Biological embedding of childhood adversity: From physiological mechanisms to clinical implications

BMC Medicine

Volumn 15, Issue 1, 2017, Pages

  Berens, Anne E ^a,b   Jensen, Sarah K G ^a,b   Nelson, Charles A ^a,b,c  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c HARVARD GRADUATE SCHOOL OF EDUCATION   (United States)

Author keywords

Adverse childhood experiences; Brain development; Health promotion; Primary care; Social disparities; Stress

Indexed keywords

C REACTIVE PROTEIN; EPINEPHRINE; FIBRINOGEN; INTERLEUKIN 1; INTERLEUKIN 6; NORADRENALIN; TUMOR NECROSIS FACTOR;

ADAPTIVE IMMUNITY; ADDICTION; AMYGDALA; ASTHMA; ATHEROSCLEROSIS; BIOLOGICAL EMBEDDING; BIOLOGICAL PHENOMENA AND FUNCTIONS CONCERNING THE ENTIRE ORGANISM; BRAIN; BRAIN FUNCTION; BRAIN STEM; CAREGIVER SUPPORT; CEREBROVASCULAR ACCIDENT; CHILD WELFARE; CHILDHOOD ADVERSITY; CHRONIC INFLAMMATION; DYSBIOSIS; DYSLIPIDEMIA; EARLY LIFE ADVERSITY; ENDOCRINE FUNCTION; EXPERIENCE; EXPOSURE; GENDER; GENETIC VARIABILITY; HEALTH PROMOTION; HEART INFARCTION; HUMAN; HYPERCORTISOLISM; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; IMMUNOSUPPRESSIVE TREATMENT; INNATE IMMUNITY; INSULIN RESISTANCE; INTESTINE FLORA; MALIGNANT NEOPLASM; MENTAL DISEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; POSITIVE FEEDBACK; PUBLIC HEALTH; REVIEW; SCREENING; SEX; SOCIAL ENVIRONMENT; SYSTEMATIC REVIEW; ADULT; ANIMAL; CHILD; CHILD ABUSE; DISEASE PREDISPOSITION; PREVENTION AND CONTROL; PSYCHOLOGY;

ADULT; ANIMALS; CHILD; CHILD ABUSE; DISEASE SUSCEPTIBILITY; HUMANS;

EID: 85025064477     PISSN: None     EISSN: 17417015     Source Type: Journal    
DOI: 10.1186/s12916-017-0895-4     Document Type: Review

References (113)

1. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-58.
2. Liu Y, Croft JB, Chapman DP, Perry GS, Greenlund KJ, Zhao G, Edwards VJ. Relationship between adverse childhood experiences and unemployment among adults from five U.S. states. Soc Psychiatry Psychiatr Epidemiol. 2013;48(3):357-69.
3. Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. 2009;163(12):1135-43.
4. Giovanelli A, Reynolds AJ, Mondi CF, Ou SR. Adverse childhood experiences and adult well-being in a low-income, urban cohort. Pediatrics. 2016;137(4):e20154016. doi: 10.1542/peds.2015-4016.
5. Flaherty EG, Thompson R, Dubowitz H, et al. Adverse childhood experiences and child health in early adolescence. JAMA Pediatr. 2013;167(7):622-9.
6. Richards M, Wadsworth MEJ. Long term effects of early adversity on cognitive function. Arch Dis Child. 2004;89(10):922-7.
7. Kelly-Irving M, Mabile L, Grosclaude P, Lang T, Delpierre C. The embodiment of adverse childhood experiences and cancer development: potential biological mechanisms and pathways across the life course. Int J Public Health. 2013;58:3-11.
8. Kelly-Irving M, Lepage B, Dedieu D, Bartley M, Blane D, Grosclaude P, Lang T, Delpierre C. Adverse childhood experiences and premature all-cause mortality. Eur J Epidemiol. 2013;28:1-14.
9. Barboza Solís C, Kelly-Irving M, Fantin R, Darnaudéry M, Torrisani J, Lang T, Delpierre C. Adverse childhood experiences and physiological wear-and-tear in midlife: findings from the 1958 British birth cohort. Proc Natl Acad Sci U S A. 2015;112(7):E738-46.
10. Hertzman C. Putting the concept of biological embedding in historical perspective. Proc Natl Acad Sci U S A. 2012;109(Supplement 2):17160-7.
11. Graignic-Philippe R, Dayan J, Chokron S, Jacquet AY, Tordjman S. Effects of prenatal stress on fetal and child development: a critical literature review. Neurosci Biobehav Rev. 2014;43:137-62.
12. Martikainen P, Bartley M, Lahelma E. Psychosocial determinants of health in social epidemiology. Int J Epidemiol. 2002;31(6):1091-3.
13. Hillis S, Mercy J, Amobi A, Kress H. Global prevalence of past-year violence against children: a systematic review and minimum estimates. Pediatrics. 2016;137(3):1-13.
14. Moussavi S, Somnath S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590):851-8.
15. McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2011;62:431-45.
16. Fox SE, Levitt P, Nelson CA. How the timing and quality of early experiences influence the development of brain architecture. Child Dev. 2010;81:28-40.
17. Avitsur R, Levy S, Goren N, Grinshpahet R. Early adversity, immunity and infectious disease. Stress. 2015;18(3):289-96.
18. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull. 2011;137:959-97.
19. Essex MJ, Boyce WT, Hertzman C, Lam LL, Armstrong JM, Neumann SM, Kobor MS. Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. Child Dev. 2013;84:58-75.
20. Reuben A, Moffitt TE, Caspi A, Belsky DW, Harrington H, Schroeder F, et al. Lest we forget: comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health. J Child Psychol Psychiatry. 2016;57(10):1103-12.
21. Bick J, Nelson CA. Early adverse experiences and the developing brain. Neuropsychopharmacology. 2016;41:177-96.
22. Knickmeyer RC, Gouttard S, Kang C, Evans D, Wilber K, Smith JK, et al. A structural MRI study of human brain development from birth to 2 years. J Neurosci. 2008;28(47):12176.
23. Deoni SCL, Dean DC, O'Muircheartaigh J, Dirks H, Jerskey BA. Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping. Neuroimage. 2012;63(3):1038-53.
24. Hart H, Rubia K. Neuroimaging of child abuse: a critical review. Front Hum Neurosci. 2012;6:52.
25. Nemeroff CB. Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron. 2016;89:892-909.
26. McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3-23.
27. Tottenham N, Sheridan MA. A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Front Hum Neurosci. 2010;3:68.
28. Uno H, Eisele S, Sakai A, Shelton S, Baker E, DeJesus O, Holden J. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav. 1994;28(4):336-48.
29. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29-39.
30. Do KQ, Cuenod M, Hensch TK. Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophr Bull. 2015;41(4):835-46.
31. Sarro EC, Sullivan RM, Barr G. Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA. Neurosci. 2014;258:147-61.
32. Berens AE, Nelson CA. The science of early adversity: is there a role for large institutions in the care of vulnerable children? Lancet. 2015;386(9991):388-98.
33. Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci. 2004;16:1412-25.
34. McLaughlin KA, Sheridan MA, Winter W, Fox NA, Zeanah CH, Nelson CA. Widespread reductions in cortical thickness following severe early-life deprivation: a neurodevelopmental pathway to attention-deficit/hyperactivity disorder. Biol Psychiatry. 2014;76(8):629-38.
35. McLaughlin KA, Sheridan MA, Lambert HK. Childhood adversity and neural development: Deprivation and threat as distinct dimensions of early experience. Neurosci Biobehav Rev. 2014;47:578-91.
36. Doom JR, Gunnar MR. Stress in infancy and early childhood: effects on development. In: Wright JD, Ed. International Encyclopedia of the Social & Behavioral Sciences. Amsterdam: Elsevier Science & Technology; 2015. Vol. 23. pp. 577-82.
37. Liston C, Gan WB. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo. Proc Natl Acad Sci U S A. 2011;108(38):16074-9.
38. Jensen SK, Dickie EW, Schwartz DH, et al. Effect of early adversity and childhood internalizing symptoms on brain structure in young men. JAMA Pediatr. 2015;169(10):938-46.
