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Neuroprotection for Perinatal Hypoxic Ischemic Encephalopathy in Low- and Middle-. Income Countries. Authors: 1. Corresponding. Mohamed Tagin MB BCh, ...
Neuroprotection for Perinatal Hypoxic Ischemic Encephalopathy in Low- and MiddleIncome Countries Authors: 1. Corresponding Mohamed Tagin MB BCh, Winnipeg Regional Health Authority, WS012 Women's Hospital, 735 Notre Dame Avenue, Winnipeg, MB, R3E 0L8, Canada Tel: 204-430-4250 Fax: 204-787-1587 Email: [email protected] 2. Hesham Abdel-Hady PhD, Professor of Pediatrics/Neonatology, Mansoura University Children's Hospital, Gomhoria Street, Mansoura 35516, Egypt, Email: [email protected] 3. Sajjad ur Rahman MBBS. DCH. MCPS. FCPS. FRCPCH, Senior Consultant Neonatal Perinatal Medicine, Women’s Hospital Hamad Medical Corporation & Associate Professor of Clinical Pediatrics, Weill Cornell Medical College, PO Box 3050, Doha State of Qatar, Email: [email protected] 4. Denis V. Azzopardi FRCPCH, Professor of Neonatal Medicine, Centre for the Developing Brain, Department of Perinatal Imaging, King’s College London, St Thomas’ Hospital, Westminister Bridge Road, London SE17EH, United Kingdom, Email: [email protected] 5. Alistair J. Gunn, MBChB, PhD, Professor of Physiology and Paediatrics, Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, Private Bag 92019, New Zealand. Email: [email protected] Address correspondence to: Mohamed Tagin MB BCh, Winnipeg Regional Health Authority, WS012 Women's Hospital, 735 Notre Dame Avenue, Winnipeg, MB, R3E 0L8, Canada. Email: [email protected] Short title: Neuroprotection in low- and middle-income countries Abbreviations: Hypoxic ischemic Encephalopathy (HIE); Hypoxic Ischemic (HI); Low- and Middle-Income (LMI) Key Words: Neonatal, Encephalopathy, Hypoxia Ischemia, Asphyxia Word count: 1977 Funding Sources: None Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. 1

Conflict of Interest: The authors have no conflicts of interest to disclose. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. Contributor’s Statement: The corresponding author confirms on behalf of all authors that this work is not and will not be submitted to any other journal while under consideration by your journal. The authors have no conflict of interest to declare. Mohamed A Tagin: Dr. Tagin initiated and conceptualized the viewpoint, drafted the initial manuscript, arranged the references and approved the final manuscript as submitted. Hesham Abdel-Hady: Dr. Abdel-Hady reviewed and edited the manuscript and approved the final manuscript as submitted. Sajjad ur Rahman: Dr. Rahman reviewed and edited the manuscript and approved the final manuscript as submitted. Denis V. Azzopardi: Dr. Azzopardi reviewed and edited the manuscript and approved the final manuscript as submitted. Alistair J. Gunn: Dr. Gunn reviewed and edited the manuscript and approved the final manuscript as submitted.

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Neuroprotection for Perinatal Hypoxia Ischemia in Low- and Middle-Income Countries Background Perinatal Hypoxic Ischemic Encephalopathy (HIE) is associated with approximately one quarter of global neonatal deaths.1 In 2010, there were an estimated 1.15 million cases of neonatal encephalopathy, of which 96% of were from low- and middle-income (LMI) countries.2 In the developed world, therapeutic hypothermia is now widely accepted as standard care for treatment of newborns with moderate to severe HIE.3 Therapeutic hypothermia reduced the risk of death or major neurodevelopmental disability at 18 months of age (risk ratio [RR], 0.76; 95% confidence interval [CI], 0.69-0.84) and increased survival with normal neurological function (RR, 1.63; 95% CI, 1.36-1.95).4,5 Recent studies have confirmed improved neurocognitive outcomes at school age.6,7 However, these studies predominantly involved developed countries. In contrast, a systematic review of seven trials including 567 newborns from LMI countries, mainly using lowcost cooling techniques, did not show a significant reduction in neonatal mortality (RR, 0.74; 95% CI, 0.44 to 1.25).8 Although the point estimate is consistent with estimate from the developed world,4,5 the wide CIs of the result means that clinically important benefit or harm could not be excluded. Further, there was insufficient long-term follow-up to assess whether hypothermia had improved neurodevelopmental outcomes. The heterogeneity of outcomes in studies from LMI countries may be an artifact of poor study design; many of which were very small.8 The largest study in that review which carries almost half of the weight in the primary outcome (neonatal mortality), may have introduced selection bias by including more boys (85%) and violated its protocol by including 20% of cases with mild encephalopathy.9 Overall, 15% of patients in these studies had mild encephalopathy, and consistent with this, only 12% needed ventilation.8 Newborns with mild HIE have a low risk of 3

