International Small for Gestational Age Advisory Board Consensus Development Conference Statement: Management of Short Children Born Small for Gestational Age, April 24–October 1, 2001
Objective. To provide pediatric endocrinologists, general pediatricians, neonatologists, and primary care physicians with recommendations for the management of short children born small for gestational age (SGA).
Methods. A 13-member independent panel of pediatric endocrinologists was convened to discuss relevant issues with respect to definition, diagnosis, and clinical management of short children born SGA. Panel members convened over a series of 3 meetings to thoroughly review, discuss, and come to consensus on the identification and treatment of short children who are born SGA.
Conclusions. SGA is defined as birth weight and/or length at least 2 standard deviations (SDs) below the mean for gestational age (≤−2 SD). Accurate gestational dating and measurement of birth weight and length are crucial for identifying children who are born SGA. Comprehensive pregnancy, perinatal, and immediate postnatal data may help to confirm the diagnosis. Maternal, placental, and fetal causes of SGA should be sought, although the cause is often not clear. Most children who are SGA experience catch-up growth and achieve a height >2 SD below the mean; this catch-up process is usually completed by the time they are 2 years of age. A child who is SGA and older than 3 years and has persistent short stature (ie, remaining at least 2 SD below the mean for chronologic age) is not likely to catch up and should be referred to a pediatrician who has expertise in endocrinology. Bone age is not a reliable predictor of height potential in children who are SGA. Nevertheless, a standard evaluation for short stature should be performed. A diagnosis of SGA does not exclude growth hormone (GH) deficiency, and GH assessment should be performed if there is clinical suspicion or biochemical evidence of GH deficiency. At baseline, insulin-like growth factor-I, insulin-like growth factor binding protein-3, fasting insulin, glucose, and lipid levels as well as blood pressure should be measured, and all aspects of SGA—not just stature—should be addressed with parents. The objectives of GH therapy in short children who are SGA are catch-up growth in early childhood, maintenance of normal growth in childhood, and achievement of normal adult height. GH therapy is effective and safe in short children who are born SGA and should be considered in those older than 2 to 3 years. There is long-term experience of improved growth using a dosage range from 0.24 to 0.48 mg/kg/wk. Higher GH doses (0.48 mg/kg/wk [0.2 IU/kg/d]) are more effective for the short term. Whether the higher GH dose is more efficacious than the lower dose in terms of adult height results is not yet known. Only adult height results of randomized dose-response studies will give a definite answer. Monitoring is necessary to ensure safety of medication. Children should be monitored for changes in glucose homeostasis, lipids, and blood pressure during therapy. The frequency and intensity of monitoring will vary depending on risk factors such as family history, obesity, and puberty.
The term “small for gestational age” (SGA) describes a neonate whose birth weight or birth crown-heel length is at least 2 standard deviations (SD) below the mean (≤−2 SD) for the infant’s gestational age, based on data derived from a reference population. SGA has also been defined in some publications as birth weight or length below the 10th, 5th, or 3rd percentile for gestational age. Although segregation of SGA from normal is somewhat arbitrary, <−2 SD was selected because it likely encompasses the majority of patients with disordered fetal growth and because most studies that have defined postnatal growth patterns and response to growth-promoting therapies have selected patients whose birth size is approximately −2 SD or less. Gestational age is most accurately gauged with the use of ultrasonography during pregnancy1 and the date of the last menstrual period. Ultrasonographic fetal indices such as crown-rump length during the first trimester correlate well with gestational age,2 but they must be recorded accurately and birth length must subsequently be measured precisely for a correct diagnosis of SGA to be made from these data. In addition, crown-rump length and gestational age are well correlated only when no growth defect has occurred during the first trimester. If a growth defect has occurred during the first trimester, then crown-rump length becomes a less reliable indicator of gestational age and last menstrual period is an important measure.
In 1999, the most recent year for which adult birth data are available from the National Center for Health Statistics, 3 959 417 infants were born in the United States.3 Using a 2.3% definition of SGA (−2 SD is equivalent to the 2.3 percentile), one can calculate that ∼91 000 infants in the United States are born SGA annually. By comparison, the same cohort would produce only 800 female infants with Turner syndrome (assuming an incidence of 1 in 2500 female births) and ∼1100 individuals with growth hormone (GH) deficiency (incidence of 1 in 3500). A Swedish study found that among 3650 healthy full-term neonates born in 1973, 1974, or 1975, 5.4% (198) were SGA, defined as <−2 SD for birth length and/or height.4 Among those who were born SGA, 1.5% were both light and short, 2.4% were short only, and 1.6% were light only. Thus, compared with the incidence of other growth disorders, the incidence of SGA births is relatively high.
