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Air pollution and stunting: a missing link?

2020; Elsevier BV; Volume: 8; Issue: 4 Linguagem: Inglês

10.1016/s2214-109x(20)30063-2

2572-116X

Sheela Sinharoy, Thomas Clasen, Reynaldo Martorell,

Birth, Development, and Health

Child linear growth impairment, particularly stunting, remains a global health challenge. Stunting is defined as a height-for-age Z-score more than two SDs below the WHO child growth standards reference median for age and sex. The number of children younger than 5 years who are stunted was 59 million (34%) in south Asia and 58 million (33%) in sub-Saharan Africa in 2018.1UNICEFWHOWorld Bank GroupLevels and trends in child malnutrition: joint child malnutrition estimates. Key findings of the 2019 edition. World Health Organization, Geneva2019Google Scholar Stunting is associated with poor child development, lower productivity and earnings in adulthood, and increased risk of chronic diseases later in life.2de Onis M Branca F Childhood stunting: a global perspective.Matern Child Nutr. 2016; 12: 12-26Crossref PubMed Scopus (533) Google Scholar, 3Hoddinott J Behrman JR Maluccio JA et al.Adult consequences of growth failure in early childhood.Am J Clin Nutr. 2013; 98: 1170-1178Crossref PubMed Scopus (243) Google Scholar In this Comment, we argue that air pollution has been largely ignored as a potentially important cause of stunting, we outline a conceptual framework for how air pollution might lead to impaired linear growth in children, and we call for additional research into these mechanisms. Child linear growth is a complex, multifactorial process, with the highest risk of growth impairment occurring between conception and 2 years of age. Stunting can begin in utero, caused by intrauterine growth retardation, or the programming of later growth, or both.2de Onis M Branca F Childhood stunting: a global perspective.Matern Child Nutr. 2016; 12: 12-26Crossref PubMed Scopus (533) Google Scholar, 4Christian P Lee SE Donahue Angel M et al.Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries.Int J Epidemiol. 2013; 42: 1340-1355Crossref PubMed Scopus (308) Google Scholar Postnatally, immediate causes of impaired growth include inadequate dietary intake and recurrent infection. Underlying causes of impaired growth include inadequate access to food, inadequate care for women and children, and unhealthy environments.5UNICEFStrategy for improved nutrition of children and women in developing countries.Indian J Pediatr. 1991; 58: 13-24Crossref PubMed Scopus (46) Google Scholar Interventions to address specific causes have had small but consistent effects on linear growth, and more comprehensive efforts have led to much larger improvements at the population level.6Victora CG Aquino EM do Carmo Leal M Monteiro CA Barros FC Szwarcwald CL Maternal and child health in Brazil: progress and challenges.Lancet. 2011; 377: 1863-1876Summary Full Text Full Text PDF PubMed Scopus (559) Google Scholar, 7Bhutta ZA Das JK Rizvi A et al.Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost?.Lancet. 2013; 382: 452-477Summary Full Text Full Text PDF PubMed Scopus (1616) Google Scholar Given that stunting is a marker of complex systemic effects, improvements in both immediate and underlying causes are necessary to dramatically reduce its prevalence. Poor water, sanitation, and hygiene conditions are thought to be a major cause of stunting, through repeated episodes of diarrhoea and environmental enteric dysfunction.8Humphrey JH Child undernutrition, tropical enteropathy, toilets, and handwashing.Lancet. 2009; 374: 1032-1035Summary Full Text Full Text PDF PubMed Scopus (514) Google Scholar However, recent, large randomised controlled trials found that water, sanitation, and hygiene interventions failed to improve child linear growth.9Humphrey JH Mbuya MNN Ntozini R et al.Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.Lancet Glob Health. 2019; 7: e132-e147Summary Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 10Luby SP Rahman M Arnold BF et al.Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Bangladesh: a cluster randomised controlled trial.Lancet Glob Health. 2018; 6: e302-e315Summary Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 11Null C Stewart CP Pickering AJ et al.Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Kenya: a cluster-randomised controlled trial.Lancet Glob Health. 