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A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France

  • REPRODUCTIVE EPIDEMIOLOGY
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Abstract

Introduction: Between 2019–2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. Methods: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases’ homes concerning their plant product use. Results: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. Discussion: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

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Acknowledgements

The authors would like to thank the professionals from Santé publique France, anses, and the experts consulted for providing the scientific expert committee with all the necessary information, as well as the teams of the Brittany and Rhône-Alpes registries of congenital anomalies. We also thank the professionals from the Loire-Atlantique health structures who participated in the collection and transmission of data to Santé publique France. Furthermore, our thanks to Martin Kulldorff who very kindly answered our questions about the statistical software he developed and Etienne Lucas and Francis Chin, from Santé publique France, who performed research cases in the PMSI (Programme de Médicalisation des systèmes d’information). Finally, our thanks to all the families who agreed to participate in this study, and to Jude Sweeney (Milan, Italy) for copyediting this manuscript.

Funding

The authors declare that no funding, grant or other financial support was received during the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Non-Communicable Diseases and Injuries Department, Santé Publique France, Saint Maurice, France

    Julie Boudet-Berquier, Anne Gallay, Eugenia Gomes & Nolwenn Regnault

  2. Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Centre Hospitalier Universitaire de Nîmes, Nîmes, Languedoc-Roussillon, France

    Christophe Demattei

  3. Environment and Work Department, Santé Publique France, Saint Maurice, Health, France

    Laurence Guldner & Mélina Le Barbier

  4. Reference Centre of Developmental Anomalies and Defect Syndromes, RADEME Maladies Rares du Développement Et du Métabolisme, Université Lille, 7364, Lille, EA, France

    Sylvie Manouvrier

  5. EPI-PHARE Scientific Interest Group in Epidemiology of Health Products from the French National Agency for the Safety of Medicines and Health Products and the French National Health Insurance, Saint-Denis, France

    Jérémie Botton

  6. Faculty of Pharmacy, Paris-Saclay University, Orsay, France

    Jérémie Botton

  7. Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, University Grenoble Alpes, Grenoble, France

    Claire Philippat

  8. INSERM, BPH, UMR1219, EPICENE Team, University of Bordeaux, Bordeaux, France

    Fleur Delva

  9. Environmental and Occupational Health Department, Bordeaux University Hospital, 33000, Bordeaux, France

    Fleur Delva

  10. ANSES, Maisons-Alfort, France

    Juliette Bloch & Jean-Claude Desenclos

  11. Executive Department, Santé Publique France, Saint-Maurice, France

    Caroline Semaille

  12. Reference Centre of Developmental Anomalies and Defect Syndromes, Hôpital Sud, CHU de Rennes, Rennes, France

    Sylvie Odent

  13. Auvergne registry of congenital anomalies (CEMC-Auvergne), Department of clinical genetics, Centre de Référence des Maladies Rares, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France

    Isabelle Perthus

  14. La Réunion registry of congenital anomalies, Centre Hospitalier Universitaire de La Réunion, Île de la Réunion, France

    Hanitra Randrianaivo

  15. Molecular Oral Pathophysiology Laboratory, Centre de Recherche des Cordeliers, INSERM UMRS, Université Paris Cité, Sorbonne Université, 1138, Paris, France

    Sylvie Babajko

  16. Fédération Hospitalo-Universitaire DDS-ParisNet, INSERM, Université Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France

    Sylvie Babajko

  17. UR2496, Biomedical Research in Odontology, Université Paris Cité, Montrouge, France

    Sylvie Babajko

  18. Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire de Saint-Étienne, Saint-Étienne, France

    Tiphaine Barjat

  19. INSERM U1059 SAINBIOSE, Université Jean Monnet, Saint-Étienne, France

    Tiphaine Barjat

  20. Department of Human Genetics, University Hospital Hôtel Dieu, Nantes, France

    Claire Beneteau

  21. French National Reference for Children Limb Defect, Hôpitaux de Saint-Maurice, Saint Maurice, France

    Naima Brennetot

  22. Department of Pediatrics and Adolescent Medicine, Lillebaelt Hospital, University Hospital of Southern Denmark, Kolding, Denmark

    Ester Garne

  23. CH Simone Veil, Blois, France

    Georges Haddad

  24. Conservatoire National des Arts et Métiers, Paris, France

    Mounia Hocine

  25. REGARDs Network, Pharmacologie Médicale et Clinique, CERPOP INSERM UMR 1295—SPHERE team, Faculté de Médecine Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

    Isabelle Lacroix

  26. Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France

    Klervi Leuraud

  27. INRAE, BIOGECO, UMR 1202, University of Bordeaux, F‑33615, Pessac, France

    Michel Mench

  28. Population Health Research Institute, St George’s University of London, London, UK

    Joan Morris

  29. Department of Pathology, Rouen University Hospital, Rouen, France

    Sophie Patrier

  30. Clinical Department of Ruminant, University of Liège, 4000, Liège, Belgium

    Arnaud Sartelet

  31. Genetics Department, APHP, Robert-Debré University Hospital, Paris, France

    Alain Verloes

  32. Methodology and Biostatistics Department, Santé Publique France, Saint Maurice, France

    Christophe Bonaldi & Andrea Guajardo-Villar

  33. Cellule Bretagne, Santé Publique France, Rennes, France

    Bertrand Gagnière

  34. Cellule Auvergne-Rhône-Alpes, Santé Publique France, Clermont-Ferrand, France

    Philippe Pépin

  35. Cellule Pays-de-la Loire, Santé Publique France,, Nantes, France

    Ronan Ollivier, Monique Bitoun & Lisa King

  36. Department of Obstetrics and Gynecology, DMU Santé des femmes et des nouveau-nés, Hopital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris Saclay, Clamart, France

