborn Epigenetics STudy (NEST), a prospective study of women and their infants. Detailed methods for enrollment of study participants have been reported elsewhere [36]. Briefly, pregnant women who were 18 years and older and who planned to give birth at Duke University or Durham Regional Hospitals were recruited from Durham County, NC prenatal clinics. HIV-1 infected women were excluded. Of the 1101 women approached, 940 (85%) consented and were enrolled; most of the enrolled sample (81%) was successfully followed to delivery (). IGF-I analyses were performed on the first 251 women and had a gestational age ≥37 weeks. Data from these participants were comparable to participants in whom IGF-I was not measured with respect to maternal age, gestational age, race/ethnicity, and maternal prepregnancy BMI.

2.2. Data Collection

Interviewer- or self-administered questionnaires were obtained at the time of enrollment and medical records during pregnancy were abstracted at parturition. Data collected using questionnaires included sociodemographic characteristics, reproductive factors, and lifestyle factors such as cigarette smoking and self-reported prepregnancy anthropometric measurements. Information on anthropometric measurements during pregnancy, birth outcomes, including birth weight and length, was abstracted from medical records. Umbilical cord blood specimens were also collected at birth, as previously described [36, 37].

2.3. IGF-I Cord Blood Levels

Plasma concentrations of IGF-I were measured using microplate enzyme-linked immunosorbent assays (ELISA, Diagnostic Systems Laboratories, Webster, TX, USA) according to the manufacture instructions, and triplicate assays per sample were performed. Absorbance was read using a microplate reader (DSL, Webster, TX, USA). The plasma IGF-I concentrations ranged from 3.65 ng/L to 418.36 ng/L, and assay sensitivity was 2.2 ng/mL.

2.4. Statistical Analysis

Infant birth weight was normally distributed and was used as a continuous variable. Because both high birth weight (HBW) and low birth weight (LBW) have been linked to maternal obesity [1], we also analyzed birth weight as a categorical variable: LBW, <2500 g, normal birth weight, 2500–4000 g, and HBW, >4000 g. We used chi-squared tests to examined distribution of factors that have been previously associated with birth weight >4000 g and <2500 g in relation to maternal age (categorized as 18–25, 26–30, and >30 years); prepregnancy mothers’ body mass index (BMI) (categorized as <30 and ≥30 kg/m²); race/ethnicity (categorized as White, African American, and other); and maternal education (categorized as less than college, college, and graduate level education), maternal smoking, and infant gender. Although some of these factors were not statistically significantly associated with BW in this study, we adjusted for maternal age, BMI, race, education, delivery route, gestational age at delivery, maternal smoking during pregnancy, and infant gender, as they are associated with BW and IGF-I in the population. The distribution of IGF-I levels departed from normality and thus they were categorized into tertiles. We then dichotomized at the top tertile (67th percentile) and compared this tertile (high IGF-I; >67th percentile) to the remainder (low IGF-I; ≤67th percentile). Linear regression models were used to examine the extent to which IGF-I levels differed by birth weight, as described in [36]. All statistical analyses were conducted in SAS v9.2 (SAS Institute Inc., Cary, NC, USA).

3. Results

Approximately 4% of the 251 newborns were born <2500 g and ~8% were born >4000 g. Mean gestational age at delivery was 39 weeks (). Table 1 summarizes the characteristics of the study participants in relation to birth weight. Most low birth weight infants (<2500 g) were born to African Americans (89%), cigarette smokers (before and during pregnancy, 80%), and those with a lower educational achievement (67%); however the differences were not statistically significant. LBW were however comparable to infants born 2500–4000 g with respect to maternal age. HBW infants were comparable to those born 2500–4000 g with respect to education and maternal smoking, although they were more frequently born to white women and those with a BMI ≥30 before pregnancy. No statistically significant differences in IGF-I levels were found between birth weight <2500 g infants and birth weight >4000 g infants; however birth weight <2500 g infants were born two weeks earlier than infants born 2500–4000 g and birth weight >4000 g infants () (Table 1).

Table 1: Characteristics of study participants.