Some children who are born SGA fail to manifest spontaneous catch-up growth. Persistent short stature has been associated with psychosocial disadvantages and behavioral problems in individuals who may or may not also have cognitive impairment.5–13 For example, one study showed that absence of catch-up growth among male infants who were born SGA was the most important predictor of subnormal performance on standard psychological tests.13 In addition, adverse metabolic outcomes such as hypercholesterolemia may be related to failure to achieve catch-up.14
The International SGA Advisory Board Panel met in April, July, and October 2001 to discuss the definition of SGA, diagnosis and cause of SGA, catch-up growth among children who are born SGA, evaluation before GH therapy, and the role of GH therapy in the treatment of short children who are born SGA. This independent panel considered the scientific evidence and subsequently drafted this consensus statement on the treatment of short children who are born SGA, which addresses the following issues:
How should SGA be defined?
How should the causes of SGA be identified?
How should catch-up growth be defined?
How should short children who are born SGA be evaluated before starting GH therapy?
What is the role of GH therapy in the treatment of short children who are born SGA?
HOW SHOULD SGA BE DEFINED?
For representing most accurately the expected birth weight or length of an infant for his or her gestational age, AGA should be defined as birth weight and length SDS within ±2 SD for gestational age. According to this definition of AGA, SGA represents a statistical grouping of infants whose birth weight and/or length is at least 2 SD below the mean (≤−2 SD) for gestational age, which is approximately the third percentile for gestational age.15 Stated differently, neonates with either low birth weight or length or both for gestational age should be considered SGA. Accordingly, subject to available data, those who are born SGA may be further classified as SGAW (low birth weight), SGAL (low birth length), or SGAWL (low birth weight and length).4 It is important to describe these classifications, as different SGA subsets may respond differently to GH therapy.
The term “SGA” refers not to fetal growth but to the size of the infant at birth; the term “intrauterine growth retardation” (IUGR) suggests diminished growth velocity in the fetus as documented by at least 2 intrauterine growth assessments.16 SGA and IUGR are not synonymous. IUGR indicates the presence of a pathophysiologic process occurring in utero that inhibits fetal growth. A child who is born SGA has not necessarily suffered from IUGR, and infants who are born after a short period of IUGR are not necessarily SGA.
Accurate classification of infants who are SGA depends on access to the appropriate reference data for birth weight and birth length available for the population, and country- or ethnic-specific normative data are important for identifying those at risk. In the United States, the most commonly used data on intrauterine growth come from charts developed by Usher and McLean.17 However, such data do not exist in many countries, and efforts should be made to improve the existing standard reference data. Although population-specific birth weight and birth length standards are important for identifying those who are born SGA, the accuracy of birth weight and length measurements and, particularly, of gestational dating is more crucial. Pediatricians should be encouraged to ask parents whether ultrasonographic dating was performed during pregnancy. Data are not available for male or female infants separately, and such would not seem to be necessary for purposes of diagnosing SGA. Furthermore, although data are not available for multiple births, the same standards should apply for these children in terms of expected catch-up growth and height, although multiple births may be the cause of the diminished birth weights.
In certain situations, it may be difficult to distinguish between neonates who are SGA and AGA, especially when gestational age data are unavailable or less than accurate. In addition, some very premature (gestational age <30 weeks) infants who are AGA and have very low birth weight may exhibit early postnatal growth failure. Pediatricians must be aware that early postnatal growth curves for these infants may mimic those for infants who are born SGA. Early postnatal growth data may be helpful to confirm the birth data, and comprehensive data from pregnancy and from perinatal and immediate postnatal states should be obtained and recorded.
HOW SHOULD THE CAUSES OF SGA BE IDENTIFIED?
The cause of SGA should be identified whenever possible, as underlying mechanisms are diverse and may influence treatment. In addition, the mechanisms underlying associated metabolic abnormalities are varied and may affect treatment considerations. It should also be noted that the diagnosis of familial short stature, Turner syndrome, other short-stature syndromes, GH deficiency, or skeletal dysplasia does not preclude a concurrent classification of SGA.
