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Smallness for Gestational Age Is Associated with Persistent Change in Insulin-Like Growth Factor I (IGF-I) and the Ratio of IGF-I/IGF-Binding Protein-3 in Adulthood

Institut National de la Santé et de la Recherche Médicale, Unité 690 (R.V., D.J., S.D., P.C., C.L.-M.), and Department of Biochemistry (D.C.), Hôpital Robert Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Dr. Rasa Verkauskiene, Institut National de la Santé et de la Recherche Médicale, Unité de Recherche 690, Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France. E-mail: verkauskiene{at}rdebre.inserm.fr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Implication of the IGF-IGF-binding protein (IGFBP) axis in the development of metabolic and cardiovascular diseases has been well documented. It has also been shown that an adverse intrauterine environment alters the IGF-IGFBP axis during childhood.

Objective: The objective of this study was to investigate whether these alterations persist into adulthood.

Design and Methods: Fasting serum IGF-I, IGFBP-3, and insulin concentrations were measured, and their determinants were analyzed in a cohort of young adult subjects (22 yr of age) born either small (SGA; n = 461) or appropriate (AGA; n = 568) for gestational age.

Results: In adulthood, subjects born SGA had significantly lower mean serum IGF-I (320 ± 137 vs. 348 ± 143 µg/liter; P = 0.0015), IGFBP-3 (4700 ± 700 vs. 4800 ± 800 µg/liter; P = 0.04), and IGF-I/IGFBP-3 ratio (0.067 ± 0.026 vs. 0.072 ± 0.025; P = 0.01) than those born AGA. The fasting IGF-I concentration and the IGF-I/IGFBP-3 ratio were significantly inversely associated with age, body mass index, smoking, and oral contraception and were positively related to birth weight and fasting insulin levels. The IGFBP-3 concentration was significantly negatively correlated to age and smoking and was positively related to insulin concentration and oral contraception. After adjustment for age, height, body mass index, gender, smoking, and oral contraception, the mean IGF-I concentration and the mean IGF-I/IGFBP-3 ratio remained significantly lower in the SGA compared with the AGA group (P = 0.003 and P = 0.01, respectively).

Conclusions: Serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio are lower in adult subjects born SGA. Although the origin of this persisting alteration of the IGF-IGFBP axis in adulthood needs to be elucidated, its potential contribution to the long-term metabolic and cardiovascular complications associated with fetal growth restriction is important to consider in the future.

	Introduction

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REGULATION OF FETAL growth depends mainly on the nutrient availability to the fetus, the predominant axis being the glucose-insulin-IGF-I axis (1). Fetal undernutrition lowers IGF-I levels (2). In humans, both fetal and neonatal size correlate directly with circulating IGF-I levels; small for gestational age (SGA) newborns have significantly lower levels of both IGF-I and IGF-binding protein-3 (IGFBP-3) than appropriate for gestational age (AGA) newborns (3). Postnatally, IGF-I concentrations increase slowly in childhood and predict height velocity in the subsequent year in healthy children (4). In infants with intrauterine growth retardation, low cord IGF-I levels normalize rapidly after birth, but remain significantly reduced in intrauterine growth retardation children with height below –2 SD at 2 yr of age (5). At older ages, mean IGF-I levels were low in SGA children of both short and normal statures compared with healthy children born AGA (6, 7, 8).

Whether alterations of the IGF-IGFBP-3 axis persist into adulthood in SGA subjects remains unclear. However, it has recently been shown that IGF-I plays an important role in the pathophysiology of metabolic and cardiovascular diseases in adulthood (9). Because it is known that subjects born SGA are prone to develop such disorders (10), it seems important to investigate the IGF-IGFBP-3 axis in adulthood in this population. Thus, the present observational case-control study aimed at describing IGF-I and IGFBP-3 status in a cohort of young adults and investigating the influence of size at birth and adult anthropometry on serum IGF-I and IGFBP-3 concentrations after achievement of final height by comparing subjects born either SGA or AGA.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The study population was derived from a cohort of young adults, constituted between 1995 and 2000 to investigate the long-term consequences of being born SGA (11, 12). Briefly, subjects were identified from a population-based registry of the metropolitan area of the city of Haguenau in France. This registry included information about all pregnancies and deliveries occurring in this maternity unit from 1971–1985 (n = 27,366), and the degree of ascertainment of this registry was more than 80%. In this region (northeast France), non-Caucasian subjects represent less than 0.1% of the population.