Characteristic
Birth weight

<2500 g ()
2500–4000 g ()
>4000 ()
value

Maternal age at enrollment (yrs)

0.79

    18–25 ()
4 (40%)
67 (31%)
6 (28.5%)

    26–30 ()
4 (40%)
65 (30%)
6 (28.5%)

    >30 ()
2 (20%)
86 (39%)
9 (43%)

Maternal BMI before pregnancy

0.17

    <30 ()
7 (87.5%)
140 (71%)
11 (55%)

    ≥30 ()
1 (12.5%)
56 (29%)
9 (45%)

    Mean BMI
26.61 (SD = 4.8)
28.4 (SD = 9.4)
31.3 (SD = 12.3)
0.37

Race/ethnicity

0.1

    African American ()
8 (89%)
110 (51%)
8 (38%)

    White ()
1 (11%)
85 (39%)
9 (43%)

    Other ()
0 (0%)
21 (9.7%)
4 (19%)

Education

0.18

    <High School HS Graduate/GED ()
6 (67%)
79 (39%)
9 (43%)

    Some College/College Graduate/
3 (33%)
136 (63%)
12 (57%)

    Graduate education ()

Maternal smoking

0.14

    Never smoked ()
2 (20%)
120 (55%)
13 (62%)

    Smoked during pregnancy ()
3 (30%)
36 (17%)
1 (5%)

    Quit smoking before pregnancy ()
5 (50%)
62 (28%)
7 (33%)

Gender of infant

0.12

    Male ()
5 (50%)
86 (39%)
13 (62%)

    Female ()
5 (50%)
132 (61%)
8 (38%)

Delivery route

0.75

    Vaginal ()
7 (70%)
131 (61%)
10 (48%)

    Caesarean section ()
3 (30%)
86 (39%)
11 (52%)

Gestational age at delivery in weeks

0.006

    Mean (SD)
37 (0.22)
39 (1.11)
39 (0.93)

IGF-I

0.12

    ≤3rd Tertile ()
5 (50%)
153 (70%)
11 (52%)

    >3rd Tertile ()
5 (50%)
65 (30%)
10 (48%)

Numbers do not necessarily add up due to missing values.

Median IGF-I concentration in newborns was 35.55 ng/L (IQR, 17.35–65.68) with a mean of 58.92 ng/L. Birth weight ranged between 2000 and 5160 g (, ). Infants with higher levels of IGF-I (>3rd tertile) were born slightly heavier than infants with lower IGF-I concentrations (≤3rd tertile), although the differences were not statistically significant. Infants with higher IGF-I levels were comparable to those with lower levels with respect to maternal age (), race (), maternal education (), maternal smoking (), obesity (), and gestational age () (Table 2), although they may differ by delivery route ().

Table 2: Characteristics of study participants by Infant IGF-I levels (ng/L).

IGF-I Levels
value

≤3rd tertile ()

>3rd tertile ()

Maternal age at enrollment (yrs)

0.65

    18–25 ()
50 (29%)
28 (35%)

    26–30 ()
54 (32%)
22 (27%)

    >30 ()
66 (68%)
31 (38%)

Maternal BMI

0.28

    <30 ()
104 (68%)
55 (75%)

    ≥30 ()
48 (32%)
18 (25%)

Race

0.83

    African American ()
86 (51%)
40 (500%)

    White ()
64 (38%)
33 (4111%)

    Other ()
18 (11%)
7 (9%)

Education

0.38

    <High School HS Graduate/GED ()
67 (40%)
28 (35%)

    Some College/College Graduate/
99 (60%)
53 (65%)

    Graduate Education ()

Delivery route

0.14

    Vaginal ()
94 (55%)
55 (68%)

    Caesarean section ()
75 (44%)
26 (32%)

Maternal smoking

0.63

    Never smoked ()
95 (56%)
40 (49%)

    Smoked during periconception ()
27 (16%)
15 (19%)

    Quit smoking before periconception ()
48 (28%)
26 (32%)

Gender of infant

0.29

    Male ()
75 (44%)
30 (37%)

    Female ()
95 (56%)
51 (63%)

Mean Gestational age in weeks (SD)*
39 (1.16)
39 (1.08)
0.91

Mean Birth weight (SD)*
3273 (460.6)
3414.74 (523.5)

0.56

Numbers do not necessarily add up due to missing values.

*Unadjusted.

