The Variability of Growth and Puberty in Growth Hormone-treated Children Born Small for Gestational Age.

Growth is a complex process in which numerous factors each have different impacts on adult height. A person’s genetics is one of the major determinants of adult height, hence the utility of calculating the mid-parental height (MPH) when making an adult height prediction during the evaluation of short stature. Other factors include nutrition, especially in the infant years; the pulsatile action of the GH-insulin growth-like factor 1 (IGF-1) axis driving height later in childhood; and sex hormones during puberty, which have a critical effect on both the rate and the timing of completion of growth (1). Puberty is a phase that has cardinal effects on height, as the age at which puberty begins, the duration of puberty, and the rate of growth during puberty strongly influence adult height (1). Indeed, growth during puberty comprises 17% to 18% of adult height (2).

Children born small for gestational age (SGA) are below normal at birth for weight, length, or both. Although the great majority of children born SGA catch up to their peers in the first years of life, up to 15% do not catch up by 2 years of age, and many of these remain abnormally short. These children are candidates for growth hormone (GH) treatment to improve their height outcomes (3).

The report by Upners et al (4) presents data from a prospective longitudinal multicenter clinical trial of 102 children born SGA who were treated with GH. Of these children, 47 were followed until they reached their adult height. A little more than half (57%) of the study participants reached an adult height above −2 SD. Participants overall had heights below their MPH, although 53% reached heights within 1 SD of MPH. As seen in other studies, there was a significant increase in height SD score from baseline in both girls and boys (P < 0.001). The boys in this cohort began puberty earlier compared to the selected reference cohort (P = 0.002) and had a lower peak height velocity. In girls, the peak height velocity was also lower than in controls, but the onset of puberty was normally timed (P = 0.18). In both boys and girls, the age of peak height velocity of GH-treated children born SGA was not different from that of the control group. Adult height was positively correlated with height SD score at the start of treatment (P < 0.01), but the investigators did not identify any other associated factors. When compared to their pretreatment predicted adult heights, on average, boys gained 4 cm and girls gained 4.5 cm. Adult height did not differ in children who followed the 3 GH dosing strategies during the first 3 years of the trial.

The use of GH in short children born SGA has been explored for many years, and in 2001 GH was approved by the US Food and Drug Administration as treatment for short stature in children born SGA who do not have spontaneous catch-up growth. Studies have shown that one reason why untreated children remain short as adults is that they tend to have an earlier onset of puberty and menarche and more rapid progression through puberty compared to children born appropriate for gestational age (5). Furthermore, although GH deficiency in this population is rare, some studies have demonstrated that SGA children have IGF-1 insufficiency or IGF-1 resistance that might explain their poor catch up growth (6).

A report from Sweden provided long-term follow-up of children born SGA treated with GH and showed that children who started GH treatment earlier (>1 year before onset of puberty) achieved the greatest benefit in height gain (7). Another long-term study of 78 SGA children receiving GH showed that patients with greater height gain were lighter, shorter, and younger at the start of treatment, and the greatest increase in growth velocity was during the first year of GH treatment (8).

Results from the Upners et al study differ from some earlier studies in that the peak height velocity was less than in controls. Additionally, consistent with some other studies, the age at onset of puberty was younger in boys than in controls. Because the total amount of pubertal growth depends in part on the magnitude of the growth spurt, a lower peak height velocity may translate into a lower overall adult height. Further, the earlier the onset of puberty, the shorter the duration of childhood growth, and this also may have contributed to less overall growth in boys. Although study participants clearly gained adult height as a result of GH treatment, the previously mentioned factors likely had negative effects on their response. As Upners et al noted, there is a high degree of heterogeneity in the SGA population, including different ethnic backgrounds and distinct genetic milieus and pathologies that are important factors contributing to variations in response to GH treatment, and this may account for some of the differences seen when comparing clinical trial results.

A limitation of this study is the large proportion of patients that were lost to follow-up (55/102), which is difficult to manage in longitudinal studies. Additionally, the patients who were lost to follow-up differed from the study population in terms of body mass index and had more delayed bone age, both of which are important factors that influence height and the timing of puberty.

The complexity of growth makes it challenging to understand and predict the response to GH, especially in children born SGA, and this has led to numerous clinical studies that sometimes report conflicting findings. The data presented by Upners et al were accumulated over a 17-year timeframe, and the investigators are to be commended for their perseverance in shedding additional light on factors influencing long-term growth in this group of children.