Version May 2024
INTRODUCTION — Growth hormone (GH) affects many of the metabolic processes carried out by somatic cells, the best known of which is the effect of increasing body mass. Although generalized growth is stimulated, it is not evenly distributed among the protein, lipid, and carbohydrate compartments. Body protein content increases, total body fat content falls, and an increase in plasma and liver lipid content occurs because of mobilization of free fatty acids from peripheral fat stores. The ability of insulin to promote fatty acid synthesis is antagonized by GH.
Most children who were born small for gestational age (SGA) have adequate catch-up growth without pharmacologic intervention. However, for a minority, treatment with recombinant human growth hormone (rhGH) can augment growth.
The indications for and efficacy of rhGH treatment in children who were born SGA are reviewed here. The causes of and diagnostic approach to the child with short stature are discussed separately. (See "Causes of short stature" and "Diagnostic approach to children and adolescents with short stature".)
The use of rhGH for children with other conditions is addressed in separate topic reviews:
●(See "Treatment of growth hormone deficiency in children".)
●(See "Growth hormone treatment for idiopathic short stature".)
●(See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)
●(See "Prader-Willi syndrome: Management", section on 'Recombinant growth hormone treatment'.)
SMALL FOR GESTATIONAL AGE INFANTS
Definition — Small for gestational age (SGA) is generally defined as a weight and/or length at birth that is 2 standard deviations (SD) or more below the mean for gestational age (ie, <-2 SD) [1]. This means that 2.3 percent of human infants are born SGA by this definition. Most, but not all, SGA infants (either term or premature) have sufficient postnatal catch-up growth to normalize their stature by two years of age [2,3]. Approximately 90 percent of term SGA infants display sufficient catch-up growth to attain a height above -2 SD by the age of 2 years, whereas 10 percent remain short throughout childhood and adolescence [4-6]. The terms fetal growth restriction and SGA have been used interchangeably in the literature, albeit there is a difference. Fetal growth restriction is a clinical definition that indicates that a neonate is born with clinical features of malnutrition and in utero growth compromise irrespective of birth weight and/or length percentiles, having deviated from the intrauterine growth curves. Many neonates with fetal growth restriction are also born SGA. Other aspects of the SGA infant and alternate definitions for SGA are discussed separately. (See "Infants with fetal (intrauterine) growth restriction".)
Fetal growth hormone physiology — Growth-restricted fetuses tend to hypersecrete GH. This may be the direct or indirect result of reduced negative feedback exerted by insulin-like growth factor 1 (IGF-1) that circulates in lower concentrations in growth-restricted fetuses. The endocrine milieu of the human fetus with growth restriction is characterized not only by low circulating insulin, IGF-1, IGF-2, and insulin-like growth factor-binding protein 3 (IGFBP-3), but also by elevated IGFBP-1 and GH levels [7,8].
Hyperresponsiveness to GH-releasing factor also has been described in SGA infants [9]. This may reflect either deficient negative regulation or diminished feedback, as occurs in GH-resistant states such as undernutrition.
Intense activity of the somatotropic axis is thought to be one of the mechanisms driving the postnatal catch-up growth that occurs in the majority of SGA infants [9]. The role of the GH-IGF-1 axis in postnatal growth in children born SGA is unclear. One study suggests the presence of GH resistance with high levels of circulating GH and low levels of IGF-1 and IGFBP-3 [10]. A separate report noted high circulating IGF-1 levels consistent with IGF-1 resistance [11].
Postnatal growth and development — During the first two years of life, most SGA children born preterm grow faster than children born full-term; this period of intense catch-up growth allows most to attain normal height by the age of two to four years [12]. A minority of SGA children born preterm have catch-up growth after two years of age [13,14]. They are often born prematurely as well.