Table 3 shows coefficient estimates (’s) and their standard errors (SEs) for five multivariate linear regression models of birth weight on IGF-I levels, in which IGF-I ≤67th percentile concentrations or ≤3rd tertile served as referents; one for all participants, one restricted to African Americans, one restricted to Whites, one restricted to maternal BMI <30, and one restricted to maternal BMI ≥30. The first model shows that after adjusting for infant gender, race, gestational age at delivery, delivery route, maternal BMI and smoking during pregnancy, infants in the upper tertile of IGF-I were larger at birth (, , ), corresponding to 130 g increased birth weight in infants born to those with high IGF-I levels (Table 3). We also found that this association was slightly higher in African American infants () compared to White infants (). However, the cross-product term for race and IGF-I was not significant (). Since the prevalence of BMI ≥30 in African American women in our study is higher (67%) compared to Whites (24%) , we examined the role of maternal BMI on the relationship between IGF-I levels and birth weight. The pair of models restricted by BMI revealed that the association of IGF-I levels and infant size was limited to women with a BMI ≥30 (, , ). We found a strong positive association in infants born to obese women; the cross-product term for maternal BMI and IGF-I was .

Table 3: 1Adjusted regression coefficients and standard errors (SE) for the associations between newborn IGF-I and Birth Weight in African American and White infants.

Birth weight

All

()
African American

()
Whites

()
Maternal BMI < 30

()
Maternal BMI ≥ 30

()

-coefficient, SE,

value
-coefficient, SE,

value
-coefficient, SE,

value
-coefficient, SE,

value
-coefficient, SE,

value

High IGF-I**
230.46, 58.0, 0.0001
280.98, 90.24, 0.002
202.05, 89.72, 0.02
122.31, 62.65, 0.05
617.78, 134.68, <0.0001

Female infants***
−51.7, 55.68, 0.35
67.36, 80.54, 0.40
−172.47, 90.08, 0.06
−137.68, 62.1, 0.03
146.20, 111.10, 0.19

White Race****
240.60, 63.07, 0.0002
—
—
202.11, 46.26, <0.0001
35.21, 87.27, 0.68

High maternal BMI (≥30)∧
201.68, 62.55, 0.001
261.81, 82.95, 0.002
161.64, 125.81, 0.2
—
—

Gestational age at delivery∧ ∧
205.92, 23.84, <0.0001
206.58, 35.92, <0.0001
172.63, 37.79, <0.0001
213.25, 24.9, <0.0001
187.13, 54.47, 0.001

Smoking during

Pregnancy∧ ∧∧
−8.11, 31.02, 0.79
−5.90, 47.40, 0.90
−39.63, 47.26, 0.40
−46.36, 33.28, 0.16
2.36, 68.16, 0.97

Delivery route∧ ∧∧ ∧
151.57, 56.58, 0.008
229.73, 84.34, 0.008
74.06, 86.27, 0.40
146.23, 62.58, 0.03
178.73, 111.78, 0.11

Factors mutually adjusted for each other: IGF-I levels, infant gender, race, maternal BMI, maternal smoking, delivery route, and gestational age at delivery, to predict birth weight.

**Referents are individuals with lower (≤3rd Tertile) IGF-I at delivery.

***Referents are male infants.

****Referents are African Americans.

∧Referents are BMI < 30.

∧ ∧Referents are lower gestational age.

∧ ∧∧Referents are nonsmoking mothers.

∧ ∧∧ ∧Referents are vaginal delivery infants.

4. Discussion

Our key finding was a positive association among term infants with elevated IGF-I levels and an increased risk of higher birth weight. This positive association was most apparent in infants born to obese women. High birth weight and high IGF-I levels—a potent mitogen—have been linked to CVD, T2D, and some cancers [2–7]. Importantly, our data also demonstrate that, after accounting for maternal obesity before pregnancy, the influence of ethnicity/race on the association between IGF-I and birth weight (an important risk factor for common chronic diseases) is dramatically diminished.

The extent to which the positive association between IGF-I at birth and early postnatal growth that is maintained during life course to adulthood is still unclear, although a few studies report that elevated IGF-I levels measured at birth are associated with age 4-5 year obesity [38, 39].

