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

Abstract

Prophylactic cyclooxygenase inhibitor (COX-I) drugs such as indomethacin, ibuprofen and acetaminophen may prevent morbidity and mortality in extremely preterm infants (born ≤28 weeks gestational age). Extensive variability in clinical practice exists based on controversy around which COX-I drug is the most effective and has the best safety profile. This project was designed to develop rigorous clinical practice guideline recommendations for the prophylactic use of COX-Is in extremely preterm infants through a de novo synthesis of evidence from RCTs using a network meta-analysis (NMA), and a cross-sectional mixed-methods study exploring family values and preferences conducted in parallel. The Bayesian random-effects NMA of 28 RCTs (3999 infants) demonstrated that prophylactic indomethacin probably resulted in a small reduction in severe intraventricular hemorrhage (IVH) and a moderate reduction in death. Prophylactic ibuprofen probably resulted in a small reduction in severe IVH and may result in a moderate reduction in death. The evidence was very uncertain about the effect of acetaminophen on any of the clinically relevant outcomes. The two-phase cross-sectional mixed methods study conducted using results from the above-mentioned NMA included 44 participants (34 parents of preterm infants; 10 adults born preterm). The study showed that there was minimal variability in how participants valued the main outcomes, with death and severe IVH being rated as the two most important undesirable outcomes. While indomethacin was the most preferred form of prophylaxis, variability was noted in the choice of COX-I interventions when participants were presented with the benefits and harms of each drug. Finally, the 12-member guideline panel, that included five experienced neonatal care providers, two methods experts, one pharmacist, two parents of former extremely preterm infants and two adults born extremely preterm, was presented with the results from the above-mentioned NMA and the cross-sectional mixed methods study. Using the GRADE Evidence-to-Decision framework for multiple comparisons, the panel provided a conditional recommendation in favor of indomethacin prophylaxis, a conditional recommendation against ibuprofen prophylaxis and a strong recommendation against acetaminophen prophylaxis in extremely preterm infants. The panel strongly encouraged shared decision making with parents to evaluate their values and preferences prior to prescribing either indomethacin or ibuprofen.