2018; 6: e316-e329Summary Full Text Full Text PDF PubMed Scopus (318) Google Scholar While these results raise questions about the effectiveness of water, sanitation, and hygiene approaches generally, they highlight the need for a broader view of environmental factors that might affect child linear growth, and the complex ways in which these factors might operate, interact, and synergise.12Cumming O Arnold BF Ban R et al.The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement.BMC Med. 2019; 17: 173Crossref PubMed Scopus (106) Google Scholar The potential relationship between air pollution and child linear growth has received little attention, compared with the effect of water, sanitation, and hygiene on child linear growth. Air pollution includes both ambient (outdoor) and household (indoor) air pollution. Ambient air pollution sources include agricultural and industrial processes and vehicle fuel combustion. Household air pollution is linked primarily to cooking with solid biomass fuels (eg, wood, charcoal, and dung), which are used by approximately 3 billion people globally.13WHOAir pollution and child health: prescribing clean air. World Health Organization, Geneva2018Google Scholar Damaging agents in air pollution include solid particles, carbon monoxide, and nitrogen oxides. Exposure is widespread; WHO reports that 98% of children younger than 5 years in low-income and middle-income countries are exposed to air pollution above the recommended concentrations.13WHOAir pollution and child health: prescribing clean air. World Health Organization, Geneva2018Google Scholar To date, evidence for a link between air pollution and linear growth has come from retrospective and observational studies. These studies focused mainly on prenatal exposure to ambient air pollution and adverse birth outcomes such as low birthweight and preterm birth. In 2017, a systematic review and meta-analysis showed that increased prenatal exposure (per IQR increment) to ambient air pollution, measured as fine particulate matter (PM2·5), slightly increased the risk of preterm birth (odds ratio [OR] 1·03 [95% CI 1·01–1·05]) and low birthweight at term (1·03 [1·02–1·03]).14Li X Huang S Jiao A et al.Association between ambient fine particulate matter and preterm birth or term low birth weight: an updated systematic review and meta-analysis.Environ Pollut. 2017; 227: 596-605Crossref PubMed Scopus (266) Google Scholar Low birthweight at term is a proxy for intrauterine growth restriction that is also independently associated with stunting.4Christian P Lee SE Donahue Angel M et al.Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries.Int J Epidemiol. 2013; 42: 1340-1355Crossref PubMed Scopus (308) Google Scholar The evidence was judged to be of good quality, though the data were all from observational studies and therefore had inherent limitations. Few studies have addressed links between air pollution and postnatal growth. A systematic review and meta-analysis of household air pollution and child survival identified four studies that reported stunting as an outcome.15Bruce NG Dherani MK Das JK et al.Control of household air pollution for child survival: estimates for intervention impacts.BMC Public Health. 2013; 13: S8Crossref PubMed Scopus (69) Google Scholar Three of these studies were secondary analyses of national survey data.15Bruce NG Dherani MK Das JK et al.Control of household air pollution for child survival: estimates for intervention impacts.BMC Public Health. 2013; 13: S8Crossref PubMed Scopus (69) Google Scholar The meta-analysis identified associations (based on adjusted estimates) between exposure to household air pollution (defined as use of solid fuel for cooking) and both moderate stunting (OR 1·27 [95% CI 1·12 to 1·43]) and severe stunting (1·55 [1·04 to 2·30]) but found the quality of the evidence to be low to very low.15Bruce NG Dherani MK Das JK et al.Control of household air pollution for child survival: estimates for intervention impacts.BMC Public Health. 2013; 13: S8Crossref PubMed Scopus (69) Google Scholar A later analysis of national data from India found that exposure to 100 μg/m3 of PM2·5 in the month of birth was inversely associated (ie, height-for-age Z-scores were decreased by 0·05 for every 100 μg/m3 increase in PM2·5) with child height-for-age Z-score at the time of the survey (change in height-for-age Z-score −0·05 [95% CI −0·01 to −0·09]).16Spears D Dey S Chowdhury S Scovronick N Vyas S Apte J The association of early-life exposure to ambient PM2.5 and later-childhood height-for-age in India: an observational study.Environ Health. 2019; 18: 62Crossref PubMed Scopus (27) Google Scholar The authors of the analysis note that these effect sizes might be underestimated because of potential residual confounding and measurement error.16Spears D Dey S Chowdhury S Scovronick N Vyas S Apte J The association of early-life exposure to ambient PM2.5 and later-childhood height-for-age in India: an observational study.Environ Health. 2019; 18: 62Crossref PubMed Scopus (27) Google Scholar The figure presents a conceptual framework for air pollution as a contributor to stunting. Studies investigating air pollution and intrauterine growth impairment focus primarily on effects at the cellular level, particularly on the interlinked processes of oxidative stress and epigenetics. Exposure to air pollution during pregnancy can induce reactive oxygen species, leading to mitochondrial dysfunction and reduced telomere length, inflammation, and potentially poor fetal growth.17Iodice S Hoxha M Ferrari L et al.Particulate air pollution, blood mitochondrial DNA copy number, and telomere length in mothers in the first trimester of pregnancy: effects on fetal growth.Oxid Med Cell Longev. 