39. Hensch TK, Bilimoria PM. Re-opening windows: manipulating critical periods for brain development. Cerebrum. 2012;2012:11.
40. Nusslock R, Miller GE. Early-life adversity and physical and emotional health across the lifespan: a neuroimmune network hypothesis. Biol Psychiatry. 2016;80:23-32.
41. Dillon DG, Holmes AJ, Birk JL, Brooks N, Lyons-Ruth K, Pizzagalli DA. Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol Psychiatry. 2009;66(3):206-13.
42. Tawakol A, Ishai A, Takx RAP, et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet. 2017;389(10071):834-45.
43. Meaney MJ. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci. 2001;24:1161-92.
44. Lovallo WR. Early life adversity reduces stress reactivity and enhances impulsive behavior: Implications for health behaviors. Int J Psychophysiol. 2013;90:8-16.
45. Rao U, Hammen C, Ortiz LR, Chen L, Poland RE. Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents. Biol Psychiatry. 2008;64:521-6.
46. Tyrka AR, Price LH, Gelernter J, Schepker C, Anderson GM, Carpenter LL. Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psyc. 2009;66:681-5.
47. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000;284(5):592-7.
48. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160(9):1554-65.
49. Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer. 2006;6(3):240-8.
50. McEwen BS. Brain on stress: How the social environment gets under the skin. Proc Natl Acad Sci U S A. 2012;109:17180-5.
51. Meaney MJ, Szyf M. Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci. 2005;28:456-63.
52. McGowan P, Szyf M. The epigenetics of social adversity in early life: Implications for mental health outcomes. Neurobiol Dis. 2010;39:66-72.
53. Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R, et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry. 2011;1(12), e59.
54. McGowan PO, Roth TL. Epigenetic pathways through which experiences become linked with biology. Dev Psychopathol. 2015;27:637-48.
55. Alkon A, Wolff B, Boyce WT. Poverty, Stress, and Autonomic Reactivity. The Oxford Handbook of Poverty and Child Development. New York, NY: Oxford University Press; 2012.
56. El-Sheikh M, Kouros CD, Erath S, Cummings E, Keller P, Staton L. Marital Conflict and Children's Externalizing Behavior: Interactions between Parasympathetic and Sympathetic Nervous System Activity. Monographs of the Society for Research in Child Development Series. Wiley; 2009.
57. Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry. 2009;14:681-95.
58. Kanterman J, Sade-Feldman M, Baniyash M. New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol. 2012;22:307-18.
59. Fagundes CP, Glaser R, Kiecolt-Glaser JK. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behav Immun. 2013;27:8-12.
60. Shirtcliff EA, Coe CL, Pollak SD. Early childhood stress is associated with elevated antibody levels to herpes simplex virus type 1. Proc Natl Acad Sci U S A. 2009;106(8):2963.
61. Slopen N, McLaughlin KA, Dunn EC, Koenen KC. Childhood adversity and cell-mediated immunity in young adulthood: does type and timing matter? Brain Behav Immun. 2013;28:63-71.
62. Lemieux A, Coe CL, Carnes M. Symptom severity predicts degree of T cell activation in adult women following childhood maltreatment. Brain Behav Immun. 2008;22:994-1003.
63. Miller GE, Chen E. Harsh family climate in early life presages the emergence of a proinflammatory phenotype in adolescence. Psychol Sci. 2010;21(6):848-56.
64. Miller GE, Chen E, Fok AK, et al. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci U S A. 2009;106(34):14716-21.
65. Powell ND, Sloan EK, Bailey MT, et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc Natl Acad Sci U S A. 2013;110(41):16574-9.
66. Slopen N, Koenen KC, Kubzansky LD. Childhood adversity and immune and inflammatory biomarkers associated with cardiovascular risk in youth: a systematic review. Brain Behav Immun. 2012;26:239-50.
67. Baumeister D, Akhtar R, Ciufolini S, Pariante C, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Mol Psychiatry. 2016;21(5):642-9.
68. Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. J Neuroimmune Pharmacol. 2006;1(4):421-7.
69. Thomas C, Hypponen E, Power C. Obesity and type 2 diabetes risk in midadult life: the role of childhood adversity. Pediatrics. 2008;121:e1240-9.
70. Maniam J, Antoniadis C, Morris MJ. Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes. Front Endocrinol. 2014;5:73.
71. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661-71.
72. Mason SM, Flint AJ, Field AE, Austin SB, Rich-Edwards JW. Abuse victimization in childhood or adolescence and risk of food addiction in adult women. Obesity. 2013;21(12):E775-E81.
73. Moloney RD, Desbonnet L, Clarke G, Dinan TG, Cryan JF. The microbiome: stress, health and disease. Mamm Genome. 2014;25:49-74.
74. O'Mahony SM, Clarke G, Dinan TG, Cryan JF. Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle? Neuroscience. 2017;342:37-54.
75. Clarke G, O'Mahony SM, Dinan TG, Cryan JF. Priming for health: gut microbiota acquired in early life regulates physiology, brain and behaviour. Acta Paediatr. 2014;103:812-9.
76. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558(1):263-75.
77. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014;34(46):15490-6.
78. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701-12.
79. Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17:565-76.
80. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour: Epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014;13(1):69-86.