    Alexandra Benachi

Authors
  1. Julie Boudet-Berquier
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  2. Christophe Demattei
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  3. Laurence Guldner
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  4. Anne Gallay
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  5. Sylvie Manouvrier
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  6. Jérémie Botton
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  7. Claire Philippat
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  8. Fleur Delva
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  9. Juliette Bloch
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  10. Caroline Semaille
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  11. Sylvie Odent
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  12. Isabelle Perthus
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  13. Hanitra Randrianaivo
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  14. Sylvie Babajko
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  15. Tiphaine Barjat
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  16. Claire Beneteau
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  17. Naima Brennetot
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  18. Ester Garne
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  19. Georges Haddad
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  20. Mounia Hocine
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  21. Isabelle Lacroix
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  22. Klervi Leuraud
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  23. Michel Mench
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  24. Joan Morris
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  25. Sophie Patrier
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  26. Arnaud Sartelet
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  27. Alain Verloes
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  28. Christophe Bonaldi
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  29. Mélina Le Barbier
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  30. Bertrand Gagnière
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  31. Philippe Pépin
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  32. Ronan Ollivier
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  33. Monique Bitoun
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  34. Lisa King
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  35. Andrea Guajardo-Villar
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  36. Eugenia Gomes
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  37. Jean-Claude Desenclos
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  38. Nolwenn Regnault
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  39. Alexandra Benachi
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Contributions

All authors contributed to the study. Bertrand Gagnière, Philippe Pépin, Ronan Ollivier, Lisa King, Eugenia Gomes and Christophe Bonaldi performed the initial investigations between 2013 and 2018. Julie Boudet-Berquier, Eugenia Gomes, Andrea Guajardo-Villar, Laurence Guldner, Nolwenn Regnault, Mélina Le Barbier, Anne Gallay performed additional investigations for Santé publique France. Juliette Bloch and Caroline Semaille performed investigations for the anses agency. Christophe Demattei, Sylvie Manouvrier, Jérémie Botton, Claire Philippat, Fleur Delva, Naima Brennetot, Tiphaine Barjat, Claire Benneteau, Naima Brennetot, Ester Garne, Georges Haddad, Mounia Hocine, Isabelle Lacroix, Klervi Leuraud, Michel Mench, Joan Morris, Sophie Patrier, Arnaud Sartelet, Alain Verloes were experts in the SEC, which was headed by Alexandra Benachi. Sylvie Manouvrier, Sylvie Odent, Isabelle Perthus, Hanitra Randrianaivo, Ester Garne, Alexandra Benachi were the six specialists in TURLD diagnosis who conducted a blind analysis of children’s medical files. The spatiotemporal scan statistic analysis was performed by Christophe Demattei. All the experts in the CES reanalysed the results of the investigations performed. The first draft of the manuscript was written by Julie Boudet-Berquier. All authors commented on the various versions of the manuscript. All read and approved the final manuscript.

Corresponding author

Correspondence to Julie Boudet-Berquier.

Ethics declarations

Conflict of interest

All authors declare they have no financial or other conflict of interest.

Ethics approval

The investigations carried out were part of the response to a health alert, and insofar as the need for emergency implementation can be characterized and justified, benefited from the exemption from the authorisation requirement set out in article 67 of law no. 78-17 on information technology, files and freedoms (loi informatique et libertés). This waiver was valid for one year only. In this way, Santé publique France collected the data under the legal authorisation number 341 194 v42 of the French national commission for information technology and civil liberties (ie CNIL:Commission nationale de l’informatique et des libertés). This authorisation allowed the agency to collect and analyse data on investigations performed in the context of a health warning, especially a suspected cluster, data from families and healthcare professionals. The processing of their data was part of the management of a health alert carried out under the responsibility of Santé publique France. This processing based on a mission of public interest, was thus established in accordance with the provisions of articles L. 1413-7 and L.1413-12-3 of the French Public Health Code. The experts from the SEC, bound by medical secrecy, provided signed commitment to confidentiality and only had access to pseudonymised data (without first and last names). Families of cases included in the suspected clusters in Loire-Atlantique and Morbihan received a letter from Santé publique France informing them of the transfer of their home address details to anses within the framework of their investigations. The storage period for data sent by families was 5 years. They were informed that they could at any time exercise their right to oppose, access, rectify or delete the data collected.

Consent to publish

Personal data may not be published without the express and specific consent of the persons concerned. A face-to-face interview was conducted with each concerned family in order to present to families how data collected during the investigations could be presented in a public report, with their consent.

Santé publique France publications must comply with the confidentiality provisions of Articles L. 311-6 and L. 311-7 of the French Code of relations between the public and the administration. Thus, Santé publique France publications may not disclose information:

  • the disclosure of which would infringe on the protection of privacy, medical secrecy and business secrecy, which includes the secrecy of processes, economic and financial information and commercial or industrial strategies

  • making an assessment or value judgment about a natural person, by name or easily identifiable revealing the behavior of a person, where disclosure of this behaviour could be prejudicial to that person.

Some families expressed their wish that neither the name of the commune (sub-département administrative area) where they were living at the time of the pregnancy, nor the year of birth of their child should be published. Therefore, the only specific geographical names given are those of the three départements involved (Ain, Morbihan, and Loire-Atlantique), and the regions to which they belong (Rhône-Alpes, Brittany, and Pays de la Loire, respectively). Furthermore, only periods of pregnancy covering several years are presented.

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Boudet-Berquier, J., Demattei, C., Guldner, L. et al. A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France. Eur J Epidemiol (2024). https://doi.org/10.1007/s10654-024-01125-5

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