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August 26, 2014; 83 (9) Article

Growth hormone treatment for childhood short stature and risk of stroke in early adulthood

Amélie Poidvin, Emmanuel Touzé, Emmanuel Ecosse, Fabienne Landier, Yannick Béjot, Maurice Giroud, Peter M. Rothwell, Jean-Claude Carel, Joël Coste
First published August 13, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000737
Amélie Poidvin
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Emmanuel Touzé
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Emmanuel Ecosse
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Fabienne Landier
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Yannick Béjot
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Maurice Giroud
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Peter M. Rothwell
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Jean-Claude Carel
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Joël Coste
From the Biostatistics and Epidemiology Unit (A.P., E.E., J.C.), and APEMAC Equipe d’Accueil 4360, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Université de Lorraine and University Paris Descartes, Paris; University Paris Diderot (A.P., F.L., J.-C.C.), Sorbonne Paris Cité; Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance (A.P., F.L., J.-C.C.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris; Institut National de la Santé et de la Recherche Médicale Unité CIE-5 (A.P., F.L., J.-C.C.), Paris; Université Caen Basse Normandie (E.T.), Inserm U919, CHU Côte de Nacre, Caen; Dijon Stroke Registry (Y.B., M.G.), EA4184, University Hospital, Medical School of Dijon, University of Burgundy, Dijon, France; and Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK.
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Citation
Growth hormone treatment for childhood short stature and risk of stroke in early adulthood
Amélie Poidvin, Emmanuel Touzé, Emmanuel Ecosse, Fabienne Landier, Yannick Béjot, Maurice Giroud, Peter M. Rothwell, Jean-Claude Carel, Joël Coste
Neurology Aug 2014, 83 (9) 780-786; DOI: 10.1212/WNL.0000000000000737

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Abstract

Objectives: We investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood.

Methods: Adult morbidity data were obtained in 2008–2010 for 6,874 children with idiopathic isolated GH deficiency or short stature who started GH treatment between 1985 and 1996. Cerebrovascular events were validated using medical reports and imaging data and classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. Case ascertainment completeness was estimated with capture-recapture methods. The incidence of stroke and of stroke subtypes was calculated and compared with population values extracted from registries in Dijon and Oxford, between 2000 and 2012.

Results: Using both Dijon and Oxford population-based registries as references, there was a significantly higher risk of stroke among patients treated with GH in childhood. The excess risk of stroke was mainly attributable to a very substantially and significantly higher risk of hemorrhagic stroke (standardized incidence ratio from 3.5 to 7.0 according to the registry rates considered, and accounting or not accounting for missed cases), and particularly subarachnoid hemorrhage (standardized incidence ratio from 5.7 to 9.3).

Conclusions: We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.

GLOSSARY

CI=
confidence interval;
GH=
growth hormone;
ICD-10=
International Classification of Diseases, tenth revision;
ICH=
intracerebral hemorrhage;
IS=
ischemic stroke;
SAGhE=
Safety and Appropriateness of Growth hormone treatments in Europe;
SAH=
subarachnoid hemorrhage;
SIR=
standardized incidence ratio

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 776

  • Supplemental data at Neurology.org

  • Received January 17, 2014.
  • Accepted in final form April 16, 2014.
  • © 2014 American Academy of Neurology
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Letters: Rapid online correspondence

  • Growth hormone treatment for childhood short stature and risk of stroke in early adulthood
    • Sergio Stagnaro, Consultant in Gastroenterology and Internal Medicine, xkpieper@neurology.org
    • Dr Simone Caramel, Mathematician, Lancenigo-Treviso (Italy), Dr Marco Marchionni, MD, Bristol, United Kingdom
    Submitted February 17, 2015
  • Should learned societies be blind to new safety evidence?
    • Joel Coste, Biostatistics and Epidemiology Unit, Hotel Dieu, Assistance Publique-Hopitaux de Paris, University Pjoel.coste@htd.aphp.fr
    • Emmanuel Touze, Caen, France; Jean-Claude Carel, Paris, France
    Submitted September 18, 2014
  • Statement from the Pediatric Endocrine Society, the Endocrine Society, and the Growth Hormone Research Society
    • Mitchell E. Geffner, President, Pediatric Endocrine Societymgeffner@chla.usc.edu
    • Richard Santen, President, Endocrine Society, Charlottesville VA; John Kopchick, President, Growth Hormone Research Society,Athens OH
    Submitted September 15, 2014
  • Premature warning
    • Agnes Linglart, President of the French Society of Pediatric Endocrinology and Diabetology, APHP and Paris Sud Universityagnes.linglart@bct.aphp.fr
    • Agnes Linglart, le Kremlin-Bicetre, FR; Maithe Tauber, Toulouse, FR; Pierre Bougneres, Le Kremlin-Bicetre, FR; Yves Lebouc, Paris, FR; Pierre Chatelain, Lyon, FR
    Submitted August 29, 2014
  • Keep going blind?
    • Joel Coste, Biostatistics and Epidemiology Unit, Hotel Dieu, Assistance Publique-Hopitaux de Paris, Paris Descarjoel.coste@htd.aphp.fr
    • Jean-Claude Carel, Paris, France ; Emmanuel Touze, Caen, France ; Joel Coste, Paris, France
    Submitted August 26, 2014
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