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Small for Gestational Age: Short Stature and Beyond

Department of Pediatrics (P.S.), Albert Einstein College of Medicine, Bronx, New York 10467; Hôpital Robert Debré (P.C.), 75019 Paris, France; Department of Paediatrics (I.H.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; and Baystate Medical Center (E.O.R.), Tufts University School of Medicine, Springfield, Massachusetts 01199

Correspondence: Address all correspondence and requests for reprints to: Professor Paul Saenger, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10467. E-mail: PHSaenger{at}aol.com

	Abstract

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

I. Introduction

II. Definition of SGA

III. Epidemiology

IV. Diagnosis

V. Intrauterine Growth

VI. Factors Influencing Intrauterine Growth

A. Maternal nutrition

B. Placental size and function

C. Parity and maternal age

D. Smoking

E. Genetic factors

F. Sex of the fetus

G. Endocrine factors

VII. Postnatal Growth

A. Hormonal regulation of growth in children born SGA

B. Postnatal growth in preterm infants

C. Definition of catch-up growth

VIII. Consequences of Being Born SGA

IX. SGA and Metabolic Consequences in Adulthood

A. SGA and insulin resistance in children and adults

B. SGA and the metabolic syndrome

C. The origins of insulin resistance

X. Reversibility of Metabolic Programming

XI. Other Potential Sequelae

A. Premature adrenarche and puberty

B. Reproductive function

C. Reproductive tract abnormalities

D. Effects on other organ systems

E. Neurodevelopmental, psychosocial, and behavioral outcomes

XII. GH Treatment in Short Children Born SGA

A. Natural history of growth after an SGA birth

B. Indications for treatment

C. Clinical experience with GH in children born SGA

D. Safety of GH therapy

XIII. Conclusion

	I. Introduction

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
IT IS ESTIMATED THAT, depending on geographical region, between 8 and 26% of all infants born worldwide are of low birth weight (1). The World Health Organization has defined low birth weight as a weight of less than 2500 g (2), but this is an all-encompassing classification for international comparison of neonatal and public health, which includes premature infants, who though small, have a weight and length that is appropriate for their gestational age (AGA). The term "small for gestational age" (SGA) is used to describe fetuses or newborn infants whose weight and/or crown-heel length is less than expected for their gestational age and sex (3, 4). This is a basic description of the term, but an accurate definition of SGA that takes into account physiological variation (enabling the exclusion of constitutional smallness, which is not pathological) is under continued development and should eventually lead to individually customized fetal growth curves and birth weight percentiles (5).

There is a lack of data on the incidence of SGA births in many countries because birth length and gestational age are rarely recorded in national databases; however, based on available data, it has been estimated that between 2.3 and 10% of all infants are born SGA (4, 6, 7), although this may still be a gross underestimate in global terms (8). Of those born SGA, most go on to achieve appropriate catch-up growth by 2 yr of age, but approximately 15% do not (9, 10) and most of these children continue to experience poor growth throughout childhood.

It is becoming increasingly recognized that being born SGA carries an elevated risk of developing metabolic disease in later life, particularly obesity, insulin resistance, carbohydrate intolerance, and dyslipidemia. Studies of individuals exposed in utero to famine during the Dutch Hunger Winter of 1944 have revealed that poor maternal nutrition, especially during the last trimester of pregnancy, can lead to growth restriction of the fetus and is associated with poor glucose tolerance and insulin resistance (11, 12). In addition, developmental sequelae affecting the GH-IGF axis, and adrenal and gonadal function are seen, particularly in individuals with abnormal weight gain in infancy and childhood. The tempo of postnatal weight gain is emerging as particularly important in the relationship between birth weight and adult disease. For example, recent evidence from Barker et al. (11) shows that excessive weight gain during childhood and adolescence in individuals whose weight was low at birth presents a particularly poor prognosis for the development of coronary heart disease in later life.

It now appears that the role of early postnatal growth, from birth to 2 yr of age, is even more critical than growth beyond the age of 2 yr. Unlike the findings of Barker et al. (11), observational studies of full-term infants and randomized trials of premature infants demonstrate that rapid weight gain in infancy—even within the first few weeks of life—can lead to hypertension, obesity, and related morbidities before the third decade of life (12, 13, 14). This is much sooner after being born SGA than identified by Barker et al. (11).

Being born SGA, therefore, confers a substantial risk of morbidity in adulthood. Moreover, insufficient catch-up growth in infancy is associated with continued short stature and an array of psychosocial and metabolic consequences. Attempts to promote catch-up growth in the perinatal period should, however, be tempered against the additional risk of subsequent metabolic disease, because rapid weight gain in early infancy is also associated with poor adult health. This review presents our current understanding of the SGA phenomenon, the possible mechanisms involved, the metabolic consequences, and the efficacy and safety of GH therapy. In addition, it summarizes recent studies that may challenge some of the hypotheses of fetal programming proposed originally by Barker and colleagues.

	II. Definition of SGA

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
Traditionally, the term SGA has been used to describe a neonate whose weight and/or crown-heel length at birth is at least 2 SD below the mean for the infant’s gestational age, equivalent to the 2.3 percentile, based on data derived from an appropriate reference population (4, 15). Some publications define SGA as a birth weight or length below the 3rd, 5th, or 10th percentiles for gestational age (16, 17, 18); however, –2 SD is likely to capture the majority of infants with impaired fetal growth. Certainly, numerous studies defining growth patterns and patients’ response to GH therapy have used –2 SD as the cutoff for SGA (6, 15, 19, 20).

