The first-year growth response to growth hormone treatment predicts the long-term prepubertal growth response in children

Abstract

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 microg/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 microg/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 SD res) 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 SD res 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.

Figures

Figure 1

Graphic illustration of the two equations that, when combined, produce the non-linear growth response curve. The hyperbolic equation FCU(t) can be regarded as a 'catch-up' equation, (by multiplying with the individual parameter MModel) asymptotically modulating individual amplitude with time. The "1" on the y-axis gives the asymptotic value of the FCU(t), and the Equation FBG(t) can be interpreted as a 'baseline growth' equation that introduces a delayed general growth response with a greater relative impact on individuals with low levels of catch-up growth than on individuals with high levels of catch-up growth.

Figure 2

GH response chart for visualization of Response Scores (RS) on different levels (i.e. growth responses for children with variable individual responsiveness to GH). Left panel: The RS chart is given with 'isolines' ('channels') for RS = 1, 2, 3 and 4 which is indicated in the figure. For the individual child at treatment time 1 year (x-axis), the observed growth response (Δheight SDS) is found on the y-axis to the left and following the corresponding curve the individual RS can be found to the right. Middle panel: Observed first-year Δheight SDS on treatment for three prepubertal children from the validation group (filled circles). The individual calculated Response Score (dotted line) is found on the right axis. The function for the Response score is: RS(t) = (Δheight SDSobs - FBG(t))/FCU(t), where FBG(t) = elog (1 + t*(0.205 - 1/(1 + 2.1*t))) and FCU(t) = t/(t + 0.894); t = GH treatment time in years. Right panel: Individual Response Scores from the same three children, based on observed Δheight SDS on treatment at different time points (filled circles at treatment time 2, 3, 4, 5 and 6 years) in comparison with the predicted (dotted line). Response Score was consistent over time within an individual child, and the inclusion in the model of measurements made later than 1 year after the start of GH treatment are acceptable.

Figure 3

The group mean values ± SEM for the Response Score calculated at 1, 2, 3 and 4 years of GH treatment. The equation was applied to data from children who have values from all four annual measurements on GH treatment: the model group (n = 51) and validation group (n = 54). The observed height at the yearly measurement is used for estimation of the RS (1–4 years). This shows that a reliable model gives constant RS values during 4 years of GH treatment.