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The Relationship among Circulating Insulin-Like Growth Factor (IGF)-I, IGF-Binding Proteins-1 and -2, and Birth Anthropometry: A Prospective Study

Tropical Metabolism Research Unit (M.S.B., M.T., F.I.B., T.E.F.), Tropical Medicine Research Institute, The University of the West Indies, Mona, Kingston 7, Jamaica; Medical Research Council Environmental Epidemiology Unit (C.O.), University of Southampton, Southampton General Hospital, Southampton, United Kingdom SO16 6YD; and Department of Medicine (J.P.M.), King’s College School of Medicine and Dentistry, London, United Kingdom SE5 9PJ

Address all correspondence and requests for reprints to: Prof. Terrence E. Forrester, Tropical Metabolism Research Unit, Tropical Medicine Research Institute, The University of the West Indies, Mona, Kingston 7, Jamaica. E-mail: tesgf{at}mail.infochan.com.

	Abstract

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Fetal IGF-I is a determinant of birth weight, but whether maternal IGF-I plays a significant role is controversial. We sought to examine the relationships among maternal IGF-I, IGF-binding protein (IGFBP)-1, and IGFBP-2, with maternal and newborn anthropometry, in a cohort of 325 nondiabetic pregnant women of African origin. Blood was collected for IGF-I, IGFBP-1, and IGFBP-2 at 9, 25, and 35 wk gestation and in cord blood at delivery.

In the second and third trimesters, maternal IGF-I was significantly correlated (P < 0.005) with maternal body mass index and triceps skinfold thickness. Maternal IGFBP-1 and -2 had an inverse correlation (P < 0.0001), with maternal anthropometry. Maternal IGF-I at 35 wk, and fetal IGF-I by cord blood were significantly correlated with birth weight (P = 0.001 and 0.048, respectively). IGFBP-1 in the third trimester and cord blood were negatively correlated with birth weight (P = 0.012 and 0.002). In multiple regression analyses, maternal IGF-I at 35 wk, fetal IGF-I, maternal weight at the first antenatal visit, gender, and gestational age were significant independent factors in the determination of birth weight. In conclusion, maternal IGF-I levels, especially during late pregnancy, positively influence birth weight.

	Introduction

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FETAL GROWTH IN healthy pregnancies is the result of the complex interplay of genetic, nutritional, and endocrine factors. Three peptide hormones that share structural homology (IGF-I and -II and insulin), seem to be the most important endocrine regulators in this process. IGF-I, which is produced in fibroblasts or other cells of mesenchymal origin, has many mitogenic actions, including stimulation of cell growth, division, and differentiation via specific receptors on target cell surfaces (1). IGF-I also has an anabolic effect, enhancing glucose and amino acid uptake and inhibiting protein breakdown (2). The essential role for IGF-I in fetal growth has been demonstrated in knockout animal models (3). Also, fetal IGF-I, as obtained by cordocentesis, correlates well with fetal size at birth (4, 5, 6, 7).

IGF-I circulates, bound to six specific, high-affinity binding proteins [IGF-binding proteins (IGFBPs)-1 to -6] that regulate the bioavailability and biological activity of IGF-I. The activity of the binding proteins themselves is modulated by proteolysis and phosphorylation. IGFBP-1 is synthesized in large amounts by the secretory endometrium and decidua of early pregnancy (8). In the fetus, IGFBP-1 is produced mainly in the liver, but production has also been demonstrated in other tissues, including the fetal pancreas (9). IGFBP-1 is thought to have an inhibitory effect on fetal growth (10), because there is an inverse relationship between IGFBP-1 levels, in both third-trimester maternal blood and cord blood at delivery, with birth weight (11, 12, 13, 14).

Maternal serum levels of IGF-I rise progressively throughout pregnancy (13, 15, 16), and its levels are determined by the mean concentration of GH derived from the placenta. Unlike fetal IGF-I, many investigators have failed to show a direct relationship between maternal serum IGF-I at term and birth weight in normal pregnancies (13, 16, 17, 18). A few studies have shown an association (12, 15, 19, 20), but they were limited by measuring maternal IGF-I only shortly before birth, small numbers of subjects, or the fact that they were done in pregnancies complicated by intrauterine growth retardation or diabetes mellitus. Also of note, the associations of maternal and fetal IGF-I and their binding proteins were rarely studied in non-Caucasians.

In the present study, we sought to examine the relationships among maternal IGF-I, IGFBP-1, and IGFBP-2, with maternal and birth anthropometry, in a relatively large cohort of nondiabetic Jamaican women of African origin, followed prospectively throughout pregnancy (9–35 wk gestation). Fetal IGF-I, IGFBP-1, and IGFBP-2 were also measured at birth.