This broad description of SGA includes individuals with a low birth weight but normal birth length or, conversely, individuals who may have been born short in length with a normal birth weight. Indeed, some children born SGA are both short in length and low in weight. Consequently, infants born SGA may be classified as SGA with a low birth weight, SGA with a low birth length, or SGA with a low birth weight and length (21). In practice, it is important to use these classifications, because the prognosis and response to GH therapy may be different for different SGA subtypes.

The term "intrauterine growth retardation" (IUGR) is often used synonymously with the term SGA. However, because IUGR implies an underlying pathological process that prevents the fetus from achieving its growth potential, its use should be restricted to describing infants whose small size can be attributed to a specific cause and whose prenatal growth has been confirmed by several anomalous intrauterine growth assessments. Being born SGA does not necessarily mean that IUGR has occurred. Similarly, infants who are short after confirmed IUGR are not inevitably SGA. The designation SGA calls for the availability of birth weight and length reference data, specific to the ethnicity and geographic location of the population. In the United States, population-specific birth weight and length data derived by Usher et al. (22) are in common use; however, similar data are rarely available in other countries, making accurate definition of SGA problematic. Perhaps, even more important than reference data is the need for accuracy in gestational dating and in measurement of length and weight at birth. Birth weight is commonly recorded in developed countries; however, birth length is still not routinely, or accurately, recorded in many situations. Consequently, it can sometimes be difficult to distinguish an SGA neonate from one that is AGA, especially where gestational age data or appropriate birth measurements are lacking.

Despite the availability of normal growth curves in some countries, there are certain circumstances where they are not the most appropriate reference model. For example, some extremely premature infants born AGA at less than 30 wk may experience some postnatal growth restriction and their subsequent growth may actually be similar to that of SGA infants. Furthermore, there are currently no standard data for multiple births, and it is widely acknowledged that multiple gestation per se may be a cause of low birth weight; however, normal standards for catch-up in growth and height should, nevertheless, apply to individuals from multiple births. A new definition of SGA based on fetal growth potential has recently been developed (5) and is discussed in further detail in the diagnosis section of this review.

	III. Epidemiology

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
According to recent estimates, 4,115,590 infants were born in the United States in 2004 (23). This means that, at 2.3% of the population, there were approximately 95,000 infants born SGA. By contrast, the incidence of GH deficiency is estimated at 1 in 3500 (24) and would have been diagnosed in almost 1200 infants in the same interval. Achondroplasia, the most common form of skeletal dysplasia, with an estimated incidence of between 1 in 10, 000 and 1 in 25,000 (25, 26, 27), would have occurred in 160–400 infants in the same cohort. At one in 43, therefore, the incidence of SGA births is relatively high, compared with other growth disorders. Thus, those individuals born SGA who fail to show catch-up growth (approximately 10%) constitute a relatively high proportion of children and adults with short stature.

	IV. Diagnosis

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
It is widely accepted that the most accurate methods for estimating gestational age are ultrasonography and the date of the last menstrual period (28, 29). In order for an infant to be identified as SGA, gestational ultrasonographic data must be supplemented by precise measurement of length at birth. Nevertheless, the validity of ultrasonographic indices, such as crown-rump length and biparietal diameter, in determining gestational age is dependent on accurate recordings being made throughout gestation (30). Moreover, anomalies in fetal growth can invalidate any predictions based on these measurements, leaving the date of the last menstrual period as a chief predictor of gestational age.

It should be noted that the original data published by Barker and colleagues, relating low birth weight to metabolic and cardiovascular disease in later life, are marred by the fact that the epidemiological data frequently did not contain birth weight data but contained only weight at 1 yr of age. Moreover, there was no ultrasonographic assessment, which could mean that many of the individuals in Barker’s cohorts may have been prematurely born infants, rather than SGA neonates. Indeed, later studies by Huxley et al. (31, 32) have suggested that the strength of associations between birth weight and adult disease may have been overestimated due to selective emphasis on specific measures from particular studies and may have been confounded by inappropriate adjustment for current weight and other variables. Although the "Barker hypothesis" is intriguing, data from Huxley et al. (31, 32) and others (33, 34, 35, 36) have failed to confirm that birth weight is of relevance to blood pressure in later life. Further epidemiological studies should, therefore, critically appraise the available evidence and, most importantly, devise critical tests of the fetal programming hypothesis, rather than merely replicate its predicted associations (35, 36). As an alternative explanation to intrauterine programming, Neel (37) and Hattersley and Tooke (38) have proposed that insulin resistance is genetically mediated. This insulin-resistant genotype could result in low birth weight, glucose intolerance, insulin resistance, diabetes, and hypertension (Fig. 1).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Two possible explanations for the association of being born SGA with insulin resistance, type 2 diabetes, and ischemic heart disease: intrauterine environment and fetal genetics. [Adapted with permission from Hattersley and Tooke (38 ).]

Customized growth curves and birth weight percentiles have been shown to be better correlated with Apgar scores (40), neonatal morphometry indices (43, 44), and adverse gestational events (45, 46) than standard charts. A recent study from New Zealand revealed the superiority of customized charts over standard population-based charts in defining SGA. It showed that infants designated SGA by individually customized data were significantly at risk of several adverse events, including cesarean section for fetal distress, abnormal uterine and umbilical artery Doppler analysis, low ponderal index, hypoglycemia, and overall perinatal mortality, whereas infants designated SGA by the regular population standards alone were not at increased risk of any of the same outcomes (47). These and other studies suggest that infants defined as SGA by customized growth charts have probably suffered IUGR and are at risk of associated morbidities and mortality, whereas small-normal infants are at no greater risk than normal-sized infants (5).

