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

J Clin Endocrinol Metab. 2021 May 13;106(6):1728-1741. doi: 10.1210/clinem/dgab080.


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.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Dwarfism, Pituitary / drug therapy
  • Dwarfism, Pituitary / epidemiology
  • Europe / epidemiology
  • Female
  • Growth Disorders / drug therapy*
  • Growth Disorders / epidemiology
  • Human Growth Hormone / adverse effects*
  • Human Growth Hormone / deficiency
  • Human Growth Hormone / therapeutic use
  • Humans
  • Incidence
  • Longitudinal Studies
  • Male
  • Mortality
  • Outcome Assessment, Health Care
  • Registries
  • United States / epidemiology


  • Human Growth Hormone

Associated data

  • ClinicalTrials.gov/NCT00960128
  • ClinicalTrials.gov/NCT01009905