Impaired fetal growth has multiple causes, including a number of maternal, placental, and fetal factors (see Table 1).18–21 Maternal factors include age, parity, medical conditions such as hypertension, infections (particularly toxoplasmosis, rubella, cytomegalovirus, and herpesvirus), malnutrition, alcohol abuse, and cigarette smoking. Placental factors involve any mismatch between placental perfusion and fetal oxygenation.18 Examination of the placenta by a pathologist could help to define specific causes, including vascular. Fetal factors include chromosomal abnormalities and genetic defects. Specialized genetic tests and/or consultation with a geneticist may be valuable. A standard questionnaire, incorporating a core list of causes, should be developed to assist obstetricians, neonatologists, general pediatricians, and primary care physicians in determining the cause of SGA as early and as accurately as possible.
HOW SHOULD CATCH-UP GROWTH BE DEFINED?
Catch-up growth in short children who are born SGA has been defined in a number of ways. A general definition is growth velocity (cm/y)22 greater than the median for chronologic age and gender. Definitions based on the normal height range for the population (eg, catch-up is 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 target height—that is, an estimate of genetic potential in stature—is a strong predictor of response to GH therapy.23 Target height is commonly estimated by the midparental height corrected for gender.22
Most children who are born SGA experience catch-up growth and will achieve a height >−2 SD. Catch-up is typically an early postnatal process that in most SGA infants is completed by the age of 2 years;24,25 within this 2-year period, premature SGA infants (<37 weeks’ gestation) may take longer to catch up than full-term SGA infants.26 In >80% of infants who are born SGA, catch-up growth occurs during the first 6 months of life.27 For this reason, growth monitoring during the early postnatal period provides useful information; different growth patterns may be identified in infants as young as 3 months.
Approximately 10% of children born SGA will remain ≤−2 SD for height throughout childhood and adolescence and into adulthood.27,28 Among children who are born SGA and do not achieve catch-up by 2 years of age, the relative risk of short stature (<−2 SD) at 18 years of age is 5.2 for those with low birth weight and 7.1 for those with low birth length.25 Therefore, a short child who was born SGA and has not caught up by 2 to 3 years of age and whose catch-up growth has stopped should be referred to a pediatrician who has expertise in endocrinology.
HOW SHOULD SHORT CHILDREN WHO WERE BORN SGA BE EVALUATED BEFORE STARTING GH THERAPY?
Pediatricians should perform a standard evaluation for short stature in children who were born SGA and fail to catch up.22,29 Specific disorders that limit growth may occur with the SGA phenotype, and the presence of concomitant nutritional insufficiency, renal disease, or a genetic condition for which GH therapy might be hazardous (eg, Bloom syndrome) would alter management. Although radiologic assessment of skeletal maturation is routinely performed, it should be noted that predictions of adult height based on estimates of bone age are unreliable in these children.30
Whether measures of GH secretion provide clinically useful information for the routine treatment of short children who were born SGA is controversial. Arguments that favor evaluation for GH deficiency stem from data suggesting that many short patients who were born SGA have diminished GH output, as evidenced by low levels of spontaneous GH secretion31–36 and depressed circulating concentrations of markers of GH secretion, such as insulin-like growth factor-I (IGF-I).33,37 Thus, the lack of catch-up growth in some cases might be attributable to reduced GH secretion. Tests of GH release might, in theory, be used to predict response to different therapeutic regimens in addition to being used to identify an underlying pathologic condition. However, distinguishing normal from abnormal pituitary function by GH testing is frequently not straightforward,38,39 and standard GH stimulation tests (eg, arginine, insulin-induced hypoglycemia) do not predict growth response in most short patients who are SGA and treated with GH at doses now accepted as generally efficacious.37,40–42 Furthermore, GH deficiency cannot explain all growth deficits, because children who are born with severe congenital GH deficiency are usually not born SGA. Thus, mandating direct measurement of GH secretion, either spontaneous or in response to provocative agents, for all short children who are born SGA is not adequately justified by current published data. The present recommendation is that tests of GH release be performed when GH deficiency is suspected on clinical or biochemical grounds. Accordingly, measurement of circulating concentrations of IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) before the start of GH therapy not only provides a baseline against which to assess the biochemical response to GH therapy but also serves as a useful screen for possible GH deficiency in this patient population.