	V. Intrauterine Growth

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
Size at birth is determined by two important factors: placental function and duration of pregnancy. Although low birth weight is associated with a variety of peri- and postnatal diseases, fetal overgrowth is also associated with significant neonatal and subsequent morbidity. Prevention of poor intrauterine growth and preterm labor relies upon problems being detected through routine antenatal assessments; however, such observations are only as reliable as the methods used to make them. Although ultrasonography is considered to be the most reliable method for assessing fetal growth and gestational age, it does suffer from some intrinsic limitations. For example, among the measurements routinely made at 18–20 wk gestation is femur length; however, ultrasonography detects only ossification and not cartilaginous mass at the end of the bone, which could introduce errors. Another problem with determining fetal growth and age is that the values obtained are used to assign the fetus to a particular percentile to predict birth outcome. Although this is desirable, in practice adherence to a particular height percentile is only evident beyond the age of 2 yr. Before this age, "percentile crossing" is common, including in utero (48).

Traditionally, it has been believed that intrauterine growth disruption in the first and early second trimesters of pregnancy results in infants that are proportionately small in weight and length, that is, subject to symmetric growth restriction. Intrauterine growth anomalies in late pregnancy are thought to result in disproportionately small, thin infants; that is, these infants are said to have suffered from asymmetric growth restriction. Several studies suggest that asymmetric growth in fetuses predisposes to worse perinatal outcomes than symmetric growth (49, 50) and that both proportionate and disproportionate growth restriction may occur from early in the second trimester (51, 52). These observations suggest that popular thinking about symmetry and asymmetry in fetal growth may be somewhat misguided, particularly in the "fetal origins of disease" hypothesis, which places great emphasis on the stage at which IUGR occurs and, hence, assumes symmetric or asymmetric growth restriction to be important in determining the risk of adult disease (53).

The UCL (University College of London) Fetal Growth Study by Hindmarsh et al. (51) looked at the determinants of shape at birth. Among all normal full-term pregnancies that were free of complications in their study, they found that the major determinant of shape at birth was the proportionality between anthropometric measures of size at birth. Interestingly, they found that classic concepts of disproportionate growth did not contribute significantly to shape at birth, suggesting that in this low-risk, normal population, clinically important disproportionality was not present. Shape at birth was also significantly affected by gender, with male infants exhibiting greater birth weight and head circumference and lower skinfold thickness than females.

It is commonly assumed that intrauterine growth follows a predictable pattern, but in practice this is not the case. In the UCL Fetal Growth Study, anthropometric measures at 20 wk gestation, 30 wk gestation, and birth were compared. Correlations between parameters at all dates were poor, and the predictive value of any of these measures for size at birth was weak. The authors ascribe the poor predictive power of these measurements to percentile crossing in utero, as is also seen in the first 2 yr of life. It is not known what the mechanism for percentile crossing is; however, it has been suggested that changes in placental nutrient delivery or inherent fluctuations in growth in utero may be responsible (48).

	VI. Factors Influencing Intrauterine Growth

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
Normal fetal growth is dependent on an optimal intrauterine environment, particularly in relation to the delivery of oxygen and nutrients via the placenta (54). Some of the many factors known to cause IUGR are listed in Table 1.

During the first two trimesters of pregnancy, maternal metabolism, mediated by placental and pituitary hormones, is directed toward energy storage and uteroplacental development. In addition to increased maternal food intake, first-stage insulin secretion typically increases by approximately 60%, whereas sensitivity to insulin and fasting glucose concentrations remains relatively normal (59). The etiology of weight gain during early to midgestation is multifactorial but is likely to include a consequence of the ever-decreasing levels of pituitary GH, which normally inhibits adipogenesis, and the increasing levels of progesterone, prolactin, and placental lactogen, which stimulate food intake, fat storage, and insulin production (59). The hyperinsulinemic state of early and midpregnancy promotes lipogenesis and the storage of fat and is associated with a rise in plasma leptin concentrations and a concomitant decrease in plasma lipid and IGF-I levels (59).

In the later stages of pregnancy, although food intake and fat deposition continue to rise, changes in insulin production and action mean that maternal metabolism is redirected toward supporting fetal, placental, and mammary growth. Maternal insulin resistance is typical of this stage of gestation. Insulin-mediated glucose utilization by skeletal muscle can drop by 40% or more in the third trimester of gestation, whereas a more modest reduction in insulin-stimulated glucose uptake by cardiac and adipose tissue is normal. Total body insulin sensitivity at this stage of pregnancy can be up to 70% lower than in nonpregnant women (59). These changes in insulin activity during late gestation facilitate efficient storage of energy during times of nutritional abundance, while permitting rapid nutrient mobilization during periods of fasting.

B. Placental size and function
Throughout pregnancy, the size of the placenta changes and remains highly correlated with birth weight; small placentae generally give rise to small babies (60). At approximately midgestation, the fetus and placenta are of similar weights, but from 32 wk, fetal growth exceeds that of the placenta and the fetal/placental weight ratio increases. It is unlikely that the size of the placenta causes fetal growth restriction (48), because the placenta is able to withstand functional inactivation of up to 40% of its villous population without affecting fetal growth (61) and is, in any case, capable of compensatory growth (62).

C. Parity and maternal age
Parity and maternal age have unavoidable consequences on birth weight. For example, infant birth weight in primagravidae is frequently lower than subsequent births (63), and pregnancy in girls under 16 yr of age is commonly associated with suboptimal fetal growth (64). Fetal growth restraint is particularly evident in first pregnancies, whereupon infants tend to be thinner and lighter than subsequent siblings, although they have similar lengths and head circumferences.