	Subjects and Methods

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Subjects

Three hundred twenty-five women attending the antenatal clinic of the University Hospital of the West Indies were recruited to the study. Women were included if they were between 15 and 40 yr old, were sure of the date of their last menstrual period (which was confirmed by a 14-wk ultrasound), had singleton pregnancies, and did not have systemic illnesses or genetic abnormalities, e.g. sickle cell disease. Women provided a venipuncture blood sample at 9, 25, and 35 wk gestation for IGF-I, IGFBP-1, and IGFBP-2. IGF-I, IGFBP-1, and IGFBP-2 levels were also measured on cord blood at delivery. Women who developed gestational diabetes or preeclampsia were excluded.

Anthropometric measurements

Maternal weight was measured to the nearest 0.01 kg by use of a Weylux beam balance (CMS Weighing Equipment Ltd., London, UK). Height was measured to the nearest 0.1 cm by use of a stadiometer (CMS Weighing Equipment Ltd.). Triceps skinfold thickness was measured to the nearest 0.1 mm using a Harpenden skinfold caliper (Holtain Ltd., Crymych, UK).

Newborn anthropometric measurements were obtained within 24 h of delivery. Birth weight was measured by a Health O Meter (Bridgeview, IL) 459 scale, and placental weight was measured with an electronic balance (Soehnle, Murrhardt, Germany; 800100 digimail). Crown heel length was measured with a length board (Holtain Ltd.). Head, chest, and abdominal circumferences were measured with a fiberglass measuring tape.

Three individuals (M.T., a nurse, and a medical technologist) made all measurements. All three were trained to make the measurements with minimum inter- and intraobserver variability. At the start, and at 3-month intervals (for the duration of the study), inter- and intraobserver measurement variability was assessed, and training and recertification prescribed for any observer whose scores were not acceptable (21). The Ethics Committee of the University of the West Indies approved the study.

Assays

Serum IGF-I was measured after acid-ethanol extraction of the binding proteins, by RIA, using a sensitive rabbit antiserum (R557A) raised against purified human IGF-I as previously described (22). The sensitivity of this assay is 5 µg/liter. The interassay coefficients of variation (CV) are 9.0%, 4.5%, and 6.2% at analyte levels of 654, 231, and 78.4 µg/liter, respectively, with an intra-assay CV of 4% at 231 µg/liter.

IGFBP-1 was measured by immunoradiometric assay using reagents supplied from Diagnostic Systems Laboratories, Inc. (Webster, TX). This assay has a sensitivity of 0.33 µg/liter, with intra-assay CV of 5.2% at 5.2 µg/liter and 4.6% at 50.2 µg/liter. The interassay CV are 6.0% at 47 and 3.6% at 142 µg/liter. IGFBP-2 was measured by RIA using reagents from Diagnostic Systems Laboratories, Inc.. This assay has no cross-reactivity with IGFBP-1, -3, or -4 and has a sensitivity of 0.5 µg/liter. The intra-assay CV at 32.0 µg/liter is 6.2%, with an interassay CV of 7.2% at 170.0 µg/liter.

Statistical methods

Levels of IGF-I, IGFBP-1, and IGFBP-2 were positively skewed. The first two were square-root-transformed, whereas the latter was log-transformed to normality before the analysis. Descriptive data are presented as mean ± SD and median with the interquartile range. Pearson’s correlation coefficients were used to examine the relationships among levels of hormones, binding proteins, and their relationships to maternal size, weight, and body proportion at birth. Multiple linear regression was used to examine the effect of IGF-I and birth weight, controlling for maternal weight, gestation, and gender of child.

	Results

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There were 325 mothers, with a mean (±SD) age of 26.4 ± 5.1 yr. They had average nutritional status [body mass index (BMI) of 24.6 ± 4.5 kg/m² and triceps skinfold thickness of 18.8 ± 7.5 mm] at the first antenatal visit. The mean birth weight (3100 ± 510 g), crown-heel length (48.9 ± 2.6 cm), and head circumference (34.2 ± 1.6 cm) corresponded closely to values obtained from a sample of Jamaican newborns studied in the 1970s (23), indicating that there were no significant secular trends or differences in birth weight. Newborns had a mean mid-upper arm circumference of 10.3 ± 0.89 cm and abdominal circumference of 30.7 ± 2.2 cm. The mean placental weight was 563.0 ± 126.0 g.

Maternal IGF-I increased steadily throughout pregnancy, from the first (median concentration, 261 µg/liter) to the third trimester (465 µg/liter), but IGFBP-1 increased in only the second trimester (Fig. 1). IGFBP-2 levels changed little throughout pregnancy. There was no significant relationship between maternal IGF-I in the first trimester and measures of maternal size (triceps skinfold thickness and BMI). However, in the second and third trimesters, there was a significant, direct relationship between maternal IGF-I and BMI (Fig. 2) and also triceps skinfold thickness (P 0.005; data not shown). IGFBP-1 and -2 had a significant inverse relationship with maternal size from as early as the first trimester, which persisted throughout pregnancy. There was no significant association among IGF-I, IGFBP-1, or -2 in cord blood and maternal size (P > 0.05). Also, there was no correlation of maternal IGF-I with fetal IGF-I levels (P = 0.6).