IGF-I levels found in this study (median = 36 ng/L, ICR 17 ng/L–66 ng/L) are slightly lower than those reported in previous studies [25]; however our findings that higher IGF-I levels at birth are associated with increased birth weight are consistent with those of others [18], and with reports which found positive associations between both placental [40] and cord plasma IGF-I concentrations and lower birth weight infants, compared with IGF-I concentrations in normal birth weight infants [19, 41–44]. Our findings however contrast with those of Wang et al. [45] and Deiber et al. [46], who found low birth weight associated with higher IGF-I in populations of infants born to White women. Divergent findings may be due, in part, to lower incidence of maternal obesity among European women; the strongest association between IGF-I and birth weight was found in infants born to obese women. It is speculated that such differences may involve the IGF axis through IGF-I and growth hormone (GH) signaling, which differ by obesity [21, 23, 47].

These race/ethnic similarities exist despite IGF-I concentrations being generally lower in African American than in White neonates born with normal weight, as shown in male [25] and in female newborns [26], and in studies performed in adults [33].

Our findings that elevated IGF-I levels are associated with increased birth weight in infants born to obese mothers, are consistent with at least three other studies comprising European, Maori, South Asian, and Pacific Islands’ cohorts [33, 47, 48], supporting the hypothesis that IGF-I and insulin resistance perhaps driven by genetic factors may play a role in fetal growth. IGF-I levels in pregnant women have been positively correlated with maternal body weight [33, 49]. Maternal insulin sensitivity has been proposed as an important endogenous environmental factor in fetal size [50]. Maternal hyperglycemia, a correlate of obesity, even considered in the normal range, may affect fetal weight [51]. Together, these findings suggest that the IGF axis may play a key role in fetal overgrowth and maternal obesity may be an important driver in placental IGF-axis concentrations, and thus increasing the risk for higher birth weight and infant obesity in childhood.

The main limitation of this study was relatively small sample size for analyses restricted to maternal BMI ( versus ); however, findings are consistent with the expected role of IGF-I, and IGF-I values themselves (range, median, and skewness of IGF-I levels) and the magnitude of the positive associations with higher birth weight and growth are similar to previous reports [25, 26]. Also, we relied on a single measure of IGF-I levels at delivery; however it was not feasible to obtain IGF-I levels before birth in these infants. However, at least postnatally, interindividual variation seems stable and most studies relating cord blood IGF-I protein concentrations and birth weight reported single measurements at birth [18, 52], and findings are similar. Consideration should also be given to the fact that infant’s race/ethnicity is the self-reported mother’s race/ethnicity and the study is predominantly African Americans and Whites. Future studies should use ancestral markers to further clarify race specific associations. Another limitation was that we did not measure other components of the IGF axis, including growth hormone, insulin, IGF binding proteins (IGFBP1-5), and receptors’ (IGF-1R and 2R) concentrations in the newborns, to further establish the potential implication of other components of the IGF system in fetal growth. However the assay used measured total cord blood IGF-I in circulation. Despite these limitations, our findings support the hypothesis that elevated IGF-I is an important growth factor in early development that has been linked to a number of common chronic diseases, regardless of race/ethnicity.

In summary, we found that elevated IGF-I levels in newborns increase the risk of higher birth weight in African American and White infants. Our findings also suggest that maternal BMI ≥30 may modify positive associations between IGF-I and higher birth weight, supporting the idea that maternal obesity may be key in increasing the risk of higher birth weight in the newborns, an important risk factor for several chronic diseases, including cancer. These findings suggest that the potential utility of IGF-I levels as a marker of future obesity in the offspring is limited to those born to obese women. As the prevalence of maternal obesity continues to increase, larger multiethnic studies with followup at shorter intervals that allow for maternal obesity-specific analyses are required to further elucidate the nature of the positive association between IGF-I levels and higher birth weight.

Conflict of Interests

The authors declare no conflict of interests.

Acknowledgments

The authors are grateful to the participants in the NEST study project, without whom this work would not have been possible. They thank Stacy Murray for her recruiting efforts. This work was funded by NIH R01-ES016772 and R01CA142983-02S1. The Newborn Epigenetics Study (NEST) was funded through the US National Institutes of Health (Agreement no. R01ES016772).