2018; 2018: 5162905Crossref PubMed Scopus (26) Google Scholar Reactive oxygen species are also known to affect the epigenetic state of the cell; reduced DNA methylation might be one of several epigenetic mechanisms through which air pollution leads to poor fetal growth.18Burris HH Baccarelli AA Air pollution and in utero programming of poor fetal growth.Epigenomics. 2017; 9: 213-216Crossref PubMed Scopus (16) Google Scholar Observational studies suggest that exposure to nitrogen oxides and particulate matter in utero might modulate DNA methylation, potentially affecting fetal growth, although detailed mechanisms remain unclear.19Rider CF Carlsten C Air pollution and DNA methylation: effects of exposure in humans.Clin Epigenetics. 2019; 11: 131Crossref PubMed Scopus (122) Google Scholar, 20Gruzieva O Xu CJ Yousefi P et al.Prenatal particulate air pollution and DNA methylation in newborns: an epigenome-wide meta-analysis.Environ Health Perspect. 2019; 127: 57012Crossref PubMed Scopus (74) Google Scholar The placenta might mediate these effects through its barrier, transport, and signalling functions.21Luyten LJ Saenen ND Janssen BG et al.Air pollution and the fetal origin of disease: A systematic review of the molecular signatures of air pollution exposure in human placenta.Environ Res. 2018; 166: 310-323Crossref PubMed Scopus (60) Google Scholar Beginning in utero, and continuing throughout early life, poor nutrition and environmental exposure to air pollution and pathogens can adversely affect immune ontogeny.22Goenka A Kollmann TR Development of immunity in early life.J Infect. 2015; 71: S112-S120Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar Defects in innate and adaptive immune function might then contribute to inter-relationships between air pollution, infection, and undernutrition, resulting in a cycle of recurrent illness and malnutrition.23Bourke CD Berkley JA Prendergast AJ Immune dysfunction as a cause and consequence of malnutrition.Trends Immunol. 2016; 37: 386-398Summary Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 24Bourke CD Jones KDJ Prendergast AJ Current understanding of innate immune cell dysfunction in childhood undernutrition.Front Immunol. 2019; 10: 1728Crossref PubMed Scopus (20) Google Scholar Specifically, air pollution might impair linear growth through repeated episodes of febrile respiratory illness, which are associated with increased risk of child stunting.25Dewey KG Mayers DR Early child growth: how do nutrition and infection interact?.Matern Child Nutr. 2011; 7: 129-142Crossref PubMed Scopus (142) Google Scholar It is likely that this association is because of immune activity leading to increased metabolic requirements, anorexia and reduced dietary intake, increased catabolism, and altered metabolism of key nutrients, such as retinol and iron, which are redirected as part of the body's defence mechanisms.25Dewey KG Mayers DR Early child growth: how do nutrition and infection interact?.Matern Child Nutr. 2011; 7: 129-142Crossref PubMed Scopus (142) Google Scholar, 26Sederquist B Fernandez-Vojvodich P Zaman F Sävendahl L Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth.J Mol Endocrinol. 2014; 53: T35-T44Crossref PubMed Scopus (50) Google Scholar This combination can lead to a nutrient imbalance, and hence to impaired growth. Interactions between respiratory and enteric infections might be an additional factor, leading to comorbidity with acute lower respiratory tract infection and diarrhoea.27Walker CL Perin J Katz J Tielsch JM Black RE Diarrhea as a risk factor for acute lower respiratory tract infections among young children in low income settings.J Glob Health. 2013; 3: 010402Crossref PubMed Scopus (37) Google Scholar Another indirect pathway is possible, in which households allocate incomes away from food and nutrition, and instead towards health-care expenses related to infections, leading to inadequate diets for children and impaired linear growth. In addition to clinical infection, subclinical biological mechanisms might be similar to those thought to result from poor water, sanitation, and hygiene, in which repeated insults from enteric pathogens affect gut barrier function and trigger chronic immune activation, local and systemic inflammation, and growth hormone resistance.8Humphrey JH Child undernutrition, tropical enteropathy, toilets, and handwashing.Lancet. 2009; 374: 1032-1035Summary Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 28Humphrey JH Jones AD Manges A et al.The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial: rationale, design, and methods.Clin Infect Dis. 2015; 61: S685-S702Crossref PubMed Scopus (110) Google Scholar Repeated exposure to air pollution might affect lung structure and function, triggering a similar biological response to the effect of enteric pathogens on the gut. Intervention studies of air pollution and inflammatory biomarkers in children are rare, but observational evidence exists of chronic systemic inflammation among schoolchildren (mean age 7 years) exposed to high concentrations of ambient air pollution.29Calderón-Garcidueñas L Engle R Mora-Tiscareño A et al.Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children.Brain Cogn. 2011; 77: 345-355Crossref PubMed Scopus (237) Google Scholar Proinflammatory cytokines can directly regulate growth via the growth plates through local regulation of chondrocytes.26Sederquist B Fernandez-Vojvodich P Zaman F Sävendahl L Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth.J Mol Endocrinol. 2014; 53: T35-T44Crossref PubMed Scopus (50) Google Scholar In combination with endocrine and nutritional factors, proinflammatory cytokines can also systemically regulate growth by suppressing insulin-like growth factor 1, which mediates the effect of growth hormone on longitudinal bone growth.26Sederquist B Fernandez-Vojvodich P Zaman F Sävendahl L Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth.J Mol Endocrinol. 2014; 53: T35-T44Crossref PubMed Scopus (50) Google Scholar Both prenatally and postnatally, air pollution might lead to vitamin D deficiency through several pathways, with implications for immune function and bone metabolism.30Mousavi SE Amini H Heydarpour P Amini Chermahini F Godderis L Air pollution, environmental chemicals, and smoking may trigger vitamin D deficiency: evidence and potential mechanisms.Environ Int. 2019; 122: 67-90Crossref PubMed Scopus (79) Google Scholar Although evidence is scarce, studies from France and India observed inverse associations between ambient air pollution (measured as PM10, nitrogen dioxide, and haze scores) and vitamin D concentrations in neonates and children aged 9–24 months.31Agarwal KS Mughal MZ Upadhyay P Berry JL Mawer EB Puliyel JM The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India.Arch Dis Child. 2002; 87: 111-113Crossref PubMed Scopus (233) Google Scholar, 32Baïz N Dargent-Molina P Wark JD Souberbielle JC Slama R Annesi-Maesano I Gestational exposure to urban air pollution related to a decrease in cord blood vitamin D levels.J Clin Endocrinol Metab. 2012; 97: 4087-4095Crossref PubMed Scopus (52) Google Scholar Inadequate vitamin D concentrations have been associated with increased risk of respiratory infection in young children.33Yakoob MY Salam RA Khan FR Bhutta ZA Vitamin D supplementation for preventing infections in children under five years of age.Cochrane Database Syst Rev. 2016; 11: CD008824PubMed Google Scholar Vitamin D also plays an important role in regulating bone metabolism and growth.34Bikle DD Vitamin D and bone.Curr Osteoporos Rep. 2012; 10: 151-159Crossref PubMed Scopus (155) Google Scholar More research is needed to explore these relationships. Much of the research done so far has been observational and focused on high-income countries, rather than on low-income and middle-income countries where exposures are generally higher. One option is for researchers to use natural experiments, in which specific events might result in an acute reduction or increase in air pollution.35Rich DQ Accountability studies of air pollution and health effects: lessons learned and recommendations for future natural experiment opportunities.Environ Int. 2017; 100: 62-78Crossref PubMed Scopus (57) Google Scholar However, these observational studies are likely to miss important explanatory mechanisms related to socioeconomic factors, lifestyle factors, and genetics.18Burris HH Baccarelli AA Air pollution and in utero programming of poor fetal growth.Epigenomics. 2017; 9: 213-216Crossref PubMed Scopus (16) Google Scholar High quality randomised controlled trials are needed in low-income and middle-income countries to examine the relationships between air pollution and child linear growth, and to understand the biological mechanisms underlying the effect. Possible interventions to reduce indoor air pollution include cleaner energy sources for cooking, heating, and lighting, and improved ventilation. Strategies to reduce ambient air pollution include measures to limit crop burning, refuse burning, and emissions from vehicle exhausts and industry. Increased attention is urgently needed to define the effect of air pollution on child linear growth during the prenatal period and early years of life. An improved understanding of these relationships is necessary for the development of new intervention strategies, which would contribute to a comprehensive approach that addresses multiple causal factors, for the prevention of stunting. Extending research efforts to include outcomes associated with stunting, such as poor child development, could have even greater implications than a focus on stunting alone. The potential to improve child linear growth and child development could provide a persuasive new argument for addressing air pollution and improving human health globally. We declare no competing interests.