Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders

Data From the Genetics and Neuroendocrinology of Short Stature International Study

Charmian A. Quigley; Christopher J. Child; Alan G. Zimmermann; Ron G. Rosenfeld; Leslie L. Robison; Werner F. Blum

Disclosures

J Clin Endocrinol Metab. 2017;102(9):3195-3205. 

In This Article

Abstract and Introduction

Abstract

Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood.

Objective: To assess mortality in children receiving GH.

Design: Prospective, multinational, observational study.

Setting: Eight hundred twenty-seven study sites in 30 countries.

Patients: Children with growth disorders.

Interventions: GH treatment during childhood.

Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population.

Results: Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non–GH-deficient conditions (2.47; 95% CI, 0.99–5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65).

Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non–GH-deficient medical conditions.

Introduction

Growth hormone (GH) treatment during childhood is approved for a number of conditions that result in short stature or growth failure. Although the most frequent diagnosis is growth hormone deficiency (GHD), other growth-related indications for GH treatment in various countries are Turner syndrome (TS), short stature homeobox-containing (SHOX) gene deficiency (SHOXD), Noonan syndrome, Prader-Willi syndrome (PWS), growth failure associated with chronic renal insufficiency (CRI), short stature in children born small for gestational age (SGA) who do not demonstrate catch-up growth, and idiopathic short stature (ISS).[1–7] GH treatment during childhood is generally considered safe when used at approved doses for approved indications.[8–10] However, concerns have been raised about potential associations between GH treatment and development or recurrence of neoplasms, intracranial hemorrhage, and premature mortality.[11–15]

In the French cohort of a multinational study examining long-term safety of European patients treated with GH during childhood [Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE)], the risk of mortality was increased in a cohort of 6928 adults who had received childhood GH for conditions considered by the authors not to increase mortality risk [isolated idiopathic growth hormone deficiency (IGHD), GH neurosecretory dysfunction, ISS, and SGA].[14] Overall and condition-specific standardized mortality related to bone tumors, cerebrovascular disease, and "symptoms, signs and ill-defined conditions" were increased, based on expected deaths using age- and sex-specific rates for the French general population.[14] However, analysis of a smaller (N = 2543) Belgian, Dutch, and Swedish SAGhE cohort did not replicate these findings.[16] Furthermore, the Childhood Cancer Survivor Study (CCSS) found no association between GH treatment and mortality risk in patients previously treated for malignancy.[11]

Because of long-held concerns, particularly regarding the potential impact of GH treatment on development or recurrence of neoplasia, investigation of mortality among patients who receive pediatric GH, whatever the indication, remains important. The observational Genetics and Neuroendocrinology of Short stature International Study (GeNeSIS) was conducted between 1999 and 2015 to examine safety and effectiveness of GH treatment in children with short stature of various etiologies followed under conditions of typical pediatric endocrine practice. Although GeNeSIS followed pediatric patients during the course of their GH treatment, rather than after completion, we nevertheless felt it was relevant to examine mortality risk in GH-treated children using similar methodology to that used in the French SAGhE study. We therefore assessed mortality for children followed in GeNeSIS using standardized mortality ratios (SMRs) by comparing observed deaths in the study population with expected deaths based on age- and sex-specific general population rates.

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