Although insulin resistance is not an unexpected finding among children who are SGA and have become obese, insulin resistance may be present in short children who are SGA43 and, subsequently, in young adults who were born SGA.28 Eight percent of 8-year-old children were found to have an abnormal glucose tolerance test, although over the subsequent 10 years none developed diabetes mellitus.44 The majority of prepubertal children who are SGA are not at risk for glucose intolerance. Because insulin resistance may increase during GH therapy, parents should be asked whether there is a family history of type 2 diabetes, although any potential long-term risk as a consequence of elevated insulin levels is unknown. In lean children without a family history of diabetes, screening of the carbohydrate status (eg, fasting, postprandial glucose and insulin levels) is suitable. More stringent measures are recommended for those who are at puberty, are obese, or have other increased risks. Short children who were born SGA may be at increased risk of dyslipidemia,14 and children are born SGA are at increased risk of hypertension.45,46 For these reasons, plasma lipid levels and blood pressure should be measured before the start of GH therapy.
WHAT IS THE ROLE OF GH THERAPY IN THE TREATMENT OF SHORT CHILDREN WHO ARE BORN SGA?
Maternal, placental, and fetal causes of SGA should be sought, although the cause is often not clear. It should be noted that some children with short stature associated with causes other than SGA may, nevertheless, have been born SGA. When history, physical findings, or laboratory studies indicate an identifiable cause of growth failure, available specific treatment for that cause should be administered, and alternative approaches to therapy should be based on alternative histories. Taking and recording thorough histories will accumulate data that may point to specific causes and therapy in the future.
Parents may not consult a pediatrician for evaluation of short stature of their prepubertal child who is SGA and has failed to catch up until there is a large height deficit. Clinical trials have shown that the growth response to GH is better when children begin therapy in early childhood31,37 and that age at the initiation of therapy is a major determinant of growth response.37,41 Therefore, the age of the child must be considered when parents are educated about treatment objectives and efficacy. In addition, target height should be considered, although it should not be used to exclude any child who is SGA and would otherwise be treated for failure to catch up. Given the known influence of parental height, treatment goals may need to be modified. Optimized or revised SGA prediction models that include genetic factors such as parental height and potential new factors involved in the catch-up mechanism are needed.
Pediatricians should discuss all aspects of SGA with parents, including the need for psychological support. One study showed that infants who are SGA may be more vulnerable to adverse social conditions than infants who are AGA.47 Lack of appropriate cognitive stimulation was found to be more likely in the home environment of children who are born SGA than in that of children who are born AGA. Cognitive impairment in such children may result not only from IUGR but also from this less-than-optimal home environment for cognitive stimulation.
SGA is more than a “height” issue. In addition to having short stature, infants who are born SGA usually have less body fat than infants who are born AGA.48 At 7 years of age, short children who were born SGA remain not only shorter but also leaner than children who were born AGA.49 Serum concentrations of leptin, a protein produced by adipose tissue and involved in the regulation of appetite and body weight,50 are reduced in short children who were born SGA, and leptin levels may reflect the nutritional state of these children.51 Many children who were born SGA may not consume an adequate number of calories because of a lack of appetite. Ideally, pediatricians and parents should document the caloric intake of such children; in those who are being treated with GH, this will serve to monitor the effect of GH therapy on appetite.
Children who are born SGA are at increased risk of impaired neurologic development,52–55 school performance,56,57 and socialization.5–11,58 These potential sequelae should be discussed with parents. Behavior and social problems in children with idiopathic short stature or short stature as a result of GH deficiency improved after treatment with GH for 3 years, but there was no improvement in mean intelligence or achievement scores.59 To our knowledge, there are no such published studies of children who are SGA.
Metabolic syndrome—type 2 diabetes, hypertension, obesity, and hyperlipidemia—has been reported in adults who were born SGA.60 The risk is increased in those who were born SGA and are overweight. Later adverse outcomes, including the metabolic syndrome with all its diverse components, have been reported primarily in children who are SGA and experienced excessive weight gain during childhood. Regular monitoring of weight, height, and body mass index during adolescence is particularly important in these patients. It remains to be determined whether GH therapy in short children who were born SGA has any beneficial or deleterious effect on their risk of developing metabolic syndrome in adulthood.
