Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child Health Landscape Zulfi qar A. Bhutta, MBBS, FRCPCH, FAAP, PhD,a, b Richard L. Guerrant, MD, c Charles A. Nelson III, PhDd, e, f abstract The last decade has witnessed major reductions in child mortality and a focus on saving lives with key interventions targeting major causes of child deaths, such as neonatal deaths and those due to childhood diarrhea and pneumonia. With the transition to Sustainable Development Goals, the global health community is expanding child health initiatives to address not only the ongoing need for reduced mortality, but also to decrease morbidity and adverse exposures toward improving health and developmental outcomes. The relationship between adverse environmental exposures frequently associated with factors operating in the prepregnancy period and during fetal development is well established. Also well appreciated are the developmental impacts (both short- and long-term) associated with postnatal factors, such as immunostimulation and environmental enteropathy, and the additional risks posed by the confluence of factors related to malnutrition, poor living conditions, and the high burden of infections. This article provides our current thinking on the pathogenesis and risk factors for adverse developmental outcomes among young children, setting the scene for potential interventions that can ameliorate these adversities among families and children at risk. a Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada; bCentre of Excellence in Women and Child Health, Aga Khan University, Karachi, Pakistan; cCenter for Global Health, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia; dLaboratories of Cognitive Neuroscience, Boston Children's Hospital, Boston, Massachusetts; eDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts; and fHuman Development Program, Harvard Graduate School of Education, Cambridge, Massachusetts Dr Bhutta was a presenter at the original Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) scientifi c meeting, served as the lead author for the paper, organized the writing team, drafted the initial manuscript, incorporated edits from the additional authors and editors, and fi nalized the manuscript; Dr Guerrant was a presenter at the original NICHD scientifi c meeting, contributed to the writing of the initial manuscript, and reviewed and revised subsequent versions of the manuscript; Dr Nelson was a panelist at the original NICHD scientifi c meeting, contributed to the writing of the initial manuscript, and reviewed and revised subsequent versions of the manuscript; and all authors approved the fi nal manuscript as submitted and are accountable for all aspects of the work. DOI: 10.1542/peds.2016-2828D Accepted for publication Dec 21, 2016 Address correspondence to Zulfi qar Bhutta, MBBS, FRCPCH, FAAP, PhD, Codirector, SickKids Centre for Global Child Health, The Hospital for Sick Children, 686 Bay St, Toronto, ON M5G A04, Canada. E-mail: zulfi [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: This supplement was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the United States National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose. Downloaded from www.aappublications.org/news by guest on September 27, 2021 SUPPLEMENT ARTICLE PEDIATRICS Volume 139 , Number s1 , April 2017 :e 20162828 Important and heartening downward TABLE 1 Global Trends in Under-5 Mortality trends in global mortality for The global under-5 mortality rate has dropped nearly 53% since 1990, from around 91 deaths per 1000 children <5 years of age have been live births to 43 per 1000 live births in 2015. 4 achieved in recent years. For a In 2000, for example, there were 9.8 million annual deaths of children <5 years of age.5 Pooled estimates summary, see Table 1. In light of for 42 countries that included >90% of all such deaths identifi ed leading causes as: ○ neonatal conditions (33%), this encouraging progress, there ○ diarrhea (22%), is an emerging recognition of the ○ pneumonia (21%), importance of newborn survival in ○ malaria (9%), and reducing child mortality. Strategies ○ HIV (3%)5 6 to address newborn survival 1 will In 2013, mortality rates reduced to 5.9 million deaths per year with a major shift in the causes: ○ preterm birth complications cause 15% of all under-5 deaths and, along with other neonatal causes, also be a critical part of the maternal represent 44% of all deaths 7; and child health goals within ○ pneumonia (15%), the United Nations’ Sustainable ○ diarrhea (9%), Development Goal 3 for health ○ malaria (7%), and ○ 8 and well-being. 2 Although global AIDS (2%) deaths have declined in relative terms, and even more so in absolute terms. burden of disease data have typically focused on children <5 years of age, (eg, sanitation), poverty, and the implications of potential insults more recent evidence points to a undernutrition. 13 More recently, the are compounded by their timing continued burden of morbidity and association of Zika virus infection (ie, during critical and sensitive ill health among older children and during pregnancy and microcephaly periods of neurodevelopment). adolescents. 3 highlights the importance of A sensitive period is a time in emerging infectious diseases and the development during which the brain Increasingly, the global health risks of adverse neurodevelopmental is particularly responsive to stimuli community is expanding child health outcomes. 14 By using Early Child or insults followed by an extended initiatives to address not only the Development Index data from period of ongoing responsiveness, ongoing need for reduced mortality, Demographic and Health Surveys but to a lesser degree (eg, language but also to decrease morbidity as well as Multiple Indicator Cluster development); by contrast, a and adverse exposures toward Surveys in 35 low- and middle- critical period refers to a time in improving health and developmental income countries, estimates of the development when the presence or 9 outcomes. In addition, reductions prevalence of neurodevelopmental absence of an experience results in in child mortality have not been deficits have recently been published, irreversible change (eg, binocular universally realized and significant indicating that 14.6% of children had vision). 17, 18 Figure 1 depicts neural disparities exist for marginalized low Early Child Development Index network development from the populations. 10 According to the scores in the cognitive domain, 26.2% prenatal period into adulthood, 2016 Global Nutrition Report, had low socioemotional scores, and including key time periods, sensitive 159 million children have stunted 36.8% performed poorly in either and critical, for specific domains. An growth worldwide, reflecting a or both domains. 15 Risk factors for example of the former might be the rate of reduction that is far lower such deficits should be considered in formation of a healthy attachment than the targets set by the World the context of sensitive time periods between infant and caregiver, which Health Assembly. 11 The data suggest in fetal and childhood physical requires an adult who is invested in that, notwithstanding the leading and neurodevelopment. For the infectious disease–associated purposes of this journal supplement, the child’s needs during the first 2 deaths, iron deficiency anemia was neurodevelopment is defined as the years of life. An example of the latter the leading cause of years lived dynamic interrelationship between is the need to treat children born with disability among children and environment, genes, and the brain with cataracts in the first few months adolescents, affecting 619 million whereby the brain develops across of life for children to ever develop children in 2013. 3 Not only are time to establish sensory, motor, normal vison. For most aspects of developmental deficits important cognitive, socioemotional, cultural, human behavioral development, the consequences of conditions and behavioral adaptive functions. concept of sensitive periods is the associated with a higher risk of This definition has been modified most applicable, given the prolonged mortality (such as intrauterine for this effort from an earlier version course of brain development and growth restriction, prematurity, recently published in Nature. 16 the enormous range of experiences and birth asphyxia), 12 but they may to which children from different also be associated with a range of As will be explored more fully below cultures and societies are exposed. factors related to living conditions and throughout this supplement, Although not all developmental Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , Number s1 , April 2017 S13 FIGURE 1 The neural network: development from the prenatal period into adulthood, including key time periods (ie, sensitive and critical) for specifi c domains. (Reprinted with permission from Bhattacharjee Y. Baby Brains – The First Year. National Geographic.