References

Z. B. Yu, S. P. Han, G. Z. Zhu et al., “Birth weight and subsequent risk of obesity: a systematic review and meta-analysis,” Obesity Reviews, vol. 12, no. 7, pp. 525–542, 2011.

A. H. Wu, R. McKean-Cowdin, and C. C. Tseng, “Birth weight and other factors and risk of breast cancer in Asian-Americans,” Breast Cancer Research and Treatment, vol. 130, pp. 917–925, 2011.

T. I. L. Nilsen, P. R. Romundstad, R. Troisi, and L. J. Vatten, “Birth size and subsequent risk for prostate cancer: a prospective population-based study in Norway,” International Journal of Cancer, vol. 113, no. 6, pp. 1002–1004, 2005.

A. J. Drake and B. R. Walker, “The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk,” Journal of Endocrinology, vol. 180, no. 1, pp. 1–16, 2004.

D. J. P. Barker, C. Osmond, J. Golding, D. Kuh, and M. E. J. Wadsworth, “Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease,” British Medical Journal, vol. 298, no. 6673, pp. 564–567, 1989.

C. N. Hales and D. J. P. Barker, “Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis,” Diabetologia, vol. 35, no. 7, pp. 595–601, 1992.

P. H. Whincup, S. J. Kaye, C. G. Owen et al., “Birth weight and risk of type 2 diabetes a systematic review,” Journal of the American Medical Association, vol. 300, no. 24, pp. 2886–2897, 2008.

G. J. Allan, D. J. Flint, and K. Patel, “Insulin-like growth factor axis during embryonic development,” Reproduction, vol. 122, no. 1, pp. 31–39, 2001.

M. E. Fant and D. Weisoly, “Insulin and insulin-like growth factors in human development: implications for the perinatal period,” Seminars in Perinatology, vol. 25, no. 6, pp. 426–435, 2001.

J. Baker, J. P. Liu, E. J. Robertson, and A. Efstratiadis, “Role of insulin-like growth factors in embryonic and postnatal growth,” Cell, vol. 75, no. 1, pp. 73–82, 1993.

R. Baserga, F. Peruzzi, and K. Reiss, “The IGF-1 receptor in cancer biology,” International Journal of Cancer, vol. 107, no. 6, pp. 873–877, 2003.

L. C. Giudice, “Maternal-fetal conflict—lessons from a transgene,” Journal of Clinical Investigation, vol. 110, no. 3, pp. 307–309, 2002.

J. Nakae, Y. Kido, and D. Accili, “Distinct and overlapping functions of insulin and IGF-I receptors,” Endocrine Reviews, vol. 22, no. 6, pp. 818–835, 2001.

M. N. Pollak, E. S. Schernhammer, and S. E. Hankinson, “Insulin-like growth factors and neoplasia,” Nature Reviews Cancer, vol. 4, no. 7, pp. 505–518, 2004.

K. Langford, W. Blum, K. Nicolaides, J. Jones, A. McGregor, and J. Miell, “The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition?” European Journal of Clinical Investigation, vol. 24, no. 12, pp. 851–856, 1994.

C. Lassarre, S. Hardouin, F. Daffos, F. Forestier, F. Frankenne, and M. Binoux, “Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation,” Pediatric Research, vol. 29, no. 3, pp. 219–225, 1991.

I. K. Ashton, J. Zapf, I. Einschenk, and I. Z. MacKenzie, “Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy,” Acta Endocrinologica, vol. 110, no. 4, pp. 558–563, 1985.

K. Ong, J. Kratzsch, W. Kiess, M. Costello, C. Scott, and D. Dunger, “Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 11, pp. 4266–4269, 2000.

G. Á. Martos-Moreno, V. Barrios, M. S. De Pipaón et al., “Influence of prematurity and growth restriction on the adipokine profile, IGF1, and ghrelin levels in cord blood: relationship with glucose metabolism,” European Journal of Endocrinology, vol. 161, no. 3, pp. 381–389, 2009.

P. Zhao, X. L. Zhang, C. Yu, X. Y. Lu, and Y. M. Wang, “Umbilical cord serum levels of insulin-like growth factor-1, insulin and growth hormone in neonates with intrauterine growth retardation,” Zhongguo Dang Dai Er Ke Za Zhi, vol. 12, no. 10, pp. 771–773, 2010.

