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.

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