THE EFFECTIVENESS AND SAFETY OF TREATMENTS USED FOR THE MANAGEMENT OF PATENT DUCTUS ARTERIOSUS (PDA) IN PRETERM INFANTS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Abstract

OBJECTIVES: The objective of this thesis is to explore the effectiveness and safety of common pharmacotherapeutic options used for the management of patent ductus arteriosus (PDA) in preterm infants. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance, article 1 develops the protocol to conduct the systematic review and network meta-analysis to answer the research question. Article 2 details the actual methods implemented to conduct the network meta-analysis and presents the results in the form of network plots, league tables, rank heat maps, rankograms and forest plots. RESULTS: Article 1 suggests the need to conduct a Bayesian random-effects network meta-analysis of randomized controlled trials (RCTs) as the analysis would involve multiple treatments with potentially both direct and indirect comparisons. Article 1 also a priori defines potential effect modifiers and statistical strategies to control for the same. In article 2, the results of the meta-analysis show that in 68 RCTs that included 4802 infants, 14 different variations of indomethacin, ibuprofen or acetaminophen were used. Oral high-dose ibuprofen was associated with a significantly higher odds of PDA closure compared with standard-dose intravenous ibuprofen (Odds Ratio [OR], 3.59; 95% Credible Interval [CrI],1.64-8.17) and intravenous indomethacin (OR, 2.35; 95% CrI,1.08-5.31). Oral high-dose ibuprofen ranked the best option for PDA closure (SUCRA [surface under the cumulative ranking curve],0.89 [SD, 0.12]) and to prevent surgical PDA ligation (SUCRA,0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis or intra-ventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. CONCLUSION: This thesis suggests that oral high-dose ibuprofen could be the best treatment option for closure of a hemodynamically significant PDA. Placebo or no treatment for a hemodynamically significant PDA may not increase morbidity and mortality.