Local standard fetal growth curves have been drawn from all births registered during 1971–1985. Gestational age was determined from the last menstrual period and was confirmed by physical examination and ultrasonography when available. The SGA group in the whole cohort included 735 singleton subjects born between 32 and 42 wk gestation with birth weight below the 10th percentile for gender and gestational age according to the local growth standard curves; the AGA group was made of 886 singleton subjects, born between 32 and 42 wk gestation with birth size between the 25th and 75th percentiles.

The present study was conducted on 461 subjects born SGA and 568 subjects born AGA included in the cohort in 2000, for whom serum IGF-I and IGFBP-3 concentrations were available. Clinical characteristics of the two groups at birth are given in Table 1. According to the selection criteria, subjects born SGA were significantly lighter, shorter, and thinner at birth than subjects born AGA when corrected for gestational age and gender.

Subjects who agreed to participate attended a medical visit at the Hospital of Haguenau. Information about medical history was recorded using a standardized questionnaire. Body weight was measured with a portable scale, and height with a wall-mounted stadiometer. Each individual’s height was measured twice, and the average was used in the analysis. Current parental heights were measured using the same protocol during the visit. Subject’s target height was calculated from midparental heights adjusted for subject’s gender. Weight for height was assessed as the body mass index (BMI; kilograms per meter squared). Waist circumference was measured at the level of the umbilicus, and hip circumference at the level of the greater trochanter. Blood samples were collected after an overnight fast for measurements of IGF-I, IGFBP-3, and insulin.

The study protocol was reviewed and approved by the ethical committee of the University of Paris-St. Louis, and all subjects gave written informed consent.

Laboratory procedures

Serum IGF-I was measured by an immunoradiometric assay (IRMA) kit (IGF-I-RIACT) from Cis Bio International (Gif-sur-Yvette, France), and serum IGFBP-3 was measured by an IRMA kit (ACTIVE IGFBP-3 IRMA) from Diagnostic Systems Laboratories (Cergy Pontoise, France). Serum insulin was measured by an IRMA kit (BI-INS-IRMA) from Cis Bio International. The cross-reactivity with proinsulin and derived metabolites was less than 1%. The assay sensitivity was 3.0 pmol/liter.

Statistical analysis

Results of continuous variables are given as the median (range) for birth data and the mean (SD) for biological parameters and adult anthropometry. Adult height, weight, and BMI were expressed as the SD score (SDS), with the AGA group being the reference population, as described previously (11). Tertiles of IGF-I, IGFBP-3, and the IGF-I/IGFBP-3 ratio were constructed on the basis of data from the control group (n = 568).

All analyses were performed using the SAS statistical package (SAS Institute, Meylan, France). The association between SGA/AGA status and quantitative variables was tested using a ² test. IGF-I and IGF-I/IGFBP-3 ratio were log transformed before analysis to remove a positive skewness.

General linear models were used to perform statistical comparisons of anthropometric parameters between the SGA and AGA groups with adjustment for gender and gestational age for neonatal parameters and for gender and current age for adult parameters.

The relative influence of clinical and biological parameters on serum hormone concentrations was assessed using multiple stepwise regression model on the whole cohort. An additional general linear model was performed to investigate the independent effect of being born SGA on adult serum IGF-I and IGFBP-3 concentrations and the IGF-I/IGFBP-3 ratio.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adult anthropometry

The mean age of the subjects at the time of the study was 22.6 yr in both groups. As adults, subjects born SGA remained significantly shorter and had lower weights compared with the AGA group (Table 2). The incidence of adult short stature (adult height less than –2 SDS) was also significantly higher among subjects born SGA (Table 2). Although mean BMIs were similar in the two groups, the mean waist to hip ratio was significantly higher in the SGA group after adjustment for current age and gender (Table 2).

