Project summary / abstract Congenital diaphragmatic hernia (CDH) is a complex congenital anomaly where an early embryologic insult disrupts diaphragmatic and pulmonary development, often resulting in severe, acute cardiopulmonary dysfunction post-natally and affects 2-4 per 10,000 births in the US, amounting to approximately 1500 children every year with an annual societal cost approaching $400 million. The CDH Study Group (CDHSG), established in 1995, is a consortium of institutions dedicated to improving the lives of families/patients affected by CDH through collaboration, data collation, investigation, and dissemination. Previous trials in CDH suffered limitations common to many uncommon disease investigative efforts including limited enrollment, prolonged trial conduct, inflated resource utilization, and suboptimal power, all for unconvincing evidence. The overarching goal of this multi-institutional initiative is to leverage the strength of collaboration, experienced clinical investigator leadership, and innovative trial design/analysis to address clinical questions in CDH. An important example is the use of inhaled Nitric Oxide (iNO) in the postnatal stabilization phase of clinical care in CDH. Despite mounting evidence concluding that, among patients with CDH, iNO is ineffective (and potentially harmful) and costly, most clinicians maintain equipoise over its effectiveness, and use remains near universal. Our investigative approach, a pragmatic, multi-center, de-implementation trial, with a stepped-wedge, cluster-randomized design, within the construct of an established registry, will address the clinical and cost-effectiveness of iNO in CDH. Nineteen participating centers will de-implement iNO - randomized at the center level. We will include 900 total neonates with CDH. Our first specific aim is to determine if de-implementation of iNO in the post-natal resuscitation / stabilization phase affects the composite outcome of extracorporeal life support (ECLS) use and/or mortality (composite primary outcome), as well as ECLS use, mortality, and/or oxygenation in CDH (secondary outcomes). Our second specific aim is to establish the cost-effectiveness of de-implementing iNO as a therapy in the post- natal resuscitation / stabilization phase of CDH management, which will be assessed as the incremental health system costs (savings) per prevented ECLS use and/or death. Our third specific aim is to evaluate factors that influence iNO de-implementation at the individual physician and site level to inform strategies to improve de- implementation throughout the trial. We believe this initiative, including an innovative design and collaborative approach, will serve as a foundation for ongoing trials in CDH and will serve as pivotal example for advancing the adoption of cost-effective, evidence-based strategies in neonatal and pediatric care.