Pubertal timing contributes to the association between SGA and short adult stature in some cases. In one study, girls born SGA were five months younger at pubertal onset and menarche as compared with girls with normal birth weight [15], and earlier puberty tends to lead to reduced adult height. This effect is particularly pronounced in girls who undergo postnatal catch-up growth in addition to being born SGA [16,17]. It remains unclear whether pharmacologic suppression of puberty enhances the effects of recombinant human growth hormone (rhGH) treatment, as discussed below. (See 'Dosing and administration' below.)
Small for gestational age children without catch-up growth — Approximately 10 percent of children born SGA will remain short at two years of age (height <-2 SD, which corresponds to height less than the second percentile for age and sex). The mechanism underlying postnatal growth failure in these children is poorly understood. An irreversible deficit in cell number, inadequate calorie intake during the first years of life, and abnormalities in GH secretion have been hypothesized. Classic GH deficiency rarely is found in these children; however, there may be subtle abnormalities in the GH secretory pattern similar to those documented in adults during prolonged critical illness [18].
Regardless of the mechanism, it appears that the abnormal environmental conditions causing intrauterine growth restriction also can have long-lasting effects on growth and metabolism [19,20]. This altered programming may either alter the tempo of development or permanently reset homeostatic control [19]. (See "Infants with fetal (intrauterine) growth restriction", section on 'Adult chronic disorders'.)
In short SGA children, IGF-1 and IGFBP-3 levels are low-normal for chronologic age, increase with high-dose recombinant human growth hormone (rhGH) therapy (77 mcg/kg per day), and decrease with the discontinuation of rhGH therapy [21].
Differential diagnosis — For SGA children without catch-up growth, the differential diagnosis includes Silver-Russell syndrome. Silver-Russell syndrome is a genetically heterogeneous syndrome characterized by intrauterine growth retardation leading to small size at birth, feeding difficulties during infancy and early childhood, severe short stature, body asymmetry, triangular face with prominent forehead, and several other minor anomalies [22,23]. A clinical scoring system helps to identify the subset of children born SGA who have Silver-Russell syndrome [24]. Individuals with Silver-Russell syndrome who are not treated with rhGH attain a mean adult height of -4.2 to -2.9 SD, representing severe short stature [25,26]. (See "Causes of short stature", section on 'Silver-Russell syndrome'.)
Other considerations include early intrauterine infections such as cytomegalovirus, rubella or toxoplasmosis, chromosomal abnormalities, and maternal substance abuse (including fetal alcohol syndrome).
GROWTH HORMONE TREATMENT — Recombinant human growth hormone (rhGH) is a recognized therapy for children who are born small for gestational age (SGA) but who fail to have catch-up growth ("short SGA children") [1]. The effective doses of rhGH are higher than those for children with GH deficiency, suggesting relative GH and/or insulin-like growth factor 1 (IGF-1) resistance.
Patients should be evaluated for other causes of growth failure before embarking on rhGH therapy. If another cause of growth failure is identified, management includes rhGH for some causes (eg, GH deficiency or Turner syndrome) and not for others. (See "Diagnostic approach to children and adolescents with short stature".)
Indications — In the United States, rhGH is approved for use in short SGA children whose length or height remains 2 standard deviations (SD) or more below the mean for age and sex at two years of age (ie, height <-2 SD) (algorithm 1) [13]. In Europe, rhGH is approved for SGA children whose height is 2.5 SD or more below the mean for age and sex at four years of age (ie, height <-2.5 SD), with low height velocity (ie, height velocity less than average for age) and low predicted height (1 SD or more below mid-parental height) [27,28].
In deciding whether to treat a short SGA child with rhGH, one should consider the expected growth response and its potential benefits to the child, as compared with the risks and psychosocial burden of prolonged treatment on the child and their family. The overall high cost of sustained treatment is also a reasonable consideration if the expected benefits are modest.
Growth response — The magnitude of the growth response to treatment depends on the rhGH dose [29], the age of the child (younger children are more responsive), and the family-corrected individual height deficit (children with a greater height deficit are more responsive) [30,31]. A mathematical model has been developed to help predict the response to rhGH treatment in these children [32].
