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Methadone, Pierre Robin sequence and other congenital anomalies: case–control study
  1. Brian Cleary1,2,
  2. Maria Loane3,
  3. Marie-Claude Addor4,
  4. Ingeborg Barisic5,
  5. Hermien E K de Walle6,
  6. Carlos Matias Dias7,
  7. Miriam Gatt8,
  8. Kari Klungsoyr9,
  9. Bob McDonnell10,
  10. Amanda Neville11,
  11. Anna Pierini12,
  12. Anke Rissmann13,
  13. David F Tucker14,
  14. Oscar Zurriaga15,16,
  15. Helen Dolk17
  1. 1 Pharmacy Department, Rotunda Hospital, Dublin, Ireland
  2. 2 School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland
  3. 3 Centre for Maternal, Fetal and Infant Research, INHR, Ulster University, Newtowanbbey, UK
  4. 4 Division Autonome de Genetique Medicale, Registre Vaudois des Malformations, Vaud, Switzerland
  5. 5 Children’s Hospital Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
  6. 6 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  7. 7 Centro de Estudos e registo de A C, Lisbon, Portugal
  8. 8 Department of Health Information, Malta Congenital Anomalies Registry, G’mangia, Malta
  9. 9 Medical Birth Register of Norway, Nasjonalt folkehelseinstitutt, Oslo, Norway
  10. 10 Health Service Executive, Dublin, Ireland
  11. 11 Azienda Ospedaliero - Universitaria di Ferrara, Registro IMER, Ferrara, Italy
  12. 12 Istituto di Fisiologia Clinica CNR, Pisa, Italy
  13. 13 Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University, Magdeburg, Germany
  14. 14 Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea, UK
  15. 15 Centro Superior de Investigación en Salud Pública, Valencia, Spain
  16. 16 Direccion General de Investigación y Salud Pública, Valencia, Spain
  17. 17 University of Ulster, Jordanstown, UK
  1. Correspondence to Professor Brian Cleary, Pharmacy Department, Rotunda Hospital, Dublin 1, Ireland; bcleary{at}


Objective Methadone is a vital treatment for women with opioid use disorder in pregnancy. Previous reports suggested an association between methadone exposure and Pierre Robin sequence (PRS), a rare craniofacial anomaly. We assessed the association between gestational methadone exposure and PRS.

Design/setting This case-malformed control study used European Surveillance of Congenital Anomalies population-based registries in Ireland, the Netherlands, Italy, Switzerland, Croatia, Malta, Portugal, Germany, Wales, Norway and Spain, 1995–2011.

Patients Cases included PRS based on International Classification of Disease (ICD), Ninth Edition-British Paediatric Association (BPA) code 75 603 or ICD, Tenth Edition-BPA code Q8708. Malformed controls were all non-PRS anomalies, excluding genetic conditions, among live births, fetal deaths from 20 weeks’ gestation and terminations of pregnancy for fetal anomalies. An exploratory analysis assessed the association between methadone exposure and other congenital anomalies (CAs) excluding PRS. Methadone exposure was ascertained from medical records and maternal interview.

Results Among 87 979 CA registrations, there were 127 methadone-exposed pregnancies and 336 PRS cases. There was an association between methadone exposure and PRS (OR adjusted for registry 12.3, 95% CI 5.7 to 26.8). In absolute terms, this association reflects a risk increase from approximately 1–12 cases per 10 000 births. A raised OR was found for cleft palate (adjusted OR 5.0, 95% CI 2.7 to 9.2).

Conclusions These findings suggest that gestational methadone exposure is associated with PRS. The association may be explained by unmeasured confounding factors. The small increased risk of PRS in itself does not alter the risk–benefit balance for gestational methadone use. The association with cleft palate, a more common CA, should be assessed with independent data.

  • methadone
  • opioid use disorder
  • Pierre Robin sequence
  • cleft palate

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  • BC and ML contributed equally.

  • Contributors BC conceptualised and designed the study, drafted the initial manuscript and reviewed and revised the manuscript. ML assessed the study concept, designed the study, carried out the analysis, drafted the initial manuscript and reviewed and revised the manuscript. HD assessed the study concept, designed the study, drafted the initial manuscript and reviewed and revised the manuscript. M-CA, IB, HEKdW, CMD, MG, KK, BM, AN, AP, AR, DFT and OZ assessed the study concept, approved the study design, facilitated data collection and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Ethics approval The ethics and consent arrangement for each EUROCAT member registry can be viewed at: Greenlees R, Neville A, Addor M-C, Amar E, Arriola L, Bakker M, Boyd P, Calzolari E, Doray B, Draper E, Vollset S E, Garne E, Gatt M, Haeusler M, Kallen K, Khoshnood B, Latos- Bielenska A, Martinez-Frias M-L, Materna-Kiryluk A, Dias C M, McDonnell R, Mullaney C, Nelen V, O’Mahony M, Pierini A, Queisser-Luft A, Randrianaivo-Ranjatoelina H, Rankin J, Rissmann A, Ritvanen A, Salvador J, Sipek A, Tucker D, Verellen-Dumoulin C, Wellesley D and Wertelecki W (2011). Paper 6: EUROCAT member registries: organization and activities. Birth Defects Research (Part A). 91: S51-S100.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Additional data are not available.

  • Patient consent for publication Not required.