81. O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho A, Quiggley EM, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65:263-7.
82. Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25:397-407.
83. Ganguly P, Brenhouse HC. Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Dev Cogn Neurosci. 2015;11:18-30.
84. Hertzman C, Boyce T. How experience gets under the skin to create gradients in developmental health. Annu Rev Public Health. 2010;31:329-47.
85. Ellis BJ, Essex MJ, Boyce WT. Biological sensitivity to context: II. Empirical explorations of an evolutionary-developmental theory. Dev Psychopathol. 2005;17:303-28.
86. Lester BM, Masten AS, McEwen BS, editors. Resilience in Children. Boston: Blackwell Publications on behalf of the New York Academy of Sciences; 2006.
87. Heim C, Binder EB. Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol. 2012;233:102-11.
88. Fredericks CA, Drabant EM, Edge MD, Tillie JM, Hallmayer J, Ramel W, et al. Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions. Brain Behave Immun. 2010;24(3):350-7.
89. Zhao J, Bremner JD, Goldberg J, Quyyumi AA, Vaccarino V. MAOA genotype, childhood trauma and subclinical atherosclerosis: a twin study. Psychosom Med. 2013;75(5):471-7.
90. Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW, Moffitt TE. MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis. Molec Psychiatry. 2006;11(10):903.
91. Brummett BH, Boyle SH, Siegler IC, et al. Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR). Behav Genet. 2008;38(1):34-43.
92. Evans GW, Kim P, Ting AH, Tesher HB, Shannis D. Cumulative risk, maternal responsiveness, and allostatic load among young adolescents. Dev Psychol. 2007;43(2):341-51.
93. Carroll JE, Gruenewald TL, Taylor SE, Janicki-Deverts D, Matthews KA, Seeman TE. Childhood abuse, parental warmth, and adult multisystem biological risk in the Coronary Artery Risk Development in Young Adults study. Proc Natl Acad Sci U S A. 2013;110(42):17149-53.
94. Chen E, Miller GE, Kobor MS, Cole SW. Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood. Mol Psychiatry. 2011;16(7):729-37.
95. Luecken LJ. Parental caring and loss during childhood and adult cortisol responses to stress. Psychol Health. 2000;15(6):841-51.
96. Brody GH, Yu T, Beach SR. Resilience to adversity and the early origins of disease. Dev Psychopathol. 2016;28:1347-65.
97. Luby J, Belden A, Botteron K, Marrus N, Harms M, Babb C, et al. The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events. JAMA Pediatr. 2013;167(12):1135-42.
98. Miller GE, Brody GH, Yu T, Chen E. A family-oriented psychosocial intervention reduces inflammation in low-SES African American youth. Proc Natl Acad Sci U S A. 2014;111(31):11287-92.
99. Drury SS, Theall K, Gleason MM, Smyke AT, De Vivo I, Wong JYY, et al. Telomere length and early severe social deprivation: linking early adversity and cellular aging. Mol Psychiatry. 2012;17:719-27.
100. Brody GH, Gray JC, Yu T, Barton AW, Beach SR, Galván A, et al. Protective prevention effects on the association of poverty with brain development. JAMA Pediatr. 2017;171(1):46-52.
101. Slopen N, McLaughlin KA, Shonkoff JP. Interventions to improve cortisol regulation in children: a systematic review. Pediatrics. 2014;133(2):312-26.
102. Shonkoff JP. Building a new biodevelopmental framework to guide the future of early childhood policy. Child Dev. 2010;81(1):357-67.
103. Center on the Developing Child at Harvard University. The JPB Research Network on Toxic Stress. 2016. http://developingchild.harvard.edu/science/the-jpb-research-network-on-toxic-stress/. Accessed 1 Nov 2016.
104. World Health Organization. Adverse Childhood Experiences International Questionnaire (ACE-IQ). Geneva: WHO; 2014. http://www.who.int/violence:injury_prevention/violence/activities/adverse_childhood_experiences/en/ , Accessed 30 Dec 2016.
105. American Academy of Pediatrics. The Resilience Project. Elk Grove Village, IL: American Academy of Pediatrics; 2016. www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/resilience , Accessed 28 Dec 2016.
106. World Health Organization. Preventing Child Maltreatment: A Guide to Taking Action and Generating Evidence. Geneva: WHO; 2006.
107. World Health Organization. mhGAP Intervention Guide for Mental, Neurological and Substance Use Disorders in Non-specialized Health Settings. Geneva: WHO; 2010.
108. Center on the Developing Child at Harvard University. Fronteirs of Innovation: Innovation in Action. Cambridge, MA: Harvard University; 2016. http://www.developingchild.harvard.edu/innovation-application/innovation-in-action/ , Accessed 28 Jan 2017.
109. National Center for Medical Home Implementation. Tools & Resources. Elk Grove Village, IL: American Academy of Pediatrics; 2016. https://medicalhomeinfo.aap.org/tools-resources/Pages/default.aspx , Accessed 28 Jan 2017.
110. World Health Organization. Advocacy for Mental Health: Mental Health Policy and Service Guidance Package. Geneva: WHO; 2003.
111. UNICEF. Policy advocacy and partnerships for children's rights. New York, NY: UNICEF; 2016. https://www.unicef.org/policyanalysis/ , Accessed 28 Jan 2017.
112. Children's Defense Fund. Children's Defense Fund Campaigns. Washington, DC: Children's Defense Fund; 2016. http://www.childrensdefense.org/campaigns/ , Accessed 1 Feb 2017.
113. Bhutta ZA, Guerrant RL. Nelson 3rd CA. Neurodevelopment, nutrition, and inflammation: the evolving global child health landscape. Pediatrics. 2017;139 Suppl 1:S12-22.