There are few long-term follow-up studies of children with assessment of (near) adult height for children born SGA [33-37]. The information from these studies is limited because of variability in dose, duration of treatment, and the age that therapy was initiated. Nonetheless, an analysis of initial adult height outcomes from three randomized controlled trials revealed significant positive effects of rhGH therapy on adult height [38]. When rhGH therapy was initiated by eight years of age and continued for at least seven years, there was a treatment-induced increase in adult height of approximately 1 SD (approximately 6 cm). There were only modest advantages of a higher-dose regimen as compared with a lower-dose regimen (67 mcg/kg/day versus 33 mcg/kg/day); higher doses yield greater short-term growth responses but confer only modest advantages on long-term height outcomes. Children who are shorter at the start of rhGH therapy appear to benefit the most from the higher-dose regimen. Although early initiation of rhGH is optimal, one study suggests that later initiation of rhGH has some benefit on linear growth. Among children who started rhGH at a median age of 11.2 years, the median height increased from -2.9 SD at the start of treatment to -1.7 SD after reaching adult height [39]. Subsequent larger series confirm and extend these earlier reports [40].
Children with Silver-Russell syndrome (SRS) also respond to rhGH therapy, but their adult height outcomes are somewhat less than for children born SGA but without SRS [36]. (See "Causes of short stature", section on 'Silver-Russell syndrome'.)
All short SGA children may benefit from rhGH therapy, whether or not they have GH deficiency. In a study of treatment with rhGH (3 or 6 international units/m2 per day [approximately 33 or 67 micrograms/kg/day] for an average of 7.8 years) in 54 short SGA children with or without GH deficiency, height was normalized in childhood followed by growth along the target height percentile [34]. The response to rhGH was independent of baseline endogenous GH secretion. The degree of response to rhGH therapy in SGA children without GH deficiency may have genetic determinants [41].
Treatment with rhGH may be less effective for short SGA children than for short children with normal birth weights. In the KIGS database (Kabi International Growth Study, now maintained by Pfizer), which contains information on a large cohort of children receiving rhGH therapy, the height gain during two years of treatment with rhGH was nearly 20 percent greater in children with normal birth weights than in those who had been SGA at birth [42]. The safety profile for rhGH treatment was similar among the two groups. (See "Treatment of growth hormone deficiency in children".)
Dosing and administration — The optimal dose and duration of rhGH therapy have not been established, but the recommended dose range is 35 to 70 mcg/kg/day. In our practice, we begin rhGH therapy with approximately 40 mcg/kg/day based on ideal body weight, which is similar to the dose used for treatment of GH deficiency in children.
During rhGH therapy, we readjust doses to maintain IGF-1 levels in the upper one-half of the normal range (ie, 0 to +2 SD) for age and/or Tanner stage of development [43]. The rhGH dose should be lowered if serum IGF-1 levels rise above the normal range, as recommended in guidelines from the Pediatric Endocrine Society [44]. This helps to avoid very high IGF-1 levels, which are thought to be associated with some of the drug's toxicity. This strategy of IGF-1-based dosing has not been studied in children born SGA but is extrapolated from the approach that we use for children with GH deficiency, in whom it has been studied but is not an established practice. (See "Treatment of growth hormone deficiency in children", section on 'Dose adjustment based on IGF-1 response'.)
Children should be monitored for evidence of complications of the treatment. Treatment is continued as long as the child is experiencing an accelerated growth rate compared with baseline or until the growth rate slows to less than 2 to 2.5 cm/year in late puberty. (See "Treatment of growth hormone deficiency in children", section on 'Growth hormone treatment' and 'Monitoring' below.)
A number of studies have evaluated different approaches to therapy:
●Dose effect – One study from Japan compared the effect of two doses of rhGH in short children born SGA, who were treated with either 33 mcg/kg/day or 67 mcg/kg/day [45]. The higher dose provided some advantage in height gain after five years of therapy but also a more rapid advancement of bone age, so the long-term effect of the higher dose on height is unclear.
