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Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in extremely preterm infants: a clinical practice guideline incorporating family values and preferences
  1. Souvik Mitra1,2,3,
  2. Leah Whitehead2,
  3. Katie Smith4,
  4. Breagh Maclean5,
  5. Rebekah Nixon6,
  6. Andrew Veysey2,
  7. Marsha Campbell-Yeo1,2,7,
  8. Stefan Kuhle1,3,8,
  9. Chris Gale9,
  10. Roger Soll10,
  11. Jon Dorling1,3,6,
  12. Bradley C Johnston3,11,12
  1. 1 Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
  2. 2 Division of Neonatal Perinatal Medicine, IWK Health, Halifax, Nova Scotia, Canada
  3. 3 Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada
  4. 4 School of Access, Education and Language, Nova Scotia Community College, Halifax, Nova Scotia, Canada
  5. 5 Department of Service Nova Scotia, Government of Nova Scotia, Halifax, Nova Scotia, Canada
  6. 6 Department of Neonatal Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  7. 7 School of Nursing, Faculty of Health, Dalhousie University, Halifax, Nova Scotia, Canada
  8. 8 Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg University of Mainz, Mainz, Germany
  9. 9 School of Public Health, Imperial College London, London, UK
  10. 10 Department of Pediatrics, University of Vermont, Burlington, New Jersey, USA
  11. 11 Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas, USA
  12. 12 Department of Epidemiology and Biostatistics, School of Public Health, Texas A&M University, College Station, Texas, USA
  1. Correspondence to Dr Souvik Mitra, Division of Neonatal Perinatal Medicine, Department of Pediatrics, Dalhousie University & IWK Health, Halifax, Nova Scotia, Canada; souvik.mitra{at}


Prophylactic cyclo-oxygenase inhibitors (COX-Is) such as indomethacin, ibuprofen and acetaminophen may prevent morbidity and mortality in extremely preterm infants (born ≤28 weeks’ gestation). However, there is controversy around which COX-I, if any, is the most effective and safest, which has resulted in considerable variability in clinical practice.

Our objective was to develop rigorous and transparent clinical practice guideline recommendations for the prophylactic use of COX-I drugs for the prevention of mortality and morbidity in extremely preterm infants.

The Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework for multiple comparisons was used to develop the guideline recommendations. A 12-member panel, including 5 experienced neonatal care providers, 2 methods experts, 1 pharmacist, 2 parents of former extremely preterm infants and 2 adults born extremely preterm, was convened. A rating of the most important clinical outcomes was established a priori. Evidence from a Cochrane network meta-analysis and a cross-sectional mixed-methods study exploring family values and preferences were used as the primary sources of evidence.

The panel recommended that prophylaxis with intravenous indomethacin may be considered in extremely preterm infants (conditional recommendation, moderate certainty in estimate of effects). Shared decision making with parents was encouraged to evaluate their values and preferences prior to therapy. The panel recommended against routine use of ibuprofen prophylaxis in this gestational age group (conditional recommendation, low certainty in the estimate of effects). The panel strongly recommended against use of prophylactic acetaminophen (strong recommendation, very low certainty in estimate of effects) until further research evidence is available.

  • Intensive Care Units, Neonatal
  • Neonatology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • X @souvik_neo, @DrCGale

  • Contributors SM conceived the project under the mentorship of BCJ and JD. SM and BCJ cochaired the panel meetings. SM drafted the manuscript. SM, LW, KS, BM, RN, AV, MC-Y, SK, CG, RS, BCJ and JD reviewed all drafts and approved the final version of the manuscript.

  • 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.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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