Figure 2 illustrates the interaction between birth order and genotype in terms of fetal head circumference (65), and Fig. 3 illustrates the effects of multiple births on birth weight (66).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Interaction between birth order and genotype on head circumference. Both the insulin gene VNTR (class I+ or class III alleles) and birth order (first vs. second or later pregnancies) were associated with head circumference at birth (interaction, P = 0.02), such that the genotype association was apparent only in offspring of second and subsequent pregnancies (P = 0.0003). The mean BMI was identical in I/I and I/III subjects. Data are means ± SEM. [Reproduced with permission from Ong et al. (65 ).]

View larger version (13K): [in this window] [in a new window]   FIG. 3. Mean birth weights decrease progressively with multiple births. [Reproduced with permission from McKeown and Record (66 ).]

E. Genetic factors
Infant birth weight is strongly associated with maternal birth weight (73), suggesting that weight at birth is an inherited trait through the maternal line (74, 75). It is likely that variation in the mitochondrial genome plays an important role in determining infant birth weight, because it is exclusively transmitted through the maternal line. Mitochondrial DNA 16189 variant, for example, is associated with thinness at birth (76). Additionally, the maternally expressed gene H19, responsible for the imprinting of IGF-II, is associated with size at birth (77). Maternal glucose levels may also contribute to birth weight or size. This may or may not be a genetic trait. Certainly, pregnancy in diabetic mothers generally results in infants with greater adiposity than the offspring of nondiabetic mothers, and the risk of gestational diabetes appears to be correlated with low maternal birth weight (78). In addition to these factors, several genetic conditions are associated with reduced size at birth. They include the chromosomal abnormalities of Turner syndrome and Down syndrome. Confirmed placental mosaicism and uniparental disomy (UPD) are increasingly recognized as influencing fetal growth and development.

It is noteworthy that a minisatellite DNA polymorphism comprising a variable number of tandem repeats (VNTR) upstream of the human insulin gene (INS) promoter is associated with size at birth (79). The effects of this polymorphism, which is thought to influence transcription of INS and IGF-II (80, 81), are more evident in second and subsequent pregnancies, suggesting that fetal genes, especially those expressed by the father, may have considerable influence on fetal growth when maternal restraint on fetal growth is less marked (82).

Genetic determinants of fetal growth restraint, through programming or epigenetic effects on the fetus, and genes that determine postnatal catch-up in weight, may be the important links between size at birth and disease in adulthood (82).

1. Imprinting.
Although imprinted genes account for no more than 0.5% of the genome, they have a disproportionately large effect on early fetoplacental development, affecting the growth, morphology, and nutrient transfer capacity of the placenta and thus delivery of nutrients to the fetus (83). The imprinted IGF-II and H19 genes, for example, are heavily involved in fetoplacental development, acting as a single epigenetic regulatory unit through coordinated action of their differentially methylated regions (84). Expression of Igf2 is sensitive to nutritional and endocrine signals, particularly glucocorticoids (85, 86); the ovine Igf2 gene has a glucocorticoid response element and is transcriptionally down-regulated by cortisol (87). The sensitivity and the complexity of the IGF-II imprinting mechanisms may have a significant impact on developmental programming and might explain the poor prognosis of the child born SGA and the wide spectrum of adult-onset diseases originating in utero (84, 85, 86, 87, 88, 89).

The importance of genetic imprinting for fetal growth is illustrated by UPD in humans and mice. Growth appears to be promoted by paternal disomies, whereas it is inhibited by maternal disomies (90). Among the imprinted genes determining fetal growth, several are involved in the IGF system. For example, Igf2 is paternally expressed, whereas Igf2r is maternally expressed, at least in the mouse; expression of this gene in humans, however, has been shown to be largely biallelic (91, 92). The IGF type 2 receptor is implicated in the degradation of extracellular IGF-II and therefore depletes circulating levels of the growth factor. This illustrates the conflicting paternal and maternal priorities in the regulation of fetal growth and development (93). Table 2 lists several growth disorders that have been associated with imprinting effects in humans and ruminants (94).

Beckwith-Wiedemann syndrome, characterized by prenatal and/or postnatal overgrowth, several anatomical abnormalities, and an increased risk of cancer in childhood, is a good example of an imprinting disorder. The syndrome results from derangement of the imprinting of the 11p15 region, which contains a cluster of imprinted genes belonging to two separately controlled domains (93). Studies in mice show that this region is prominent in fetal growth. The changes to the 11p15 region in Beckwith-Wiedemann syndrome result in down-regulation of maternally expressed genes and/or the up-regulation of paternally expressed genes.

The level of involvement of imprinted genes in IUGR is still unclear; however, IUGR has been shown to be associated with a number of maternal UPDs of chromosomes 7, 14, 16, and 20. For example, about one in 10 patients with Silver-Russell syndrome (a condition characterized by IUGR, reduced postnatal growth, and dysmorphic facial features and body asymmetry) has evidence of maternal disomy for chromosome 7; however, the precise role of the genes involved is poorly understood (90).

Because they are determinants of fetal growth, genes imprinted within the 11p15 region may also influence the link between IUGR and adult disease. Duplications in chromosome 11p15 of maternal origin have been found in patients with phenotypes suggestive of Silver-Russell syndrome (96, 97). Gicquel et al. (98) have recently shown that epigenetic defects in 11p15, resulting in the silencing of IGF-II, are found in 50% of patients with Silver-Russell syndrome. The epimutation consists of partial loss of paternal methylation at three different loci in the telomeric imprinted domain. It results in decreased expression of the gene for IGF-II and reduced fetal growth (98). Interestingly, recent studies have suggested that assisted reproductive technology may predispose to imprinting disorders (98), such as Beckwith-Wiedemann syndrome. Fetuses conceived using assisted reproductive technology are also known to be at increased risk of IUGR (99), although the mechanism is not yet understood.