The initial objective of GH therapy is to accelerate prepubertal linear growth to achieve catch-up to a normal height in early childhood and maintain normal growth later in childhood. The ultimate objective is to normalize adult height. Parental height and birth length are the only variables that seem to be predictive of adult height in untreated children who are born SGA.61 In GH-treated short children who were born SGA and were followed to (near) adult height, GH therapy effectively increased adult height above predicted height, and patients achieved target height.62
GH Therapy for SGA
GH therapy is indicated for children who were born SGA and have persistent short stature (height below −2 SD); are at least 2 to 3 years of age; and are growing at an average or subnormal rate for age, provided that other causes for short stature such as growth inhibiting medication, chronic disease, endocrine disorders, emotional deprivation or syndromes (except of Silver Russell syndrome) have been ruled out.
Before GH therapy for a short child who was born SGA is considered, it is important to wait until the spontaneous catch-up phase is completed, which usually occurs by the time a child is 2 to 3 years of age. (Some children—eg, those born very prematurely—may have a longer period of spontaneous catch-up growth.) Children who begin GH therapy much later (9 or 10 years of age) may also benefit from treatment, although they experience a mean lower growth velocity than those who start treatment earlier. Although specific recommendations regarding an optimal treatment regimen must await additional investigation, published studies have shown that GH therapy is effective and safe for persistently short children who were born SGA and achieved insufficient catch-up growth.
A number of clinical trials have confirmed that GH effectively and safely induces catch-up growth in short prepubertal children who were born SGA, some of which are summarized below. Although the increment in adult height resulting from GH treatment is not yet precisely defined, most trials reported to date demonstrate stimulation of skeletal growth of sufficient duration and magnitude to recommend therapy.
In a study of children who were a mean age of 4.5 years and had severe short stature (≥3 SD below the mean for chronologic age and gender) and a history of IUGR (birth weight <10th percentile), GH therapy induced sustained catch-up growth.63 All children received GH at a dose of 0.2 IU/kg/d (0.48 mg/kg/wk) for 3 years, although 1 of the 2 groups initially underwent a 1-year observation period, which confirmed that no clinically significant acceleration of height velocity occurred. After 3 years of treatment, mean height SDS for chronologic age had increased by 2.0 ± 0.7 in the 2 groups, and no clinical adverse events were related to treatment.
In the Nordic Multicentre Trial, short children who were born SGA, aged 2 to 8 years, achieved their target height SDS within 3 years of treatment with GH at a dose of 0.1 or 0.2 IU/kg/d (0.24 or 0.48 mg/kg/wk).41 Dose was a determinant of the growth response, with the group that received the 0.2 IU/kg dose achieving an attained height SDS of −0.90 after 3 years, compared with −1.29 for the group that received 0.1 IU/kg. Also, the younger the child at the start of treatment and the greater the family-corrected individual height deficit, the better the growth response. Treatment was well tolerated, and no GH-related adverse events were detected.
The results of 3 short-term French studies showed that the growth rate accelerated markedly, nearly doubling after 1 year of treatment, with GH doses up to 1.4 IU/kg/wk (0.48 mg/kg/wk), which is up to 3 times greater than the standard replacement doses used to treat children with GH deficiency (ie, 0.16–0.24 mg/kg/wk).64 Mean height increased by nearly 2.0 SDS over the 3-year treatment period, although, as in all GH trials, a progressive decrease in the effect on growth rate occurred over time. This treatment was well tolerated without significant adverse effects.
A review of data from the National Cooperative Growth Study showed that children who had IUGR-associated short stature and were treated with 0.30 mg/kg/wk GH for up to 4 years experienced a progressive increase in height SDS with each year of therapy.65 There was no control population. The height SDS at baseline for those with unclassified IUGR was −3.49, which improved to −1.32. Despite these encouraging results, no improvement in predicted adult heights was detected.
Five-year data from a Dutch study showed that long-term continuous GH therapy at a dose of either 3 IU/m2/d (0.24 mg/kg/wk) or 6 IU/m2/d (0.48 mg/kg/wk) in short children who were born SGA results in normalization of height and subsequent growth along the target height percentile.37 The 5-year increase in height SDS for chronologic age was 2.6 ± 0.9 for the 6-IU group and 2.2 ± 0.6 for the 3-IU group; these changes were significantly different from baseline values (P < .001) but not significantly different from each other. Also, this 5-year increase did not differ between those with GH deficiency and those without GH deficiency. No drug-related adverse events were reported.