Subjects born SGA had significantly lower mean serum IGF-I concentrations than those born AGA [320 ± 137 vs. 348 ± 143 µg/liter (41.9 ± 18 vs. 45.6 ± 18.7 nmol/liter); P = 0.0015] as well as mean serum IGFBP-3 concentration [4700 ± 700 vs. 4800 ± 800 µg/liter (165.2 ± 25.5 vs. 168.5 ± 27 nmol/liter); P = 0.04] and the IGF-I/IGFBP-3 ratio (0.067 ± 0.026 vs. 0.072 ± 0.025; P = 0.01). As a consequence, the distribution in SGA subjects was significantly shifted to the lowest tertiles of the AGA distribution of serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio (Fig. 1, A and C).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Distribution of the SGA ( ) and AGA () groups according to tertiles of IGF-I (A) and IGFBP-3 (B) concentrations and the IGF-I/IGFBP-3 ratio (C). The AGA group served as a reference population for the construction of tertiles of IGF-I and IGFBP-3 concentrations and the IGF-I/IGFBP-3 ratio.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Distribution of subjects born SGA of short () and normal ( ) stature according to tertiles of IGF-I (A) and IGFBP-3 (B) concentrations and the IGF-I/IGFBP-3 ratio (C). The AGA group served as a reference population for the construction of tertiles of IGF-I and IGFBP-3 concentrations and the IGF-I/IGFBP-3 ratio.

The influence of birth size, adult anthropometry, and biological parameters on the concentrations of IGF-I and IGFBP-3 and the IGF-I/IGFBP-3 ratio was tested in a multiple regression model on the whole cohort. The fasting IGF-I concentration and the IGF-I/IGFBP-3 ratio were significantly and inversely associated with age, BMI, smoking, and oral contraception and positively related to birth weight and fasting insulin levels (Table 3). In contrast, neither birth weight nor adult anthropometry had any effect on IGFBP-3 concentrations, which were significantly and negatively correlated to age and smoking and positively related to insulin concentration and oral contraception. In this model, final height, gender, adult waist to hip ratio, birth length, and gestational age had no independent effect on adult IGF-I and IGFBP-3 concentrations or the IGF-I/IGFBP-3 ratio. In addition, no significant interaction was found between SGA/AGA status and these parameters on IGF-I and IGFBP-3 concentrations or the IGF-I/IGFBP-3 ratio.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data clearly demonstrate that young adults born SGA have lower levels of circulating IGF-I and the IGF-I/IGFBP-3 ratio than those born AGA. This difference was not explained by the significantly reduced body height in subjects born SGA, because current height had no significant effect on the circulating IGF-I and IGFBP-3 concentrations or the IGF-I/IGFBP-3 ratio in adult subjects born either SGA or AGA. However, short adults born SGA, i.e. those with adult height below –2 SDS, had serum IGF-I levels and the IGF-I/IGFBP-3 ratio in the lowest tertile. According to previous reports (13, 14, 15), the majority of SGA subjects in our study displayed catch-up growth, and only a small proportion of them remained short in adulthood. Hence, considering the relatively small proportion of lack of catch-up growth in this study population, a possible effect of extremely short stature on the levels of IGF-I and IGF-I/IGFBP-3 ratio cannot be excluded, but might be difficult to prove. Such proportion of adult short stature among subjects born SGA in the present study is most probably due to the selection criteria, i.e. birth weight below the 10th percentile for gestational age and gender. Indeed, it rises to 11.2% within the group of SGA subjects with birth weight below the fifth percentile. However, this observation could not explain by itself the low circulating levels of IGF-I and IGFBP-3 and IGF-I/IGFBP-3 ratio in subjects born SGA.

Clinical and biological factors influencing circulating levels of IGF-I and IGFBP-3 differ from childhood to adulthood. Although age, height, and nutritional status are the key regulatory components increasing IGF-I and IGFBP-3 concentrations in childhood (4, 16, 17), their regulation in adulthood is dominated by age and BMI, which both have a negative effect. In addition, our data have shown that exogenous factors, such as smoking and oral contraception, play important roles in the regulation of IGF-I and IGFBP-3 concentrations. Interestingly, these two factors reduced the IGF-I concentration and IGF-I/IGFBP-3 ratio, which both have been shown to potentially influence the development of cardiovascular diseases (9). Hence, a dysregulation of IGF-I might be involved in the pathophysiology leading to increased risk of cardiovascular disorders associated with smoking and oral contraception.