F. Sex of the fetus
Shape and size of the fetus and neonate are influenced by gender. At birth, males tend to be heavier, with a greater head circumference than females. They also tend to be leaner, with a lower skinfold thickness, than females. These differences were discernable in utero at 20 wk gestation (48). Abdominal circumference was greater in males, whereas there was no difference in femur length at 20 wk. The differences in abdominal circumference may reflect different rates of maturation of abdominal structures, such as the liver, whereas differences in femur lengths would not be expected at 20 wk, given that peak length velocity in utero occurs at approximately 26–28 wk gestation.

G. Endocrine factors
1. The GH-IGF axis.
The insulin resistance characteristics of late gestation may be caused by the increasing concentration of placental GH, which progressively replaces pituitary GH. Placental GH differs from pituitary GH in 13 of the 191 constituent amino acids. It is thought that this change in structure significantly diminishes the affinity of placental GH for lactogenic receptors, leading to insulin resistance and an increase in IGF-I concentration in late gestation (100).

Placental GH is detectable in the maternal but not the fetal compartment. Several studies have found lower maternal levels of circulating placental GH and IGF-I in the third trimester of pregnancies complicated by IUGR than in normal controls (101, 102, 103). The mechanisms by which maternal placental GH and/or IGF-I regulate fetal growth are still not well understood (104, 105, 106, 107). In pregnancies with IUGR, the concentration of IGF-I in cord blood is reduced compared with that in fetuses with normal growth (108, 109, 110, 111, 112, 113, 114). At birth, the importance of IGF-II is surpassed by IGF-I, and IGF production becomes dependent on infantile GH, resetting the regulatory feedback cycles.

IGF-II plays an important role in regulating fetoplacental growth. The mature IGF-II results from posttranslational processing of the biologically inactive pro-IGF-II peptide. Qiu et al. (115) provide evidence that aberrant processing of IGF-II may also be a cause of SGA. They found that proprotein convertase 4, expressed in the placenta, normally cleaves pro-IGF-II to generate intermediate processed forms and mature IGF-II. Pregnant woman carrying SGA fetuses had higher levels of pro-IGF-II, compared with controls, suggesting that processing by proprotein convertase 4 in these women was abnormal. Whether this is a primary cause of SGA birth or whether it is secondary to placental dysfunction is unclear at this stage, but elevated pro-IGF-II in the maternal circulation may be a useful marker for an SGA fetus. Specific knockout of IGF-II in the placentae of mice has been shown to cause reduced fetal and placental growth (116). Furthermore, the placenta can respond to fetal demand signals through regulation of the expression of specific placental transport systems, such as GLUT1 and GLUT2 transporter genes. In mice that lack IGF-II, the placenta is small. Through increases in transporter genes, the transfer of glucose and amino acids can be regulated to meet fetal demand (117).

Over the past 10 yr, a series of elegant animal knockout experiments have identified the importance of IGF-I, IGF-II, insulin, and their respective receptors in regulating fetal growth and size at birth (53, 65, 118). Furthermore, several studies have shown the correlation between umbilical cord levels of IGF-I and IGF-II to birth weight (112, 119, 120, 121, 122). The importance of insulin in fetal growth is demonstrated by the larger-than-normal birth weight of infants born to diabetic mothers and in the correspondingly low birth weight in infants with mutations of the insulin receptor (123). Variations in insulin metabolism may also be responsible for the differences in birth weight within the normal population, as suggested by studies of the insulin variable nucleotide repeat sequence proximal to the insulin gene (65). At present, it is unclear whether this reflects a change in insulin production or an indirect effect on other genes in the same genetic locus.

Expression of IGF-I and IGF-II is present in all fetal tissue from preimplantation to the final stages of maturation before birth. IGF-II is the principal growth factor supporting early embryonic growth, whereas IGF-I becomes more of a prominent influence in the later stages of gestation. IGF-I concentrations are decreased in utero and at birth in infants and fetuses displaying IUGR and are correspondingly raised in infants born large for gestational age (124, 125). Nutrient restriction produces a decrease in serum concentrations of IGF-I and IGF-II; however, the Igf1 gene appears to be eminently more sensitive to changes in nutritional status than the Igf2 gene (125, 126). IGF-I levels are positively regulated by insulin, possibly by increasing the availability of cellular glucose through increased uptake, whereas tissue-specific expression of both the Igf1 and Igf2 genes is under the control of glucocorticoids (127).

Expression of IGF-binding proteins (IGFBPs) is developmentally regulated (125), and all six of the recognized IGFBPs have been found in fetal plasma and tissues. IGFBP-I may be the most important of the binding proteins in utero. Babies with IUGR have elevated levels of IGFBP-1, which are negatively correlated with birth weight. Such elevated levels of IGFBP-1 in the fetus would decrease the amount of IGF available for fetal growth.