View larger version (21K): [in this window] [in a new window]   Figure 1. Box and whiskers plot of the concentration of IGF-I, IGFBP-1, and IGFBP-2 at 9 wk, 25 wk, and 35 wk, and in cord blood at delivery. Each box represents the median concentration with the interquartile range (25th and 75th percentiles). The upper and lower whiskers represent the range.

View larger version (23K): [in this window] [in a new window]   Figure 2. The association of maternal IGF-I and IGFBP-1 concentrations (measured at 35 wk) with maternal BMI, birth weight, and child’s mid-upper arm circumference.

Regression analysis showed that although maternal weight, male sex, gestational age, and fetal IGF-I had a significant relationship with birth weight (P = 0.001, 0.001, 0.0001, and 0.010, respectively), maternal IGF-I at 35 wk gestation had an independent positive association with birth weight (ß = 19.35 ± 6.39; P = 0.003). This model accounted for 28.8% of the variance of birth weight.

	Discussion

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These data show a positive relationship of maternal IGF-I levels in the third trimester with birth weight in a cohort of nondiabetic women of African origin, supporting similar findings of smaller studies. It is possible that the studies that showed no relationship may have been limited by issues of sample size and/or the methodology of the IGF-I assays. This study also provided more evidence that maternal IGFBP-1 levels (but not IGFBP-2) in the third trimester and in cord blood had an inverse relationship to birth weight.

IGF-I levels increased with advancing gestation and maternal anthropometry. Consequently, maternal IGF-I may serve as a hormonal index of maternal size and, therefore, nutrient availability. Hence, if maternal IGF-I does impact on fetal growth, the mechanism is probably mediated through increased nutrient flux, especially glucose, facilitating fetoplacental anabolism. This is theoretically possible, because IGF-I increases maternal insulin sensitivity, suppresses insulin production, and increases the transplacental transfer of glucose, at least in mice (24).

There is no prior evidence of transplacental transfer of maternal IGF-I (13, 16) causing a direct growth-promoting/mitogenic effect on the fetus. The lack of correlation of maternal and fetal IGF-I in our study further supports this concept. It is possible though that IGF-I can promote placental mitogenesis, as suggested by the correlation of fetal and maternal IGF-I concentration with placental weight. It should be noted that our data can only make inferences about the role of circulating IGF-I, because a large portion of IGF-I activity may be exerted through paracrine-autocrine effects (25, 26).

The mean concentration of IGF-I in cord blood has been reported as 70–80 µg/liter (6, 27). These values are similar to those found in this study, indicating that these data may be generalizable to other populations. Previous investigators have found reduced concentrations of fetal IGF-I to be predictive of intrauterine growth retardation (4, 7). The importance of fetal IGF-I in determining fetal body size is well demonstrated in homozygote IGF-I-knockout and IGF-I receptor knockout mice. These mice have no paracrine-autocrine IGF-I activity, and their fetuses were approximately 40% smaller than controls (28). Therefore, fetal IGF-I should be predictive of truncal anthropometry and birth weight, as is seen in our data and other reports (6, 14, 27).

Like other investigators (16, 29), we found that maternal IGFBP-1, in this study, showed an inverse correlation with maternal anthropometry, and probably adiposity, as measured by triceps skinfolds throughout pregnancy. It is not clear whether this represents higher levels of free IGF-I, because 70–90% of maternal IGF-I is bound by IGFBP-3. Maternal IGFBP-1, like IGF-I, seems to regulate fetal growth. Maternal IGFBP-1 suppresses fetal growth by inhibiting the binding of IGF-I to placental receptors (30, 31). The negative correlation between maternal IGFBP-1 levels in the third trimester and birth weight is similar to the findings of previous studies (11, 12, 13) in other populations. We, however, did not find a similar relationship between maternal IGFBP-1 in early pregnancy and birth weight as reported by Hills et al. (16). Also, despite a significant inverse correlation with neonatal mid-upper arm circumference, there was no association with abdominal circumference as previously described (29).

IGFBP-1 in cord blood was inversely related to abdominal circumference and birth weight, and this finding was similar to that of Baldwin et al. (29) and Wang et al. (13). This may infer relatively high levels of free fetal IGF-I, because fetal IGFBP-1 and -2 are the main binders of fetal IGF-I. Fetal IGFBP-1 is also regulated by fetal nutrition. Hence, the expectation is that maternal malnutrition reduces maternal IGF-I concentrations and thus fetoplacental nutrient availability, especially glucose. This would lead to decreases in fetal IGF-I and IGFBP-1 levels, resulting in growth retardation of the fetus (32, 33).

In conclusion, the data in this study support the findings that maternal IGF-I levels, especially that of the third trimester, positively influence birth weight. The inverse relationship of IGFBP-1 and birth weight concurs with other studies. The mechanisms underlying the role of IGF-I and the binding proteins still need to be elucidated to improve understanding of these factors in the physiology of normal growth of the human fetus.

	Footnotes

 
Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation; IGFBP, IGF-binding protein.

Received April 24, 2002.

Accepted December 20, 2002.

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