Is safety of childhood growth hormone therapy related to dose? Data from a large observational study

Objective: Concerns have been raised of increased mortality risk in adulthood in certain patients who received growth hormone treatment during childhood. This study evaluated the safety of growth hormone treatment in childhood in everyday practice. Design: NordiNet (R) International Outcome Study (IOS) is a noninterventional, observational study evaluating safety and effectiveness of Norditropin (R) (somatropin; Novo Nordisk A/S, Bagsvaerd, Denmark). Methods: Long-term safety data (1998 - 2013) were collected on 13 834 growth hormone treated pediatric patients with short stature. Incidence rates (IRs) of adverse events (AEs) defined as adverse drug reactions (ADRs), serious ADRs (SADRs), and serious AEs (SAEs) were calculated by mortality risk group (low/intermediate/high). The effect of growth hormone dose on IRs and the occurrence of cerebrovascular AEs were investigated by the risk group. Results: We found that 61.0% of patients were classified as low-risk, 33.9% intermediate-risk, and 5.1% high-risk. Three hundred and two AEs were reported in 261 (1.9%) patients during a mean (S.D.) treatment duration of 3.9 (2.8) years. IRs were significantly higher in the high-vs the low-risk group (high risk vs low risk-ADR: 9.11 vs 3.14; SAE: 13.66 vs 1.85; SADR: 4.97 vs 0.73 events/1000 patient-years of exposure; P < 0.0001 for all). Except for SAEs in the intermediate-risk group (P = 0.0486) in which an inverse relationship was observed, no association between IRs and growth hormone dose was found. No cerebrovascular events were reported. Conclusions: We conclude that safety data from NordiNet (R) IOS do not reveal any new safety signals and confirm a favorable overall safety profile in accordance with other pediatric observational studies. No association between growth hormone dose and the incidence of AEs during growth hormone treatment in childhood was found.