●Continuous versus discontinuous treatment – In a trial of rhGH treatment of short SGA children, 59 children between two and five years of age were randomly assigned to one of two treatment regimens: four years of alternating treatment and observation (TOTO) or two years treatment followed by two years observation (TTOO) [46]. Height velocity and total height gain did not differ between the two groups, suggesting that interruption of treatment had no advantage.
●Concomitant suppression of puberty – In children who are SGA, the onset of puberty may occur early [15,16,47]. Because earlier onset of puberty tends to lead to reduced adult height, these observations have led to attempts to suppress puberty during rhGH treatment. In a randomized trial in 32 children born SGA, combination treatment with rhGH and a gonadotropin hormone-releasing agonist (GnRHa), there was a considerable gain in predicted adult height (8 to 10 cm) during the three years of treatment [48], but the effect on adult height was modest (mean gain of 4.9 cm) [49]. Similarly, reports from observational studies of children treated with rhGH suggest that adding GnRHa to the rhGH treatment regimen provides minimal benefit or even reduces growth outcomes [50,51]. Although the latter studies are limited by lack of a randomized control group, these combination regimens cannot be generally recommended at present. To determine whether combined therapy is efficacious, larger randomized trials are needed, including a significant number of SGA children treated to near-adult height [1,40,52].
Safety — The safety of rhGH therapy depends upon the modality of treatment and the individual risk factors. To date, short-term observations during rhGH therapy in short children born SGA have established no specific safety issues compared with other groups of children treated with rhGH. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)
Insulin resistance and risk of type 2 diabetes mellitus — Individuals born SGA, especially those born at term, generally have reduced insulin sensitivity as compared with individuals with normal birth weight [53]. Because rhGH therapy also has been associated with increased insulin levels and insulin resistance, concerns have been raised that this population might have additive risks for insulin resistance during rhGH therapy.
Several trials and postmarketing studies have addressed this issue. These have shown mild and reversible decreases in insulin sensitivity during rhGH therapy, without impaired glucose tolerance or type 2 diabetes mellitus [54-59].
As an example, in an observational study of 389 children born SGA treated with rhGH in Spain, indices of insulin resistance increased slightly during the first year of rhGH treatment and then remained stable and within the normal range throughout follow-up (up to 10 years) [59]. Markers of metabolic health and safety during rhGH therapy are similar for patients with SRS compared with other children born SGA but without SRS [60].
Cardiovascular risk factors — Supraphysiologic levels of GH can cause adverse changes in blood pressure and lipid profiles, raising concerns about possible adverse effects of rhGH therapy on cardiovascular risk factors in children born SGA. However, these concerns have not been substantiated in clinical studies.
In a large randomized study, children born SGA had higher baseline systolic blood pressures than age- or height-matched controls [61]. rhGH therapy for six years resulted in normalization of the blood pressure in these children. Mean values for serum lipids and the atherogenic index were normal at baseline but also decreased during rhGH therapy as compared with a reference population of healthy children. There were no significant differences in these cardiovascular risk factors between children treated with rhGH doses of 3 international units/m2/day as compared with 6 international units/m2/day. Of note, 28 percent of children in this study were GH deficient in addition to being born SGA.
Long-term effects — Many studies have noted an association between intrauterine growth restriction and long-term health risks, including type 2 diabetes, metabolic syndrome, and cardiovascular disease. However, the mechanisms underlying this association have not been established. (See "Infants with fetal (intrauterine) growth restriction", section on 'Outcomes'.)
