Long-Term Safety of Growth Hormone Treatment in Childhood: Two Large Observational Studies: NordiNet IOS and ANSWER

Abstract

Context GH treatment has a generally good safety profile; however, concerns of increased mortality risk in adulthood have been raised. Objective Assessing the long-term safety of GH treatment in clinical practice. Design Two multicenter longitudinal observational studies: NordiNet® International Outcome Study (2006–2016, Europe) and ANSWER Program (2002–2016, USA). Setting Data collected from 676 clinics. Patients Pediatric patients treated with GH, classified into three risk groups based on diagnosis. Intervention Daily GH treatment. Main Outcome Measures Incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to the GH dose. Results The combined studies comprised 37,702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130,476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (e.g. with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with >1 AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = 0.0029 and P = 0.0003, respectively) and the non-SGA subgroup (P = 0.0022 and P = 0.0015, respectively), and for SAEs in the intermediate- and high-risk groups (P = 0.0017 and P = 0.0480, respectively). Conclusions We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group.

Growth Hormone Deficiency and Treatment in Childhood Cancer Survivors

“…Other adverse events reported in all three groups were similar to prior reports (7,10). Notably, the incidence of adverse events correlated with increasing risk category, emphasizing the need for close monitoring of those with high-risk illnesses including CCS (64).…”

“…Sävendahl et al recently reported results from two large multicenter observational studies, NordiNet International Outcome Study and ANSWER Program, two international pharmacoepidemiological registry studies sponsored by Novo Nordisk (64). The study population included 37,702 patients, 1,149 patients with history of neoplasm prior to GH treatment.…”

Effectiveness and Overall Safety of NutropinAq® for Growth Hormone Deficiency and Other Paediatric Growth Hormone Disorders: Completion of the International Cooperative Growth Study, NutropinAq® European Registry (iNCGS)

“…The recurrence of previous neoplasms or secondary neoplasms occurred in <1% of patients in clinical trials ( 18 ). The reported rate of neoplasms in the iNCGS of 0.6% is therefore consistent with the experience from clinical trials of this product and registries of other GH products ( 16 , 26 ). The recent SAGhE cohort study concluded that in patients treated with GH in childhood for isolated GHD, idiopathic short stature or short stature in children born small for gestational age, there was no increased mortality from neoplasms compared with people who had never been treated with GH ( 27 ).…”

Short and Long-Term Effects of Growth Hormone in Children and Adolescents With GH Deficiency

“…An early report associating pit-hGD with an increased risk of colonic cancer in GHD ( 191 ) raised a critical discussion about the potential role of the GH-IGF axis in cancer pathogenesis ( 192 ). A particularly controversial multinational survey on the safety and appropriateness of GH in Europe (SAGhE), which investigated mortality in adults who had received GH treatment in childhood, however presented inconclusive results ( 191 , 193 , 194 ). There is strong evidence that replacement with r-hGH in children and adolescents with non-acquired GHD is safe, as they receive the usual dosage range and have a low risk of other diseases ( 195 , 196 ); nevertheless, it is prudent to ensure structured long-term follow-up and monitoring of IGF parameters during GH replacement ( 153 , 187 ).…”