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Growth hormone treatment for childhood short stature and risk of stroke in early adulthood; Adult stroke risk after growth hormone treatment in childhood: First do no harm
In this article, we analyze the ethics of elective growth hormone (GH) therapy in children with idiopathic short stature (ISS). We discuss recent clinical research regarding the efficacy, side-effects, and risks of GH therapy, and argue that GH therapy is ethically unjustifiable for most children with ISS.
Short stature may cause concern for children and their parents; on the other hand, represent the first sign of an underlying disease. It is important to make a detailed assessment of children with short stature to identify its etiology. Treatment of short stature is aimed at the primary etiology; therapy with recombinant human growth hormone (rhGH) is indicated in certain patients. Eight indications of rhGH in children with short stature have been approved: Growth hormone deficiency, chronic kidney disease, Turner syndrome, Prader Willi syndrome, small for gestational age with failure to catch up to the normal height percentiles, idiopathic short stature, SHOX gene haploinsufficiency and Noonan syndrome. Early identification and appropriate treatment of short stature is associated with better outcomes for patients.
Objectives:
We investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood.
Methods:
Adult morbidity data were obtained in 2008-2010 for 6,874 children with idiopathic isolated GH deficiency or short stature who started GH treatment between 1985 and 1996. Cerebrovascular events were validated using medical reports and imaging data and classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. Case ascertainment completeness was estimated with capture-recapture methods. The incidence of stroke and of stroke subtypes was calculated and compared with population values extracted from registries in Dijon and Oxford, between 2000 and 2012.
Results:
Using both Dijon and Oxford population-based registries as references, there was a significantly higher risk of stroke among patients treated with GH in childhood. The excess risk of stroke was mainly attributable to a very substantially and significantly higher risk of hemorrhagic stroke (standardized incidence ratio from 3.5 to 7.0 according to the registry rates considered, and accounting or not accounting for missed cases), and particularly subarachnoid hemorrhage (standardized incidence ratio from 5.7 to 9.3).
Conclusions:
We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.
Childhood precursors of adult diseases are increasingly identified by studies that span the period from birth to senescence. This is particularly relevant for cerebrovascular disease, for which links have been discovered with childhood obesity and adolescent-onset hypertension.¹ In this issue of Neurology®, Poidvin et al.² report an increased risk of stroke in adults treated with growth hormone (GH) during childhood. This report has been much anticipated by the endocrinology community because it extends and clarifies findings in a 2012 study showing increased mortality in adults treated in childhood with GH from the prospective European cohort study—the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE).³
Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question.
The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France.
This was a population-based cohort study.
The setting of the study was a French population-based register.
A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients.
All-cause and cause-specific mortality was measured in the study.
All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 μg/kg · d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed.
Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood.