Is a Two-Year Growth Response to Growth Hormone Treatment a Better Predictor of Poor Adult Height Outcome Than a First-Year Growth Response in Prepubertal Children With Growth Hormone Deficiency?

Due to the secular trend in length and height, growth references need to be updated regularly. Reference charts that were until recently used in Belgium are based on samples collected more than 30 years ago, and references for body mass index (BMI) and pubertal development have not been established before. To establish contemporary cross-sectional reference charts for height, weight, BMI, head circumference, and pubertal development from birth to 21 years of age, based on a representative sample of children from Flanders, Belgium. 15 989 healthy subjects of Belgian origin, 0-25 years of age, were measured in 2002-2004. Growth curves were fitted with the LMS method, and percentiles for the pubertal development were estimated with generalized additive models on status quo data from 8690 subjects aged 6-22 years of age. A positive secular trend in height and weight is observed in children above 5 years of age. Adult median height has increased by 1.2 cm/decade in boys and 0.8 cm/decade in girls; median weight by 0.9 kg/decade in boys, and 1.0 kg/decade in girls, and the weight distribution became more skewed. The BMI curve is comparable to that of other populations, except for higher percentiles. This reflects the increasing prevalence of overweight and obesity. Median age at menarche (13.0 years) has not advanced any more over the past 50 years. Median ages at menarche and B2 in girls and G2 or T4 in boys are comparable to other West European estimates, but approximately 10% enter G2/T4 before 9 years of age. The ongoing secular trend in height and weight makes growth charts previously used in Belgium obsolete. New representative charts for growth and pubertal development are introduced. For weight monitoring, it is advised that the now-available BMI growth charts are used.

Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of disease-specific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do not explain all of the variability in growth response, but they have a high degree of precision (low error SDs). Moreover, the parameters used are robust and easily accessible. These properties give the models' practical utility as growth prediction tools. The availability of longitudinal, disease-specific models will be helpful in the future for enabling growth-promoting therapy to be planned at the outset, optimized for efficacy and economy, and individualized to meet treatment goals based on realistic expectations.

Background Pretreatment auxological variables, such as birth size and parental heights, are important predictors of the growth response to GH treatment. For children with missing pretreatment data, published prediction models cannot be used. The objective was to construct and validate a prediction model for children with missing background data based on the observed first-year growth response to GH. The accuracy and reliability of the model should be comparable with our previously published prediction model relying on pretreatment data. The design used was mathematical curve fitting on observed growth response data from children treated with a GH dose of 33 μg/kg/d. Methods Growth response data from 162 prepubertal children born at term were used to construct the model; the group comprised of 19% girls, 80% GH-deficient and 23% born SGA. For validation, data from 205 other children fulfilling the same inclusion and treatment criteria as the model group were used. The model was also tested on data from children born prematurely, children from other continents and children receiving a GH dose of 67 μg/kg/d. Results The GH response curve was similar for all children, but with an individual amplitude. The curve SD score depends on an individual factor combining the effect of dose and growth, the 'Response Score', and time on treatment, making prediction possible when the first-year growth response is known. The prediction interval (± 2 SDres) was ± 0.34 SDS for the second treatment year growth response, corresponding to ± 1.2 cm for a 3-year-old child and ± 1.8 cm for a 7-year-old child. For the 1–4-year prediction, the SDres was 0.13 SDS/year and for the 1–7-year prediction it was 0.57 SDS (i.e. < 0.1 SDS/year). Conclusion The model based on the observed first-year growth response on GH is valid worldwide for the prediction of up to 7 years of prepubertal growth in children with GHD/ISS, born AGA/SGA and born preterm/term, and can be used as an aid in medical decision making.