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Wide variation in severe neonatal morbidity among very preterm infants in European regions
  1. Anna Karin Edstedt Bonamy1,2,
  2. Jennifer Zeitlin3,
  3. Aurélie Piedvache3,
  4. Rolf F Maier4,
  5. Arno van Heijst5,
  6. Heili Varendi6,
  7. Bradley N Manktelow7,
  8. Alan Fenton8,
  9. Jan Mazela9,
  10. Marina Cuttini10,
  11. Mikael Norman11,12,
  12. Stavros Petrou13,
  13. Patrick Van Reempts14,
  14. Henrique Barros15,
  15. Elizabeth S Draper7
  16. on behalf of Epice Research Group
    1. 1 Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden
    2. 2 Clinical Epidemiology Section, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
    3. 3 Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes, Paris, France
    4. 4 Children’s Hospital, University Hospital, Philipps University Marburg, Marburg, Germany
    5. 5 Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands
    6. 6 Department of Pediatrics, University of Tartu, Tartu University Hospital, Tartu, Estonia
    7. 7 Department of Health Sciences, University of Leicester, Leicester, UK
    8. 8 Newcastle University, Newcastle upon Tyne, UK
    9. 9 Research Unit of Perinatal Epidemiology, Clinical Care and Management Innovation Research Area, Bambino Gesù Children’s Hospital, Institute for Research and Health Care, Rome, Italy
    10. 10 Department of Neonatology, Poznan University of Medical Sciences, Poznan, Poland
    11. 11 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
    12. 12 Department of Neonatal Medicine, Karolinska University Hospital, Stockholm, Sweden
    13. 13 Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
    14. 14 Department of Neonatolog, Antwerp University Hospital, University of Antwerp, Antwerp and Study Centre for Perinatal Epidemiology Flanders, Belgium, Europe
    15. 15 EPIUnit-Institute of Public Health, University of Porto, Porto, Portugal
    1. Correspondence to Dr Jennifer Zeitlin, Obstetrical, Perinatal and Pediatric Epidemiology Research Team, Centre for Epidemiology and Biostatistics, INSERM U1153, Paris 75014, France; Jennifer.zeitlin{at}


    Objective To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates.

    Design Area-based cohort study of all births before 32 weeks of gestational age.

    Setting 16 regions in 11 European countries in 2011/2012.

    Patients Survivors to discharge from neonatal care (n=6422).

    Main outcome measures Severe neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades ≥3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics.

    Results 10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%–23.5%) and 13.8% including severe BPD (regional range 10.0%–23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%–18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P<0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P=0.50).

    Conclusion Severe neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates.

    • neonatology
    • mortality
    • epidemiology

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    • AKEB and JZ contributed equally.

    • Contributors AKEB and JZ had access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AKEB, JZ, AP, RFM, AvH, HV, LK, BNM, AF, JM, MC, SP, PVR, HB, ESD; acquisition, analysis or interpretation of data: AKEB, JZ, AP, RFM, AvH, HV, BM, AF, JM, MC, SP, PVR, HB, ESD and all authors in the Epice Research Group; drafting of the manuscript: AKEB, JZ, AP, RFM, AvH, HV, BM, AF, JM, MC, SP, PVR, HB, ESD; critical revision of the manuscript for important intellectual content and approval of final version of the manuscript: All authors (including investigators listed in Epice Research Group); statistical analysis: AKEB, JZ, AP. Final approval: all authors.

    • Funding The research leading to these results received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°259882. Additional funding is acknowledge from the following regions: France (French Institute of Public Health Research/Institute of Public Health and its partners the French Health Ministry, the National Institute of Health and Medical Research, the National Institute of Cancer, and the National Solidarity Fund for Autonomy; grant ANR-11-EQPX-0038 from the National Research Agency through the French Equipex Program of Investments in the Future; and the Prem Up Foundation); Poland (2012- 2015 allocation of funds for international projects from the Polish Ministry of Science and Higher Education); Sweden (Stockholm County Council (ALF-project and Clinical Research Appointment) and by the Department of Neonatal Medicine, Karolinska University Hospital), UK (funding for The Neonatal Survey from Neonatal Networks for East Midlands and Yorkshire and Humber regions).

    • Competing interests None declared.

    • Ethics approval French Advisory Committee on Use of Health Data in Medical Research and the French National Commission for Data Protection and Liberties. Also, ethics authorisation was obtained for each study in the participating regions.

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

    • Data sharing statement Access to data in the EPICE cohort for researchers who are not members of the consortium is not currently possible, but EPICE is part of a H2020 project (RECAP, to develop a Platform for data sharing. Please contact the corresponding author for more information.

    • Collaborators BELGIUM: Flanders (E Martens, G Martens, P Van Reempts); DENMARK: Eastern Region (K Boerch, A Hasselager, L Huusom, O Pryds, T Weber); ESTONIA (L Toome, H Varendi); FRANCE: Burgundy, Ile-de France and Northern Region (PY Ancel, B Blondel, A Burguet, PH Jarreau, P Truffert); GERMANY: Hesse (RF Maier, B Misselwitz, S Schmidt), Saarland (L Gortner); ITALY: Emilia Romagna (D Baronciani, G Gargano), Lazio (R Agostino, D DiLallo, F Franco), Marche (V Carnielli), M Cuttini; ; NETHERLANDS: Eastern & Central (C Koopman-Esseboom, A Van Heijst, J Nijman); POLAND: Wielkopolska (J Gadzinowski, J Mazela); PORTUGAL: Lisbon and Tagus Valley (LM Graça, MC Machado), Northern region (Carina Rodrigues, T Rodrigues), H Barros; SWEDEN: Stockholm (AK Bonamy, M Norman, E Wilson); UK: East Midlands and Yorkshire and Humber (E Boyle, ES Draper, BN Manktelow), Northern Region (AC Fenton, DWA Milligan); INSERM, Paris (J Zeitlin, M Bonet, A Piedvache).

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