A meta-analysis of 6-year growth responses from 4 European studies of short children who did not have GH deficiency and were born SGA determined that GH effectively normalized height during childhood and early puberty.30 Children were treated with GH continuously (33 μ g/kg/d [0.24 mg/kg/wk] or 67 μ g/kg/d [0.48 mg/kg/wk]) or discontinuously (initial treatment for 2–3 years at a dose of 33–100 μ g/kg/d [0.24–0.72 mg/kg/wk] followed by withdrawal for 1–2 years, and then either 1 or more additional treatment periods at the same dose or no additional treatment). After 6 years, height increased toward the norm by 1.9 ± 0.1 SD. In contrast, untreated controls experienced no catch-up, and their height increased toward the norm by <0.1 ± 0.1 SD. This finding suggests that the cumulative GH dose received and not the dosing regimen determines the growth response.15 Treatment with GH was well tolerated.
In July 2001, GH was approved by the US Food and Drug Administration for the long-term treatment of growth failure in children who are born SGA and do not achieve catch-up growth by 2 years of age, at dosages up to 0.48 mg/kg/wk.
GH Dosing for SGA
The dose of GH is the most important predictor of the growth response to therapy during the first year of treatment among short children who were born SGA.66 When a GH dose of 0.1 IU/kg/d (0.24 mg/kg/d) was used, the growth response of short children who were SGA matched that of children who had GH deficiency and were not SGA and were treated with a GH dose of 0.07 IU/kg/d.40 Currently available data suggest that the higher dosage—0.48 mg/kg/wk (0.2 IU/kg/d)—is efficacious and safe at initiation of therapy when rapid catch-up growth is desired. Doses <0.1 IU/kg/d (0.24 mg/kg/wk) may be effective in the long-term, although, according to the results of 2 studies, these low GH doses may be inadequate for some children who start therapy relatively late. Zucchini et al67 found that GH at a dose of 20 U/m2/wk (0.23 mg/kg/wk) for 36 to 84 months was not effective in 29 low birth weight children who had GH deficiency. In addition, Coutant et al68 found that an average dose of 0.4 U/kg/wk (0.13 mg/kg/wk) had a limited effect on adult height in 70 children who were SGA and had GH deficiency. In both these studies, GH was given at a dose less than or equal to the replacement dose for GH deficiency. In addition, treatment was started when the children’s average age was >10 years, which likely compromised the effect.
When catch-up growth has been achieved and during puberty, individual dose adjustments may be made within the 0.24 to 0.48 mg/kg/wk (0.1–0.2 IU/kg/d) range. Additional information is required before specific dose recommendations can be made for patients with “catch-down” (deceleration of growth rate) when goal height is achieved.
Although the goal of GH therapy is improved adult height, at present, too few studies using appropriate GH doses in younger children have been published that accurately determine the effect of GH therapy on final height. Nevertheless, data based on GH therapy over 6 years compose the basis for the recommendations of this consensus statement.
Monitoring During Therapy
The effect of GH on glucose metabolism in short children who were born SGA is of potential concern, and carbohydrate metabolic status should be reassessed during GH therapy. Fasting serum glucose and insulin levels should be measured annually. In children who experience excessive weight gain, develop acanthosis, belong to an ethnic group at risk, or have a strong family history of type 2 diabetes, glucose homeostasis should be monitored more frequently and intensely (oral glucose tolerance test with insulin measurements). It should be noted, however, that the effects of GH therapy on glucose metabolism are generally mild and transient. No adverse effects on serum glucose levels were found in 79 prepubertal children who were SGA and had short stature and were treated with GH continuously at a dose of either 0.24 or 0.48 mg/kg/wk (0.1 or 0.2 IU/kg/d) for 6 years.44 Notably, in a study of the relationship between insulin resistance and plasma concentrations of potential inhibitors of the insulin receptor substrate system, plasma levels of GH and IGF-I were not elevated in obese people who had impaired glucose tolerance and were at an early stage of diabetes development.69 This finding suggests that elevation of GH or IGF-I is not a primary metabolic abnormality that leads to insulin resistance.