When assessing the influence of determinants of serum IGF-I and IGFBP-3 levels and the IGF-I/IGFBP-3 ratio, no significant interactions were found between SGA/AGA status and these determinants on serum IGF-I and IGFBP-3 concentrations and IGF-I/IGFBP-3 ratio, meaning that the regulation of IGF secretion in adulthood is comparable between SGA and AGA subjects. Indeed, although statistically significant, the true differences in the mean IGF-I concentration and the IGF-I/IGFBP-3 ratio between SGA and AGA groups are rather moderate. However, the fact that these differences remained significant even after adjustment for all potential confounding factors evidenced in the present study points to the existence of other possible explanatory mechanisms. One of the possible explanation is the phenomenon known as fetal programming, suggesting that a decrease in IGF-I levels in adulthood could be a consequence of prenatal undernutrition. Because postnatal growth is GH and IGF-I dependent, failure of catch-up growth in children after an unfavorable prenatal environment has been attributed to alterations in the somatotropic axis. However, the reports in the literature are rather conflicting regarding this hypothesis. Although some studies report GH insufficiency and decreased plasma IGF-I concentrations in prepubertal children born SGA of either short or normal stature (6, 7, 8), others found elevated IGF-I levels in short SGA children compared with short children of normal birth weight (18), yet some suggest resistance to GH and IGF-I in the presence of normal IGF-I and GH profiles (19). Few studies have even found an inverse association between birth weight and IGF-I levels in healthy children (20, 21) and young adult women (22). Such discrepancies are not unexpected taking into consideration the high heterogeneity of the SGA population with respect to factors responsible for their small size at birth.

Another possible cause of the decreased IGF-I concentration in adult subjects born SGA is a genetic predisposition. The tendency to repeat SGA in the same family and over the generations has been well documented (23). Some studies have reported an association between IGF-I gene polymorphisms and a reduction in birth weight (24), birth length, head circumference, and persistent short stature in later life (25). IGF-I genotype has been shown to be associated with the SGA phenotype and with IGF-I levels in SGA children (8), but also with adult serum IGF-I levels (26). Although some controversy exists (27, 28), these data suggest that genetic variation in the IGF-I gene may account for at least a part of interindividual variation in birth weight and serum IGF-I levels later in life.

There is increasing evidence that the development of metabolic and cardiovascular diseases in adulthood is related to the adverse intrauterine environment (10). To date, the mechanism of such fetal programming is not clear. It has recently been reported that lower baseline IGF-I concentrations in adult subjects predicted subsequent increased risk of developing impaired glucose tolerance or type 2 diabetes independently of baseline insulin sensitivity (29). Another recent study has reported that individuals with low circulating IGF-I concentrations and high IGFBP-3 levels, leading to a decreased molar IGF-I/IGFBP-3 ratio, have a significantly increased risk of developing ischemic heart disease during a 15-yr follow-up period (9). Furthermore, the association of low IGF-I concentrations induced by GH deficiency in adults and abnormalities in body composition, metabolic derangements, and high incidence of adverse cardiovascular risk factors has become apparent over the last decade (30, 31). Therefore, the persistent decrease in serum IGF-I levels and the IGF-I/IGFBP-3 ratio observed in adults born SGA might be involved in the known association between restricted fetal growth and cardiovascular and metabolic diseases later in life.

In summary, in the present study we have shown that young adults born SGA, defined as birth weight below the 10th percentile for gestational age and gender, regardless of their final height, have lower serum IGF-I concentrations and IGF-I/IGFBP-3 ratio. The mechanisms responsible for this impairment of the IGF-IGFBP axis remain to be elucidated. Nevertheless, its contribution to the long-term metabolic and cardiovascular complications associated with fetal growth restriction is important to consider in future studies.

	Acknowledgments

 
We acknowledge the contributions of C. Traband; M. Grolet; M. Cominotti, R.N.; Dr. J. L. Boerher; and the laboratory staff at the Hospital of the City of Haguenau.

	Footnotes

 
This work was supported by grants from Pfizer (France) and the Institut National de la Santé et de la Recherche Médicale (PROGRES 2000–2002).

First Published Online July 19, 2005

Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; IGFBP-3, IGF-binding protein-3; IRMA, immunoradiometric assay; SDS, SD score; SGA, small for gestational age.

Received February 28, 2005.

Accepted July 7, 2005.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verkauskiene, R. Articles by Lévy-Marchal, C. Search for Related Content PubMed PubMed Citation Articles by Verkauskiene, R. Articles by Lévy-Marchal, C. Pubmed/NCBI databases Substance via MeSH Related Collections Pediatric Endocrinology Metabolism