Safety Outcomes during Pediatric GH Therapy

Final Results from the Prospective GeNeSIS Observational Program

Christopher J. Child, Alan G. Zimmermann, George P. Chrousos, Elisabeth Cummings, Cheri L. Deal, Tomonobu Hasegawa, Nan Jia, Sarah Lawrence, Agnès Linglart, Sandro Loche, Mohamad Maghnie, Jacobo Pérez Sánchez, Michel Polak, Barbara Predieri, Annette Richter-Unruh, Ronald (Ron) Rosenfeld, Diego Yeste, Tohru Yorifuji, Werner F. Blum

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Context Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective To assess incidence of key safety outcomes. Design Prospective, multinational, observational study (1999 to 2015). Setting A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment. Main outcome measures Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (-1/492,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.

Original languageEnglish (US)
Pages (from-to)379-389
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number2
DOIs
StatePublished - Nov 9 2018

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Neuroendocrinology
Pediatrics
Observational Studies
Medical problems
Safety
Neoplasms
Incidence
Tumors
Therapeutics
Mortality
Type 2 Diabetes Mellitus
Survivors
Stroke
Growth Disorders
Genetics
Cerebrovascular Disorders
Turner Syndrome
Premature Mortality
Second Primary Neoplasms
Population

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Child, C. J., Zimmermann, A. G., Chrousos, G. P., Cummings, E., Deal, C. L., Hasegawa, T., ... Blum, W. F. (2018). Safety Outcomes during Pediatric GH Therapy: Final Results from the Prospective GeNeSIS Observational Program. Journal of Clinical Endocrinology and Metabolism, 104(2), 379-389. https://doi.org/10.1210/jc.2018-01189

Safety Outcomes during Pediatric GH Therapy : Final Results from the Prospective GeNeSIS Observational Program. / Child, Christopher J.; Zimmermann, Alan G.; Chrousos, George P.; Cummings, Elisabeth; Deal, Cheri L.; Hasegawa, Tomonobu; Jia, Nan; Lawrence, Sarah; Linglart, Agnès; Loche, Sandro; Maghnie, Mohamad; Sánchez, Jacobo Pérez; Polak, Michel; Predieri, Barbara; Richter-Unruh, Annette; Rosenfeld, Ronald (Ron); Yeste, Diego; Yorifuji, Tohru; Blum, Werner F.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 104, No. 2, 09.11.2018, p. 379-389.

Research output: Contribution to journalArticle

Child, CJ, Zimmermann, AG, Chrousos, GP, Cummings, E, Deal, CL, Hasegawa, T, Jia, N, Lawrence, S, Linglart, A, Loche, S, Maghnie, M, Sánchez, JP, Polak, M, Predieri, B, Richter-Unruh, A, Rosenfeld, RR, Yeste, D, Yorifuji, T & Blum, WF 2018, 'Safety Outcomes during Pediatric GH Therapy: Final Results from the Prospective GeNeSIS Observational Program', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 2, pp. 379-389. https://doi.org/10.1210/jc.2018-01189
Child, Christopher J. ; Zimmermann, Alan G. ; Chrousos, George P. ; Cummings, Elisabeth ; Deal, Cheri L. ; Hasegawa, Tomonobu ; Jia, Nan ; Lawrence, Sarah ; Linglart, Agnès ; Loche, Sandro ; Maghnie, Mohamad ; Sánchez, Jacobo Pérez ; Polak, Michel ; Predieri, Barbara ; Richter-Unruh, Annette ; Rosenfeld, Ronald (Ron) ; Yeste, Diego ; Yorifuji, Tohru ; Blum, Werner F. / Safety Outcomes during Pediatric GH Therapy : Final Results from the Prospective GeNeSIS Observational Program. In: Journal of Clinical Endocrinology and Metabolism. 2018 ; Vol. 104, No. 2. pp. 379-389.
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abstract = "Context Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective To assess incidence of key safety outcomes. Design Prospective, multinational, observational study (1999 to 2015). Setting A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment. Main outcome measures Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95{\%} CIs for mortality, diabetes, and primary cancer using general population registries. Results Predominant short stature diagnoses were GH deficiency (63{\%}), idiopathic short stature (13{\%}), and Turner syndrome (8{\%}), with mean ± SD follow-up of 4.2 ± 3.2 years (-1/492,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95{\%} CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72{\%} had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0{\%}; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1{\%}; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.",
author = "Child, {Christopher J.} and Zimmermann, {Alan G.} and Chrousos, {George P.} and Elisabeth Cummings and Deal, {Cheri L.} and Tomonobu Hasegawa and Nan Jia and Sarah Lawrence and Agn{\`e}s Linglart and Sandro Loche and Mohamad Maghnie and S{\'a}nchez, {Jacobo P{\'e}rez} and Michel Polak and Barbara Predieri and Annette Richter-Unruh and Rosenfeld, {Ronald (Ron)} and Diego Yeste and Tohru Yorifuji and Blum, {Werner F.}",
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T1 - Safety Outcomes during Pediatric GH Therapy

T2 - Final Results from the Prospective GeNeSIS Observational Program

AU - Child, Christopher J.

AU - Zimmermann, Alan G.

AU - Chrousos, George P.

AU - Cummings, Elisabeth

AU - Deal, Cheri L.

AU - Hasegawa, Tomonobu

AU - Jia, Nan

AU - Lawrence, Sarah

AU - Linglart, Agnès

AU - Loche, Sandro

AU - Maghnie, Mohamad

AU - Sánchez, Jacobo Pérez

AU - Polak, Michel

AU - Predieri, Barbara

AU - Richter-Unruh, Annette

AU - Rosenfeld, Ronald (Ron)

AU - Yeste, Diego

AU - Yorifuji, Tohru

AU - Blum, Werner F.

PY - 2018/11/9

Y1 - 2018/11/9

N2 - Context Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective To assess incidence of key safety outcomes. Design Prospective, multinational, observational study (1999 to 2015). Setting A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment. Main outcome measures Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (-1/492,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.

AB - Context Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective To assess incidence of key safety outcomes. Design Prospective, multinational, observational study (1999 to 2015). Setting A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment. Main outcome measures Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (-1/492,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.

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