Limited evidence suggests that rhGH therapy during childhood probably does not alter the long-term metabolic outcomes of individuals born SGA, at least up to early adulthood. In a longitudinal study from the Netherlands with 12 years of follow-up, individuals treated with rhGH during childhood had similar metabolic and cardiovascular risk factors around age 30 years compared with untreated controls born SGA, including indices of insulin sensitivity, fat mass, lipids, and blood pressure [62]. Regardless of rhGH treatment, individuals born SGA had somewhat higher concentrations of serum cholesterol and lower lean body mass compared with those born appropriate for gestational age, with no difference in abdominal adiposity, liver fat fraction, or blood pressure. While this study is reassuring, large longer-term studies are required to determine whether rhGH treatment during childhood affects cardiovascular events and other outcomes later in adulthood.
Evidence regarding the safety of rhGH treatment for individuals with GH deficiency is discussed separately. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)
Monitoring — Therapy with rhGH should be initiated and monitored by a pediatric endocrinologist. Before rhGH is initiated, the child's blood pressure; IGF-1; insulin-like growth factor-binding protein 3 (IGFBP-3); and fasting lipids, insulin, and glucose should be measured [27]. During rhGH therapy, growth parameters, blood pressure and IGF-1 should be monitored. In our practice, we also monitor fasting insulin and glucose and serum lipids during rhGH therapy, based on the concern that GH tends to increase insulin resistance, although clinically significant increases in insulin resistance appear to be rare, as described in the section above [13,27]. (See 'Safety' above and "Treatment of growth hormone deficiency in children", section on 'Growth hormone treatment'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Growth hormone deficiency and other growth disorders".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Small for gestational age (SGA) is generally defined as a weight and/or length at birth that is 2 standard deviations (SD) or more below the mean for gestational age (ie, <-2 SD). Approximately 10 percent of children born SGA will remain short at two years of age. (See 'Definition' above and 'Small for gestational age children without catch-up growth' above.)
●Indications and decisions about treatment
•For children who were SGA at birth and who have not had adequate catch-up growth, we suggest treatment with recombinant human growth hormone (rhGH) (algorithm 1) (Grade 2B). This suggestion assumes that the family has realistic understanding of the expected growth response and decides that this potential benefit outweighs the cost and burden of long-term treatment. Increases in short-term linear growth rates and in adult height have been shown in a variety of studies, but the treatment is costly and height outcomes are highly variable; the potential advantages and disadvantages of treatment should be considered on a case-by-case basis. (See 'Indications' above.)
•The definition of adequate catch-up growth varies. In the United States, rhGH is approved for use in short SGA children whose height is 2 SD or more below the mean for age and sex at two years of age (ie, height <-2 SD) [13]. In Europe, the approved indication is for short SGA children whose height is <-2.5 SD at four years of age [27]. (See 'Indications' above.)
•When treatment is contemplated, it is critical for the provider to discuss realistic expectations with the patient and family. Treatment with rhGH is likely to yield only modest gains in height compared with no treatment (an increase in adult height of approximately 6 cm, provided that the treatment is started early and continued for at least seven years). Adult height will usually be below average despite therapy. (See 'Growth response' above.)
●Dosing – If treatment is chosen, we suggest beginning with rhGH doses similar to those used for treatment of GH deficiency in children, approximately 40 mcg/kg/day based on ideal body weight. During rhGH therapy, we readjust the rhGH dose to maintain insulin-like growth factor 1 (IGF-1) levels in the upper one-half of the normal range (ie, 0 to +2 SD). Children should be monitored for evidence of complications of the treatment. (See "Treatment of growth hormone deficiency in children", section on 'Growth hormone treatment' and 'Dosing and administration' above and 'Monitoring' above.)
●Outcomes – Treatment with rhGH yields the greatest increases in height when it is initiated by mid-childhood and continued for more than seven years. Children who are younger or shorter at the beginning of therapy have the greatest response as compared with untreated children. (See 'Growth response' above.)
●Safety – Short children born SGA are at increased risk for diabetes and cardiovascular disease when compared with children with normal birth weight. Whether treatment with rhGH either improves or exacerbates these long-term risks has not been established. However, there appear to be no differences in the short-term risks of rhGH treatment in this population compared with other children treated with rhGH. (See 'Safety' above.)
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