Studies in transgenic mouse models have offered valuable insights into the role of the fetal IGF system in fetal growth and development. For example, using standard gene targeting techniques, Efstratiadis and colleagues created murine cell lines lacking the genes for Igf1, Igf2, Igf1r, and Igf2r (128). Knockout of the Igf1, Igf2, or Igf1r gene in isolation leads to fetal growth retardation, which becomes more severe if additional genes are deleted (Fig. 4). Deletion of the Igf1 or Igf2 gene produces a similar degree of growth retardation, resulting in pups weighing 40% less than their wild-type littermates. Deletion of the Igf1r gene results in more severe growth retardation, producing offspring with a birth weight that is 55% less than normal, suggesting that both IGF-I and IGF-II act through the IGF type I receptor (IGF-IR). This is supported by the observation that mice lacking a functional IGF-IR do not survive beyond the perinatal period due to poor muscle development and respiratory failure. The combined deletion of Igf1r and Igf2 or Igf1 and Igf2 results in very severe growth retardation, generating offspring with birth weights that are 70% less than normal. Thus, it appears that a different receptor may mediate some of the fetal growth effects of IGF-II. A possible candidate for this receptor is a splice variant of the insulin receptor (129). Mutations in Igf1and Igf1r do not affect placental weight, unlike mutations in the Igf2 gene. Moreover, deletion of the placenta-specific Igf2 transcript leads to restriction of placental and, subsequently, fetal growth, due to decreased nutrient supply from the mother to the fetus (130). Interestingly, disruption of the Igf2r gene, causing overexpression of IGF-II, results in fetal overgrowth (Fig. 4). A similar effect is seen where there is transactivation of the Igf2 gene or biallelic expression of IGF-II after disruption of the H19 gene (125).

View larger version (30K): [in this window] [in a new window]   FIG. 4. Effects of the disruption of one or more genes of the IGF system on fetal growth in mice. Figures represent percentage of normal body weight. m–, Maternally disrupted allele; p–, paternally disrupted allele; –/–, both maternal and paternal alleles disrupted. [Reproduced with permission from Gicquel and Le Bouc (94 ).]

2. Glucocorticoids.
Glucocorticoids are also thought to have a role in the fetal origins of adult disease. Animal data have implicated lower levels of 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD 2) activity in fetal programming leading to SGA (141). Placental 11ß-HSD 2, which converts physiologically active glucocorticoids to inactive products, is an important modulator of fetal glucocorticoid exposure and is regulated by many placental hormones and factors associated with pregnancy, including estradiol, progesterone, and prostaglandins (141). Benediktsson et al. (142) showed a potential correlation between placental 11ß-HSD 2 activity and term fetal weight and a correlation with placental weight. These investigators proposed that the relationship between low birth weight, high placental weight, and increased adult blood pressure may be mediated by glucocorticoid exposure in utero (142). Inhibition of placental 11ß-HSD 2 by carbenoxolone gave similar results, producing smaller offspring with impaired glucose tolerance in later life and reduced hepatic 11ß-HSD 1 and reduced renal 11ß-HSD 2 gene expression (143, 144, 145).

3. Other endocrine factors.
Progesterone also plays a part in the development of insulin resistance in late gestation, because at high concentrations it interferes with insulin binding and glucose transport in skeletal muscle and adipose tissue (146). A further cause of maternal insulin resistance in the third trimester is the rise in plasma concentrations of TNF- and free cortisol, which inhibit glucose uptake in skeletal muscle and stimulate lipolysis in adipocytes. Furthermore, TNF- inhibits expression of adiponectin in preadipocytes, which, together with an excess of free cortisol, exacerbates the insulin resistance caused by other hormones.

	VII. Postnatal Growth

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
In addition to poor maternal nutrition during pregnancy, the quality of perinatal nutrition has been shown to influence the subsequent development of the newborn. Widdowson and McCance (147) reported that undernourishment of rat pups during the 3-wk period of lactation led to slower weight gain throughout their lifetime, compared with control pups, despite the fact that all pups had ad libitum access to food after weaning. On the other hand, 3 wk of similar energy deficiency in rats between 9 and 12 wk of age resulted in only short-term effects on weight gain. These studies show that nutritional or environmental insults in perinatal life can cause irreversible, long-term outcomes. Importantly, the timing of such insults is significant in determining the extent of later adverse consequences to health, such that there is evidently a critical period in development when unfavorable events have the potential to exert their maximal effects.

A. Hormonal regulation of growth in children born SGA
The endocrine mechanisms governing catch-up growth are still poorly understood, although Baron et al. (148) proposed that they reside within the growth plate and are based on a delay in normal growth plate senescence.

1. GH.
The growth response of infants in the first months of postnatal life appears to be fundamental to the future health and stature of individuals born SGA. Most catch-up growth occurs in this relatively brief period, yet the rate and extent of this growth has profound long-term consequences that may or may not be favorable.

Infants born SGA frequently exhibit increased concentrations of GH (114, 149, 150) and have low levels of IGF-I and IGFBP-3, suggesting that SGA neonates are GH insensitive. However, normalization of the GH-IGF axis occurs early in postnatal life (113), and most children born SGA go on to show a normal response to GH stimulation testing and have normal levels of IGF-I and IGFBP-3 (151).

In studies measuring spontaneous daily GH secretion in short children born SGA, several investigators have found high pulse frequency, attenuated pulse amplitude, and relatively elevated interpulse concentrations of serum GH, accompanied by reduced concentrations of IGF-I (152, 153, 154). This is similar to what is seen in adults with long-term critical illness (155), and it has been suggested that altered GH secretion at birth may represent a consequence of extended critical illness in utero (156).

2. The IGF system.
In addition to GH, IGF-I and IGF-II play a key role in the regulation of postnatal growth. Within the circulation, they are bound to high-affinity binding proteins that control the availability of the IGFs. Around 75% of the IGFs circulate in a ternary complex, consisting of IGF, IGFBP-3, and ALS. Approximately 20–25% of the remaining IGFs are associated with one of the other IGFBPs in a binary complex, and less than 1% exists in the free form. Decreased levels of IGF-I have been detected in fetuses and infants deemed to be SGA, indicating that dysfunction of IGF-I or its metabolism may be involved in IUGR (113, 157). Indeed, polymorphisms of IGF-I have been associated with pre- and postnatal growth retardation (134, 158), and homozygous partial deletion of the gene encoding IGF-I in humans results in severe impairment of growth pre- and postnatally (136).