Fasting serum lipids and blood pressure should be monitored periodically for purposes of long-term surveillance during GH therapy. It should be noted that neither serum lipids nor blood pressure increased from baseline during 4 and 6 years, respectively, of GH therapy for short stature among 79 children who were born SGA.46
SGA is defined as birth weight and/or length at least 2 SD below the mean for gestational age. Accurate gestational dating and measurement of birth weight and birth length are crucial for identifying children who are born SGA. Comprehensive pregnancy, perinatal, and immediate postnatal data may help confirm the diagnosis.
Maternal, placental, and fetal causes of SGA should be sought, although the cause is often not clear. Such studies may reveal important information concerning heritability in genetic disorders or the need to assess patients for associated medical conditions.
Most children who are SGA experience catch-up growth and achieve a height >2 SD below the mean, and the catch-up process is complete at 2 to 3 years of age in most infants. A short child who was born SGA and is older than 3 years and shows no evidence of continuing catch-up growth is not likely to catch up later on and should be referred to a pediatrician who has expertise in endocrinology.
A standard evaluation for short stature should be performed, although bone age is not a reliable predictor of height potential in SGA. SGA does not exclude GH deficiency, and GH assessment should be performed if there is clinical suspicion or biochemical evidence of GH deficiency. All aspects of SGA and not just increased height should be addressed with parents.
The objectives of GH therapy are catch-up growth in early childhood, maintenance of normal growth in childhood, and achievement of normal adult height. Before treatment, fasting glucose, insulin, and lipid levels; IGF-I and IGFBP-3 levels; and blood pressure should be measured. GH therapy is effective and safe in short children who were born SGA (≤−2 SD) and should be considered in those who are older than 2 to 3 years and have persistent short stature (≤−2 SD). Higher GH doses (0.48 mg/kg/wk [0.2 IU/kg/d]) are generally more effective to induce short-term catch-up growth than doses in the standard replacement range. Adult height data are required, however, to determine whether the higher GH dose is also more efficacious than a lower dose of 0.1 IU/kg/d (0.24 mg/kg/d) concerning adult height attainment. Children should be monitored for changes in glucose homeostasis, lipids, and blood pressure during and after therapy.
The support for the consensus developmental conferences were via SCIENS Worldwide Medical Education (New York, NY) using funds provided by Pharmacia, Inc. This article was developed through an unrestricted educational grant from Pharmacia Corporation. The manuscript resulting in this consensus statement was developed independent of and without input from Pharmacia personnel. All authors have served as consultants, as listed in this company’s speakers bureau, and have received research support from Pharmacia, Inc.
The authors gratefully acknowledge the contribution of David Dunger, MD, to the sections of this article relating to glucose metabolism.
International SGA Advisory Board: Kerstin Albertsson-Wikland, MD, PhD, Göteborg University, International Pediatric Growth Research Center, Göteborg, Sweden; Antonio Carrascosa, MD, PhD, Autonomous University, Hospital Vall d’Hebron, Barcelona, Spain; Steven D. Chernausek, MD, Children’s Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio; Paul Czernichow, MD, University Saint-Louis Lariboisière, Department of Pediatric Endocrinology and Diabetes, Hôpital Robert Debré, Paris, France; Francis de Zegher, MD, Department of Pediatrics, Catholic University of Leuven, University Hospital Gasthuisberg Leuven, Leuven, Belgium; David Dunger, MD, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom; Wayne Cutfield, MD, University of Auckland, Starship Children’s Hospital, Auckland, New Zealand; Anita C.S. Hokken-Koelega, MD, PhD, Sophia Children’s Hospital, Erasmus University of Rotterdam, Rotterdam, the Netherlands; Ieuan Hughes, MD, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom; Peter A. Lee, MD, PhD, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania; Robert Rapaport, MD, Mount Sinai School of Medicine, Division of Pediatric Endocrinology and Diabetes, Mount Sinai Diabetes Center, New York, New York; Luciano Tatò, MD, PhD, Department of Pediatrics, Obstetrics, Biology and Genetics, University of Verona, Department of Pediatrics, Polyclinic G.B. Rossi, Verona, Italy; and Torsten Tuvemo, MD, Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, Uppsala University, Uppsala, Sweden.
- Received August 26, 2002.
- Accepted December 12, 2002.
