The World Health Organization reports that birth asphyxia/neonatal hypoxic ischemic encephalopathy (HIE) accounts for one million deaths annually and represents the most common cause of death and disability in neonates. Fifty percent of those are in the unstudied mild HIE spectrum. Randomized trials have established that therapeutic hypothermia (TH) reduces death or disability in moderate to severe HIE, but these early trials did not include infants with mild HIE. A therapeutic drift (with limited evidence) in practice towards cooling newborns with mild HIE is occurring with a rough estimate in the United States of 50% institutions offering this treatment without testing of the safety and efficacy.
A pragmatic effectiveness design based on site predetermined existing practice to confirm effectiveness and safety in an unstudied population will bypass the problem of the current loss of equipoise and unwillingness to randomize by physicians. This type of design was also preferred by 87% of parents who have children with HIE and participated in the selection of meaningful outcomes. Therefore, the overall project aim is to establish the comparative effectiveness and safety of hypothermia versus normothermia in 430 infants with mild HIE representing all races born at 15 academic centers with balanced distribution of cooling practice per site existing practice standards. The timeline supports enrollment over two years and follow up through two years of age. The year five timeline is dedicated for analysis, publication, and dissemination of guidelines to occur. The primary aim is to determine the effectiveness and safety of hypothermia versus normothermia in improving two-year cognitive and language outcomes using the Bayley Scales of Infant and Toddler Development, the newest version of the gold standard in cooling studies, as well as parental validated questionnaires. The study is powered to test the effect of hypothermia on cognitive and language scores and safety composite risk and will detect a five-point difference in scores based on parental surveys as important. Early evaluations of sensory modulation along with standardized questionnaires of mother-infant bonding, parenting structure and attachment, mood, and stress allow a meaningful evaluation selected as most relevant to the families.
Engagement of families and community of those affected by HIE are central to this project. Hope for HIE and the Cerebral Palsy Foundation have strong relationships with Dr. Chalak (PI) and Dr. Maitre (F/U Co-I). These foundations reach large networks of families who have been affected by asphyxia and are invested in outcomes; they also have robust infrastructures including social media for parent engagement, knowledge translation, and dissemination. From the start, the project team involved these foundations to advise on study conceptualization and to create a parent survey in order to select the most relevant study outcomes and design. The project team will continue to partner with them and to leverage their expertise and their networks. The study structure champions excellence and collaborative inclusiveness, and prioritizes a partnership between families with HIE, experienced neonatologists, neurologists, epidemiologists, and biostatisticians. The executive committee consists of NIH-funded multidisciplinary experts with experience in multicenter trials.
Impact: This largest single study to address the effectiveness of hypothermia for mild HIE will fill important knowledge gaps. If the results show efficacy and safety of hypothermia for mild HIE, improved outcomes will result. If no benefit is detected, inappropriate cooling will stop, and unnecessary separation of parents and infants will be prevented. Irrespective of the results, much-needed clinical evidence-based algorithms will result. The impact is likely be substantial as injury in early life has effects on individual life span and overall quality of life, in addition to large societal impacts. The relevance to public health in a currently understudied population of children is direct and immediate: comparing widespread clinical practices for mild asphyxia will result in even and rational practices, and improve child outcomes in ways that matter to their parents.
*All proposed projects, including requested budgets and project periods, are approved subject to a programmatic and budget review by PCORI staff and the negotiation of a formal award contract.