M. P. P. Geary, P. J. Pringle, C. H. Rodeck, J. C. P. Kingdom, and P. C. Hindmarsh, “Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 8, pp. 3708–3714, 2003.

P. D. Gluckman, J. J. J. Barrett, and J. H. Butler, “Studies of insulin-like growth factor -I and -II by specific radioligand assays in umbilical cord blood,” Clinical Endocrinology, vol. 19, no. 3, pp. 405–413, 1983.

L. J. Vatten, S. T. Nilsen, R. A. Ødegård, P. R. Romundstad, and R. Austgulen, “Insulin-like growth factor I and leptin in umbilical cord plasma and infant birth size at term,” Pediatrics, vol. 109, no. 6, pp. 1131–1135, 2002.

M. S. Boyne, M. Thame, F. I. Bennett, C. Osmond, J. P. Miell, and T. E. Forrester, “The relationship among circulating insulin-like growth factor (IGF)-I, IGF-binding proteins-1 and -2, and birth anthropometry: a prospective study,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1687–1691, 2003.

S. Rohrmann, C. G. Sutcliffe, J. L. Bienstock et al., “Racial variation in sex steroid hormones and the insulin-like growth factor axis in umbilical cord blood of male neonates,” Cancer Epidemiology Biomarkers and Prevention, vol. 18, no. 5, pp. 1484–1491, 2009.

T. Agurs-Collins, S. Rohrmann, C. Sutcliffe et al., “Racial variation in umbilical cord blood sex steroid hormones and the insulin-like growth factor axis in African-American and white female neonates,” Cancer Causes Control, vol. 23, pp. 445–454, 2012.

M. H. Wu, Y. C. Chou, W. Y. Chou et al., “Relationships between critical period of estrogen exposure and circulating levels of insulin-like growth factor-I (IGF-I) in breast cancer: evidence from a case-control study,” International Journal of Cancer, vol. 126, no. 2, pp. 508–514, 2010.

M. M. Rajski, R. Zanetti-Dällenbach, B. Vogel, R. Herrmann, C. Rochlitz, and M. Buess, “IGF-I induced genes in stromal fibroblasts predict the clinical outcome of breast and lung cancer patients,” BMC Medicine, vol. 8, article 1, 2010.

J. B. Douglas, D. T. Silverman, M. N. Pollak, Y. Tao, A. S. Soliman, and R. Z. Stolzenberg-Solomon, “Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial,” Cancer Epidemiology Biomarkers and Prevention, vol. 19, no. 9, pp. 2298–2306, 2010.

P. Stattin, A. Bylund, S. Rinaldi et al., “Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study,” Journal of the National Cancer Institute, vol. 92, no. 23, pp. 1910–1917, 2000.

J. M. Chan, M. J. Stampfer, E. Giovannucci et al., “Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study,” Science, vol. 279, no. 5350, pp. 563–566, 1998.

M. D. Holmes, M. J. Stampfer, A. M. Wolf et al., “Can behavioral risk factors explain the difference in body mass index between African-American and European-American women?” Ethnicity and Disease, vol. 8, no. 3, pp. 331–339, 1998.

H. Olausson, M. Löf, K. Brismar, E. Forsum, and A. Sohlström, “Maternal serum concentrations of insulin-like growth factor (IGF)-I and IGF binding protein-1 before and during pregnancy in relation to maternal body weight and composition and infant birth weight,” British Journal of Nutrition, vol. 104, no. 6, pp. 842–848, 2010.

K. D. Henderson, M. I. Goran, L. N. Kolonel, B. E. Henderson, and L. Le Marchand, “Ethnic disparity in the relationship between obesity and plasma insulin-like growth factors: the multiethnic cohort,” Cancer Epidemiology Biomarkers and Prevention, vol. 15, no. 11, pp. 2298–2302, 2006.

S. M. Nelson, P. Matthews, and L. Poston, “Maternal metabolism and obesity: modifiable determinants of pregnancy outcome,” Human Reproduction Update, vol. 16, no. 3, Article ID dmp050, pp. 255–275, 2009.