The importance of IGF-I is further underlined by the association of pre- and postnatal growth restriction with mutations of the IGF-IR gene (138). Moreover, infants born SGA demonstrate reduced levels of IGFBP-3, with concomitantly higher levels of IGFBP-1 and IGFBP-2 (157).

Despite substantial evidence of abnormal IGF levels in infants born SGA, there does not appear to be a firm link between IGF-related variables at birth and postnatal growth (113, 114). Cianfarani et al. (159) have reported a correlation between catch-up growth and the IGF-I/IGFBP-3 molar ratio in infancy. They suggested that the affinity of IGFBPs for IGFs may be modulated by cation-dependent proteolytic enzymes that degrade the IGFBPs, thereby increasing the level and bioavailabilty of IGF-I. Postnatally, the IGF system is switched on, allowing catch-up growth in the majority of infants born SGA (159). Furthermore, the alterations in IGF-I levels observed in neonates born SGA appear to be transient, because abnormal levels of IGF-I and IGFBP-3 have not been detected in older children who were born SGA (160).

In infants with IUGR, low cord levels of IGF-I normalize rapidly after birth (Fig. 5). However, serum levels of IGF-I remain significantly reduced in infants who fail to show catch-up growth (height below –2 SD) by 2 yr of age (114, 161). Furthermore, the mean IGF-I levels of older children born SGA of both short and normal stature have been shown to be lower than in healthy children born AGA (162). This was also confirmed in a prospective study by Chellakooty et al. (163). Because low IGF-I levels in adulthood have been associated with an increased risk of ischemic heart disease (164) and because it is established that individuals born SGA are predisposed to cardiovascular disease, it is important to investigate the IGF-I/IGFBP-3 axis in adults born SGA. In an observational case-control study, Verkauskiene et al. (162) analyzed the dynamics of IGF-I and IGFBP-3 in a cohort of young adults born SGA (defined as birth weight below the 10th percentile for gestational age and gender) and a cohort born AGA. They found that serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio were lower in adults born SGA than in those born AGA. This suggests that long-term abnormality of IGF-I metabolism may be implicated in the association between IUGR and cardiovascular and metabolic diseases in later life.

View larger version (12K): [in this window] [in a new window]   FIG. 5. Mean (±SD) serum levels of IGF-I in children born SGA and controls from birth (cord blood measurements) to 3 months of age. Levels of IGF-I were significantly reduced in the cord blood of infants born SGA, but serum IGF-I levels normalized rapidly after birth. [Data from Leger et al. (114 ).]

View larger version (21K): [in this window] [in a new window]   FIG. 6. Cortisol, TSH, and free T4 concentrations in a case-control study of 20 children born SGA who achieved catch-up growth and 20 who did not, matched for age, gender, pubertal status, and BMI. *, P = 0.04 compared with those who achieved catch-up growth. [Reproduced with permission from Cianfarani et al. (166 ).]

B. Postnatal growth in preterm infants
So far, we have discussed postnatal growth regulation in the full-term infant. Wit et al. (169) have recently provided evidence for catch-up growth in preterm infants. The majority of preterm infants show evidence of growth retardation in the postnatal period. In addition to preterm growth restraint, there is also substantial postnatal growth impairment, which is largely due to inadequate nutrient intake. Embleton et al. (170) found that this nutrient intake accounts for 45% of the variation in weight SD score (SDS). Preterm infants thus accumulate a considerable nutrient deficit that cannot be replaced by feeding to current recommended daily intakes. With appropriate feeding protocols, however, catch-up growth can be achieved in preterm infants. Despite this, the prevalence of short stature in 5 yr olds who were born preterm (less than 32 wk gestation) is comparable to that seen in children born SGA and amounts to approximately 10% of the respective populations (169). The growth responses of these children were followed into adulthood, and the authors conclude that childhood growth and adult height are similar in preterm individuals born SGA, in preterm individuals born AGA with evidence of prenatal growth restraint, and in individuals with very low birth weight.

Evidence is accumulating to show that postnatal growth failure is extremely common in preterm infants. Some of this evidence suggests that growth impairment is not restricted to the early postnatal period. For example, Gibson et al. (171) investigated 200 preterm infants and 50 randomly selected healthy term infants from the same population from birth to 7 yr of age. They found early growth impairment in all preterm infants, which improved rapidly in the more mature preterm infants. In very preterm infants (born at 23–28 wk gestation), however, growth impairment continued for up to 4 yr, after which time some improvement in growth was seen, although these children never fully achieved a normal size, particularly with respect to head circumference. Similarly, in a study of 280 children born before 32 wk gestation and 210 term infants, median centiles for weight, height, head circumference, and body mass index (BMI) at 7 yr of age were 25, 25, 9, and 50 for boys and 50, 25, 9, and 50 for girls, respectively, compared with 50, 50, 50, and 75, respectively, for the controls born at term (172). The same study revealed a link between prematurity and poor cognitive behavior, with short stature and small head circumference being the strongest predictors of poor performance. One further study demonstrated an increased incidence of neurodevelopmental problems at 30 months in infants born at 25 wk gestation or less (173).

C. Definition of catch-up growth
A general definition of catch-up growth is a growth velocity (centimeters per year) greater than the median for chronological age and gender. Definitions based on the normal height range for the population (for example, catch-up growth is considered to be achieved when the patient’s height is above the third percentile) do not incorporate the patient’s expected adult height, based on parental stature. This is an important distinction, because the target height, i.e. an estimate of the genetic potential in stature, is a strong predictor of response to GH therapy. Target height is commonly estimated by midparental height corrected for gender (174, 175).

