ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study reports data from the full Kabi/Pfizer International Growth Database (KIGS), a large international database including 83803 children treated with rhGH for GHD and non-GHD conditions. The data confirm that rhGH is effective in increasing short-term height gain and adult height in various conditions and validate rhGH safety, with no new serious adverse events reported.

KIGS (Kabi/Pfizer International Growth Database), first established in Sweden in 1987, has evolved into one of the largest and longest databases for rhGH treatment, with more than 80 000 rhGH-treated children from more than 50 countries, allowing assessment of long-term efficacy and safety of rhGH treatment in real-world clinical setting.

Safety concerns regarding rhGH therapy have been raised by postmarketing surveillance databases and registries data analyses (1–5). The major concerns include recurrent or new malignancies in children with preexisting malignancies, development of intracranial hypertension, unmasking of type 2 diabetes mellitus, induction of stroke, and a possible association with increased overall mortality.

Data analysis from KIGS revealed that adverse events (AEs), serious adverse events (SAEs) and deaths occur at low frequencies, and the majority were defined by investigators as not related to rhGH therapy. Benign intracranial hypertension and epiphysiolysis (slipped upper femoral epiphysis), were infrequent in KIGS.

The Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study reported increased risks of mortality and hemorrhagic stroke after a mean follow-up of 17 years in young adults treated with rhGH in childhood. The data in KIGS seem to be reassuring in the short term, as intracranial hemorrhage events occurred at low frequencies in the full KIGS cohort and death in only 0.4% of patients during the study. However, KIGS median follow-up was 3.1 years (range, 0.5–8.2 years) considerably shorter than SAGhE follow-up, averaging 17.1 years per patient. This KIGS report shows low frequencies of both type 1 and type 2 diabetes. However, previous large observational studies reported an increased incidence of type 2 diabetes, likely driven by genetic predisposition and overweight. The overall available evidence suggests the need of monitoring glucose homeostasis in patients treated with rhGH.

The SAGhE study reported a significantly increased risk of all-site cancer for patients with a history of childhood rhGH treatment and initial cancer diagnosis. Increased risks for bone and bladder cancer in patients without prior cancer were also reported, suggesting a potential impact of rhGH therapy on these cancer types. In the present study, neoplasms were reported in 1% of patients, bone tumor events were rare, and craniopharyngioma recurrence was described in 11.9% of patients, in line with previous reports.

These KIGS data confirmed the overall efficacy of rhGH treatment in all diagnostic groups at least in the first year of treatment.

References: 1. Allen DB, Backeljauw P, Bidlingmaier M, et al. GH safety work- shop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol. 2016;174(2):P1–P9. 2. van Santen HM. Safety of GH after treatment for childhood cancer. Eur J Endocrinol. 2020;183(6):C15–C18. 3. Child CJ, Zimmermann AG, Chrousos GP, et al. Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program. J Clin Endocrinol Metab. 2019;104(2):379–389. 4. Stochholm K, Kiess W. Long-term safety of growth hormone—a combined registry analysis. Clin Endocrinol (Oxf). 2018;88(4): 515–528. 5. Savendahl L, Cooke R, Tidblad A, et al. Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study. Lancet Diabetes Endocrinol. 2020;8(8):683–692.