C. Hoyo, A. P. Murtha, J. M. Schildkraut et al., “Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy,” Epigenetics, vol. 6, pp. 928–936, 2011.

E. Perkins, S. K. Murphy, A. P. Murtha et al., “Insulin-like growth factor 2/H19 methylation at birth and risk of overweight and obesity in children,” Journal of Pediatrics, vol. 161, pp. 31–39, 2012.

K. Ong, J. Kratzsch, W. Kiess, and D. Dunger, “Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 3, pp. 1041–1044, 2002.

C. H. D. Fall, A. N. Pandit, C. M. Law et al., “Size at birth and plasma insulin-like growth factor-1 concentrations,” Archives of Disease in Childhood, vol. 73, no. 4, pp. 287–293, 1995.

S. K. Akram, C. Carlsson-Skwirut, Z. A. Bhutta, and O. Soder, “Placental IGF-I, IGFBP-1, zinc, and iron, and maternal and infant anthropometry at birth,” Acta Paediatrica, vol. 100, pp. 1504–1509, 2011.

V. L. Clifton, N. A. Hodyl, V. E. Murphy, W. B. Giles, R. C. Baxter, and R. Smith, “Effect of maternal asthma, inhaled glucocorticoids and cigarette use during pregnancy on the newborn insulin-like growth factor axis,” Growth Hormone and IGF Research, vol. 20, no. 1, pp. 39–48, 2010.

P. Zhao, X. L. Zhang, C. Yu, X. Y. Lu, and Y. M. Wang, “Umbilical cord serum levels of insulin-like growth factor-1, insulin and growth hormone in neonates with intrauterine growth retardation,” Zhongguo Dang Dai Er Ke Za Zhi, vol. 12, no. 10, pp. 771–773, 2010.

N. Ohkawa, H. Shoji, T. Kitamura et al., “IGF-I, leptin and active ghrelin levels in very low birth weight infants during the first 8 weeks of life,” Acta Paediatrica, vol. 99, no. 1, pp. 37–41, 2010.

C. Chiesa, J. F. Osborn, C. Haass et al., “Ghrelin, leptin, IGF-1, IGFBP-3, and insulin concentrations at birth: is there a relationship with fetal growth and neonatal anthropometry?” Clinical Chemistry, vol. 54, no. 3, pp. 550–558, 2008.

H. S. Wang, J. Lim, J. English, L. Irvine, and T. Chard, “The concentration of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in human umbilical cord serum at delivery: relation to fetal weight,” Journal of Endocrinology, vol. 129, no. 3, pp. 459–464, 1991.

M. Deiber, P. Chatelain, D. Naville, G. Putet, and B. Salle, “Functional hypersomatotropism in small for gestational age (SGA) newborn infants,” Journal of Clinical Endocrinology and Metabolism, vol. 68, no. 1, pp. 232–233, 1989.

W. Ricart, J. Lopez, J. Mozas et al., “Maternal glucose tolerance status influences the risk of macrosomia in male but not in female fetuses,” Journal of Epidemiology & Community Health, vol. 63, pp. 64–68, 2009.

D. Simmons, “Interrelation between umbilical cord serum sex hormones, sex hormone- binding globulin, insulin-like growth factor I, and insulin in neonates from normal pregnancies and pregnancies complicated by diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 7, pp. 2217–2221, 1995.

F. A. Hills, J. English, and T. Chard, “Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birthweight and maternal weight,” Journal of Endocrinology, vol. 148, no. 2, pp. 303–309, 1996.

P. M. Catalano, J. P. Kirwan, S. Haugel-De Mouzon, and J. King, “Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus,” Journal of Nutrition, vol. 133, no. 5, pp. 1674S–1683S, 2003.

B. Hoegsberg, P. A. Gruppuso, and D. R. Coustan, “Hyperinsulinemia in macrosomic infants of nondiabetic mothers,” Diabetes Care, vol. 16, no. 1, pp. 32–36, 1993.

W. Y. Sei and S. Y. Jee, “Relationship of insulin-like growth factor-I, insulin-like growth factor binding protein-3, insulin, growth hormone in cord blood and maternal factors with birth height and birthweight,” Pediatrics International, vol. 42, no. 1, pp. 31–36, 2000.