mortality,10 reducing the study’s power and potentially leading to a false conclusion that the intervention is not conclusive when the intervention was not applied to its target population. It is unclear whether the low frequency of mechanical ventilation reflects only selection for milder cases, or whether resource limitations constrained care. Alternatively, the heterogeneity of outcomes could potentially be ‘real’, that is to say, related to medical factors that impair the effectiveness of hypothermia. First, there may be biological differences in the populations. There is some evidence from a newborn rat model of Hypoxic Ischemic (HI) brain injury that priming with infection before the injury may reduce the protective effect of mild hypothermia.11 The rate of perinatal neonatal sepsis is higher in many LMI countries,12 and thus might reduce neuroprotection with hypothermia. However, as recently reviewed, the rate of confirmed sepsis in Ugandan or Indian infants with encephalopathy is not materially different from the rate in the recent developed world trials.13 Second, the time of the insult before treatment is critical to the effectiveness of hypothermia,14 and often difficult to quantify. In LMI countries, a higher proportion of perinatal brain injury may be due to chronic antenatal insults, such as malnutrition and intrauterine growth restriction,15 and there are many delays in providing care due to limited medical and nursing infrastructure.16 Thus, it is likely that in many cases by the time that treatment could commence, the therapeutic window may have passed.17 Third, low-resourced or less experienced centers may be less rigorous in using therapeutic hypothermia according to established protocols, or may use less rigorous selection criteria, which would reduce the apparent efficacy of hypothermia or increase complications.18,19 Fourth, such countries may not be able to provide adequate neonatal intensive care including proper monitoring, mechanical ventilation, sedation, and use of oxygen. Finally, LMI countries may be less able to afford approved devices to induce stable hypothermia within targeted goal.

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Nevertheless, low-cost alternative devices such as servo-controlled fans to blow room air, icepacks, cold water bottles, mattresses made of phase changing materials and less expensive servocontrolled cooling blankets are being developed.18,20–23

This outcome leaves LMI countries in an invidious situation, where there is no enough evidence that therapeutic hypothermia is safe and protective in their current settings, and yet it is almost certainly no longer acceptable to undertake trials of hypothermia against normothermia. This ethical conundrum is not unique and it is common to have a gap in evidence-based practice between high income countries and LMI countries. Resource limitations are understandably severe in low income countries. Thus, at present, hypothermia should not be considered standard care in extremely deprived settings, where it may be argued that primary prevention should be the primary focus. A comprehensive package of community based low cost interventions, for example Helping Babies Breathe campaign, to ensure that all babies are born with a skilled birth attendant present is likely to have a much larger effect than any secondary treatment.24,25 Similar initiatives tailored according to the sociocultural environment to improve maternal nutritional status, obstetric care and decrease infection rate will improve maternal and consequently neonatal outcomes. Consistent with this suggestion, a recent analysis in 78 LMI countries found that scaling up midwifery among other maternal and newborn interventions could avert up to 83% of all maternal deaths, stillbirths, and neonatal deaths. Further, the inclusion of specialist care could further decrease deaths, meaning that midwifery care has the greatest effect when provided within a functional health system with effective referral and transfer mechanisms to specialist care.26 Thus, secondary treatment and primary prevention should be balanced in countries where there is a wide range of resourcing.

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Ethical Complexity and Limited Resources In many LMI countries poverty, endemic diseases, and a low level of investment in health care systems will affect both the ease of performing clinical trials and the selection of trials that can benefit local citizens. A further challenge is to conduct clinical trials that make use of impoverished and, at least in some cases, illiterate populations without violating ethical behavior and protecting potential research subjects.27 At the same time, capturing a wide spectrum of patient profiles with adequate representation of all ethnic groups is essential for global implementation of any therapy. This suggests that international collaborations between LMI and high income countries are essential to systematically test the most promising agents. Naturally, LMI countries will need to demonstrate sufficient clinical expertise and motivation to undertake neuroprotection research, to ensure safety of the participants and a high chance of success for collaborative work. Such collaboration between high income and LMI countries in the design and conduct of future trials will enhance not only the participation of LMI countries but also the way results of trials are implemented. Powering clinical trials of Neuroprotection Collaboration between LMI and high-income countries may have significant benefits for the speed of development of potential treatment strategies. Assuming a target of a 20% reduction in relative risk for the primary outcome of death or major neurodevelopmental disability at 18 - 24 months from 48% (as shown in a recently) 4,5 to 38%, an α error of 0.05, and a β error of 20%, by convention; 748 newborns with moderate to severe perinatal HI will be required to test each new therapy. Based on a 20% loss to follow-up, the sample size needed would be close to 900 participants to complete a single study. Furthermore, one study is typically not sufficient to establish any intervention and to confirm generalizability. 6

