Growth hormone treatment and stroke: should we be concerned? A case for cohort studies

Biosynthetic human growth hormone (r-hGH) has an extremely good efficacy and safety profile. The use of r-hGH has expanded from classic GH deficiency (GHD) to wider indications such as Turner syndrome and chronic renal failure. This wider use has been predicated in part by the safety profile of r-hGH. Longterm outcomes of treating children with r-hGH are lacking although concern has been raised by preliminary data linking r-hGH use with premature death. These observations have been extended in a paper by Poidvin et al. from the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) French cohort. The SAGhE study analysed adult morbidity in a subgroup of patients at ‘low-risk’ of long-term problems. The study consisted of 6874 children who had received r-hGH, whilst the French mandatory register was operative (up to 1996). Seventy-five percent of this population had isolated idiopathic GHD, 13% idiopathic short stature and the remainder intrauterine growth restriction. Patients were followed for a mean period of 17 4 years. From questionnaires, review of medical records and several other National data sources, 11 patients were identified who had suffered a stroke (five subarachnoid haemorrhage, three intracerebral bleed and three ischaemic strokes). Compared to the Dijon and Oxford-based stroke registers, the standardised incidence ratio for this age group was 2 2–5 3 for all types of stroke and 5 7–7 0 for haemorrhagic stroke. The study was well designed and although retrospective fulfils the current criteria for evaluating stroke incidence. The WHO definition of stroke was used with a complete stable population and verification of stroke by imaging and independent assessment. The use of questionnaire ascertainment (five of the 11 cases) rather detracts from the data along with no control group of untreated individuals. Population-based registries were used to provide comparative stroke incidence. There are some problems with this approach. First, the Dijon registry is drawn from a population known to have a lower incidence of cardiovascular disease, which might explain the difference in estimates compared to the Oxford data set. Second, the component of the Oxford study used (OXVASC) reported a lower incidence of major stroke compared to the original data set (OCSP) probably due to interventions between the studies designed to reduce stroke incidence. This would increase the number of expected strokes if the OCSP set was used as the comparator (table 3, Poidvin et al.). The Oxford data set also lumps all aged <35 years into one group rather than the 5-year partitioning thereafter. The SAGhE population tends to straddle this cut point at least in the published data set, which means that there may be dilution of actual incidence by the paediatric population in the Oxford data set. Third, it may be that simply having GHD predisposes an individual to stroke. This is more difficult to test, as there are very few opportunities now to evaluate the natural history of GHD. Finally, those who have strokes may also have GHD by sharing a common aetiology, for example. mitochondrial disorders, although as the authors point out this is less likely to be the explanation. The sample size in this study was small and derived from a single country so, caution should be exercised in generalising these findings. This is pertinent because GH treatment was originally associated with an increased incidence of leukaemia in a relatively small sample of patients from Japan, but this association did not hold in larger and more diverse populations. Confounding factors also need to be considered. Not least is the definition of GHD. The majority of patients were labelled as GHD but there remains doubt in the study population. The mean age at start of treatment was 11 years and the children were not that small. Isolated idiopathic GHD commonly manifests in the under 5s with a diminishing diagnostic rate with advancing age. Certainly, the age at start of treatment was more than contemporaneous cohorts, which may reflect clinical practice or differences in health-care systems. Only three of the individuals who developed a stroke started treatment under Correspondence: Peter C. Hindmarsh, Developmental Endocrinology Research Group, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Tel. : 0207 405 9200 ext. 5813; E-mail: p.hindmarsh@ucl.ac. uk