Most children who are born SGA experience catch-up growth and will achieve a height above –2 SD. Catch-up growth is typically an early postnatal process that, in most SGA infants, is completed by the age of 2 yr. Within this 2-yr period, premature SGA infants (less than 37 wk gestation) may take longer to catch-up than full-term infants (10, 176, 177). In more than 80% of infants born SGA, catch-up growth occurs during the first 6 months of life. For this reason, growth monitoring during the early postnatal period provides useful information, and different growth patterns may be identified in infants as young as 3 months of age.

The situation is different for infants born SGA who have short parents. Volkl et al. (178) observed catch-down growth to the lower familial range, as defined by their parental heights, during the first 2 yr of life.

	VIII. Consequences of Being Born SGA

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
Being born SGA carries an increased risk of morbidity and mortality both in the perinatal period and in later life. In the perinatal period, these manifestations include respiratory complications, hypotension, hypoglycemia, necrotizing enterocolitis, and neonatal death (179, 180). Subsequently, infants and children born SGA are prone to neurological impairment, delayed cognitive development, and poor academic achievement (181, 182, 183, 184). Adolescents and adults born SGA are at increased risk of developing additional morbidities, such as cardiovascular complications, obstructive pulmonary disease, type 2 diabetes mellitus, renal insufficiency, and impaired reproductive function (185, 186, 187, 188, 189). Failure to achieve appropriate catch-up growth after SGA birth results in persistent short stature and is associated with greater health risks and psychosocial impairment, compared with patients born SGA who achieve their growth potential (190, 191, 192, 193).

	IX. SGA and Metabolic Consequences in Adulthood

Top Abstract I. Introduction II. Definition of SGA III. Epidemiology IV. Diagnosis V. Intrauterine Growth VI. Factors Influencing... VII. Postnatal Growth VIII. Consequences of Being... IX. SGA and Metabolic... X. Reversibility of Metabolic... XI. Other Potential Sequelae XII. GH Treatment in... XIII. Conclusion References

 
After the publication in 1989 of a paper linking size at birth to ischemic heart disease in later life (194), many researchers have investigated the possible links between fetal growth restriction and adult diseases. Early programming of such diseases has been the focus of much of this research, which has been performed in diverse ethnic groups and geographical settings. The independent effect of thinness at birth and its lack of association with gestational age strongly suggest that reduced fetal growth, rather than prematurity per se, is a major factor in defining long-term risk of metabolic disease.

The initial hypothesis of Barker and colleagues proposed that the type 2 diabetes commonly associated with low birth weight was a consequence of impaired ß-cell function that may have resulted from undernutrition at a critical stage of fetal development. It was proposed that this nutritional insult may have caused dysfunction of the endocrine pancreas (195). In a later study, the same group found a correlation between low birth weight and defective insulin secretion in 21-yr-old adults (196). More recently, however, no evidence of a defect in insulin secretion in young adults born SGA was found, and furthermore, ß-cell function appeared to be normal in these individuals (197, 198).

Additional confirmation that major ß-cell dysfunction is not the primary defect associated with undernutrition in utero is provided by the work of Beringue et al. (199). They found that ß-cell morphology, islet density, and the percentage of pancreatic area occupied by ß-cells were identical in fetuses born SGA and those born AGA.

A. SGA and insulin resistance in children and adults
One of the first reports of small size at birth being associated with elevated insulin levels in adults was published in 1993 from retrospective birth data (200). Since then, insulin resistance has been reported in children and adults born SGA (196, 197, 198, 201, 202). Importantly, the decreased insulin sensitivity found in these individuals was independent of confounding factors, such as BMI and age.

A detailed prospective case-control study of birth weight and insulin resistance took place in the Alsatian town of Haguenau, France, and included more than 1500 young adults (190). The cohort comprised individuals who were selected according to birth data from the Maternity Register in Haguenau between 1971 and 1985. Individuals were assigned to the SGA group if they were singletons born between 32 and 42 wk gestation and had a birth weight below the 10th percentile for gender and gestational age according to local growth curves. The comparable AGA group consisted of singletons born between 32 and 42 wk gestation, with a birth weight between the 25th and 75th percentiles for the local population and who were the first babies in the register to be born immediately after an infant born SGA.

Both direct and indirect measurements revealed that insulin resistance was more prominent in the SGA group, compared with the AGA group (190, 197, 203). Fasting insulin/glucose concentrations were significantly higher, and values for the quantitative insulin sensitivity check index (QUICKI) were significantly lower in the SGA group compared with the AGA group (Fig. 7) (204). Moreover, insulin sensitivity was 20% lower in 30% of the individuals born SGA than it was in individuals born AGA when assessed by the hyperinsulinemic euglycemic clamp method. This insulin resistance was independent of confounding factors, such as BMI, age, family history of diabetes or dyslipidemia, oral contractive use, and smoking.

View larger version (22K): [in this window] [in a new window]   FIG. 7. Insulin resistance in the Haguenau study of individuals born small for gestational age. A, Fasting insulin concentrations in 734 adults born SGA and 689 born AGA. B, Peripheral glucose uptake during hyperinsulinemic clamps in 26 individuals born SGA and 25 born AGA. The left-hand graphs represent individual values, and the right-hand graphs represent the mean values observed in the two groups. Black circles and bars, SGA; open circles and bars, AGA. kgffm, Kilograms fat-free mass. *, P = 0.05 compared with individuals born AGA. [Reproduced with permission from Lévy-Marchal and Czernichow (