Given the current incidence of 1 to 2 cases of neonatal encephalopathy per 1000 live births in developed world, it will be difficult to recruit such large cohorts in high income countries alone within a reasonable timeline.28 Shortening the interval between drug discovery and use in clinical practice in multiple settings is a clear benefit that would be achieved by increasing study power. Surrogate end points for clinical trials are possible, but ultimately clinical improvement will be required to convincingly demonstrate usefulness. Should low and middle income countries' perspectives be represented in future clinical trials? Investing in an intervention that would not be applicable to LMI countries will not help the majority of potential beneficiaries and will limit the global utility of such intervention. Thus, the interests of newborns in LMI countries should be considered when researchers are investigating neuroprotective interventions.2,29,30 Important considerations and shared goals Simple administration and monitoring are crucial to make new interventions successful and useable in LMI countries. Ideally any intervention would be: 1. Accessible and distributable in all pharmaceutical markets. 2. Inexpensive; the cost of the treatment in LMI countries directly affect parents decision whether to continue treatment or to withdraw care. 3. Easily administered, especially during transport to prevent delay in starting a time sensitive treatment. 4. Require minimal training for its administration and monitoring. What should be next? 7

Currently researchers in developed countries are evaluating the effectiveness of xenon and erythropoietin in conjunction with hypothermia, with little contribution from LMI countries.31–33 These agents have promising preclinical results, but relatively high costs. For example, Dingley et al presented the estimated costs of using a re-circulating circuit of xenon as a way to reduce costs, when used in conjunction to therapeutic hypothermia, to be $15.60 per hour, in addition to $200 for the ventilator circuit and $80 for the cuffed endo-tracheal tube.31 That did not include the costs for intensive care beds for ventilated newborns and long-term follow up. Thus, the final costs for such interventions remain high for LMI countries. There are added costs for knowledge translation, education and training of medical and nursing staff. These costs may preclude their implementation in LMI countries. Magnesium is in trial as an additive treatment to therapeutic hypothermia to newborns with HIE (MagCool1-NCT01646619). The neuroprotective effects of magnesium remain controversial,34,35 although, there is limited evidence from animal studies that combination treatment of mild hypothermia and magnesium after ischemia may be more effective than either treatment used alone.36 Magnesium possesses most of the attributes for an ideal neuroprotective agent in LMI countries. The cost for a treatment course is less than 3 dollars per patient based on the highest dosage and the longest treatment course evaluated in newborns with HIE. Thus, even though magnesium may not be the strongest neuroprotective intervention being evaluated nor have the safest profile, it appears to have the greatest pragmatic potential for use in LMI countries amongst the current proposed neuroprotective agents. We naturally view the cost of human life as incalculable. However, the incremental cost per disability-free life year gained might be a pragmatic way to convince policy makers to adopt new interventions. This approach may assist in directing research funding and initiatives. Such 8

analyses for therapeutic hypothermia early during its inception as standard of care showed that the cost-effectiveness of cooling treatment for neonatal encephalopathy was finely balanced over the first 18 months after birth, but increased substantially when national incidence data and an extended time horizon were considered.37 We have no doubt that similar analyses in the future for other successful interventions will have similar results. Therefore, it is crucial not only for new interventions to be feasible for use in LMI countries but also that LMI countries assist in evaluating the cost-effectiveness of new interventions in their settings. Call for global actions "In helping others, we shall help ourselves, for whatever good we give out completes the circle and comes back to us" Flora Edwards. Global health initiatives in human research pertaining to perinatal HIE should be evidence-based, economically feasible, and culturally appropriate. A key motivation to include LMI countries in the development of neuroprotective treatments should be to capture a larger patient pool, first to study the hypothesis in different cultural and medical backgrounds and second to allow protocols to be completed on a faster timeline. Mutual trust and transparency between high income countries and LMI countries must be encouraged to establish adequate funding and support to remove barriers to the evaluation of potential neuroprotective agents. In conclusion, there is strong potential for complementary contributions, given that high income countries have established expertise in medical trials and LMI countries have much larger numbers of infants with perinatal HIE. References:

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