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

Abstract

Context: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised.

Objective: This work aims to assess the long-term safety of GH treatment in clinical practice.

Methods: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to 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 (eg, 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 more than one 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 = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively).

Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Trial registration: ClinicalTrials.gov NCT00960128 NCT01009905.

Keywords: SAGhE; adverse events; childhood; human growth hormone; long-term safety; neoplasms and malignancies.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Comparison of average growth hormone dose between patients who did or did not experience at least one adverse event in A, risk groups and B, low-risk subgroups. Only significant P values (< .05) are shown. For patients with AEs, average GH dose up to the first AE onset was used. For patients without AEs, average GH dose from the full treatment period was used. AE, adverse event; GH, growth hormone; SGA, small for gestational age.

Figure 2.

A, Incidence rates (events/1000 patient-years of exposure within the study period) for reported adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs) by risk groups. B, Incidence rates for ADRs, SAEs, and SADRs by average growth hormone dose up to the first AE within each risk group. Only significant P values (< .05) are shown.

Figure 3.

A, Incidence rates (events/1000 patient-years of exposure within the study period) for reported adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs) in the low-risk group by subgroup (non–small for gestational age [SGA] vs SGA). B, Incidence rates for ADRs, SAEs, and SADRs by growth hormone dose up to the first AE in each subgroup. Only significant P values (< .05) are shown.

Figure 4.

Proportion of patients with at least one adverse drug reaction (ADR), serious adverse event (SAE), or serious adverse drug reaction (SADR) of all patients exposed in a given year by duration of follow-up. GH, growth hormone.

Figure 5.

Frequency of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs) across all risk groups by system organ class (SOC). Only SOCs with more than 10 events are shown. *Including cysts and polyps.