Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age

Anders Juul; Philippe Backeljauw; Marco Cappa; Alberto Pietropoli; Nicky Kelepouris; Agnès Linglart; Roland Pfäffle; Mitchell Geffner


J Clin Endocrinol Metab. 2023;108(5):1043-1052. 

In This Article

Abstract and Introduction


Context: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed.

Objective: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA.

Methods: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated.

Results: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported.

Conclusion: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.


Growth hormone (GH) therapy is widely used for the treatment of short stature in children with a number of disorders, including GH deficiency (GHD), Turner syndrome, Prader-Willi syndrome, Noonan syndrome, idiopathic short stature (ISS), chronic renal failure, short stature homeobox containing gene deficiency, and short children born small for gestational age (SGA). According to consensus guidelines, newborns with a birth weight and/or length standard deviation score (SDS) of <−2 for gestational age are considered SGA.[1] Although most infants born SGA show early spontaneous catch-up growth, short stature persists into childhood and adulthood in approximately 10% of patients.[2] GH therapy is approved for the treatment of children born SGA who fail to show spontaneous catch-up growth by 2 to 4 years of age in the USA,[3] or by 4 years of age or later in Europe.[4] The effectiveness of GH treatment for improving growth outcomes in children born SGA has been well documented.[5–9]

A consensus statement on the management of short children born SGA recommends starting GH therapy at a young age,[1] and in patients born SGA with Silver–Russell syndrome, initiation of GH treatment at age 2 to 4 years is recommended.[10] However, real-world data indicate that the initiation of GH treatment in SGA patients is often delayed. In the observational NordiNet® International Outcome Study (IOS), the mean age at GH treatment start was 8.5 years in France,[11] 7.7 years in Germany, and 7.1 years in the UK.[12] Early age at GH treatment initiation has been shown to be an important predictor of growth response in patients born SGA[13] and there is evidence that starting GH therapy at an early age is associated with improved height outcomes.[14] Accordingly, greater gains in height standard deviation score (HSDS) have been observed among GH-treated children born SGA aged <4 years compared with older patients.[15]

However, few studies have examined the short- and long-term effects of initiating GH treatment in children born SGA who are <4 years of age, compared with those initiating later.[15–17] The NordiNet® IOS and American Norditropin Studies: Web-Enabled Research (ANSWER) Program are international, multicenter, observational studies that assessed the long-term effectiveness and safety of somatropin (Norditropin®; Novo Nordisk A/S, Copenhagen, Denmark) in pediatric and adult patients. This paper reports an analysis from the NordiNet® IOS and the ANSWER Program registries, which assessed whether patient age at GH therapy initiation impacts long-term growth outcomes and safety in short children born SGA.