- ↵Ventura SJ, Martin JA, Curtin SC, Menacker F, Hamilton BE. Births: final data for 1999. Nat Vital Stat Rep.2001;49 :1– 23
- ↵Hokken-Koelega ACS. Intrauterine growth retardation. Int Growth Monitor.2001;11 :2– 8
- Wollmann HA. Intrauterine growth restriction: definition and etiology. Horm Res.1998;49(suppl 2) :1– 6
- ↵Reiter EO, Rosenfeld RG. Normal and aberrant growth. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR. Williams Textbook of Endocrinology. 9th ed. Philadelphia, PA: WB Saunders; 1998:1427–1507
- ↵Ong KL, Ahmed ML, Emmett PM, Preece MA, Dunger DB, for the Avon Longitudinal Study of Pregnancy and Childhood Study Team. Association between post-natal catch-up growth and obesity in childhood: prospective cohort study. BMJ.2000;320 :967– 971
- ↵Karlberg JP, Albertsson-Wikland K, Kwan EY, Lam BC, Low LC. The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age. Horm Res.1997;48(suppl 1) :17– 24
- ↵Leger J, Levy-Marchal C, Bloch J, et al. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ.1997;315 :341– 347
- ↵Brook CGD. Short stature. In: Clinical Paediatric Endocrinology. 3rd ed. Oxford, UK: Blackwell Publishers; 1995:136–172
- ↵de Waal WJ, Hokken-Koelega ACS, Stijnen T, SMPF de Muinck Keizer-Schrama, Drop SLS, and the Dutch Working Group on Growth Hormone. Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. Clin Endocrinol.1994;41 :621– 630
- ↵Stanhope R, Ackland F, Hamill G, et al. Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand.1989;349 :47– 52
- ↵Sas T, Mulder P, Hokken-Koelega A. Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. J Clin Endocrinol Metab.2000;85 :3786– 3792
- ↵Hediger ML, Overpeck MD, McGlynn A, Kiczmarski RJ, Maurer KR, Davis WW. Growth and fatness at three to six years of age of children born small- or large-for-gestational age. Pediatrics.1999;104(3) . Available at: www.pediatrics.org/cgi/content/full/104/3/e33
- ↵Boguszewski M, Dahlgren J, Bjarnason R, et al, for the Swedish Study Group for Growth Hormone Treatment. Serum leptin in short children born small for gestational age: relationship with the growth response to growth hormone treatment. Eur J Endocrinol.1997;137 :387– 395
- ↵Boguszewski MCS, de Zegher F, Albertsson-Wikland K, for the Nordic Study Group for Growth Hormone Treatment in SGA Children and the Belgian Study Groups for Pediatric Endocrinology. Serum leptin in short children born small for gestational age: dose-dependent effect of growth hormone treatment. Horm Res.2000;54 :120– 125
- McCarton CM, Wallace IF, Divon M, Vaugh HG Jr. Cognitive and neurologic development of the premature, small for gestational age infant through age 6: comparison by birth weight and gestational age. Pediatrics.1996;98 :1167– 1178
- Markestad T, Vik T, Ahlsten G, et al. Small-for-gestational-age (SGA) infants born at term: growth and development during the first year of life. Acta Obstet Gynecol Scand.1997;76(suppl 165) :93– 101
- ↵Larroque B, Bertrais S, Czernichow P, Léger J. School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study. Pediatrics.2001;108 :111– 115
- ↵Chatelain P. Children born with intra-uterine growth retardation (IUGR) or small for gestational age (SGA): long term growth and metabolic consequences. Endocr Reg.2000;33 :33– 36
- ↵Ranke MB, Lindberg A, for the KIGS International Board. Growth hormone treatment of short children born small for gestational age or with Silver-Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr Suppl.1996;417 :18– 26
- ↵Ranke MB, Guilbaud O, Lindberg A, Cole T, for the International Board of the Kabi Pharmacia International Growth Study. Prediction of the growth response in children with various growth disorders treated with growth hormone: analyses of data from the Kabi Pharmacia International Growth Study. Acta Pediatr Suppl.1993;391 :82– 88
- ↵Zucchini S, Cacciari E, Balsamo A, et al. Final height of short subjects of low birth weight with and without growth hormone treatment. Arch Dis Child.2001;84 :340– 343
- ↵Blüher M, Kratzsch J, Paschke R. Plasma levels of tumor necrosis factor-α, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care.2001;24 :328– 334
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