Neurodevelopment, Nutrition,

and Inflammation: The Evolving

Global Child Health Landscape
Zulfiqar 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.

aCentre 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) scientific 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 finalized the
manuscript; Dr Guerrant was a presenter at the original NICHD scientific 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 scientific meeting, contributed to the writing of the initial manuscript, and reviewed
and revised subsequent versions of the manuscript; and all authors approved the final 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 Zulfiqar 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: zulfiqar.bhutta@sickkids.ca
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 financial 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 conflicts of interest to disclose.

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SUPPLEMENT ARTICLE PEDIATRICS Volume 139, Number s1, April 2017:e20162828
Important and heartening downward
trends in global mortality for
children <5 years of age have been
achieved in recent years. For a
summary, see Table 1. In light of
this encouraging progress, there
is an emerging recognition of the
TABLE 1 Global Trends in Under-5 Mortality
The global under-5 mortality rate has dropped nearly 53% since 1990, from around 91 deaths per 1000
live births to 43 per 1000 live births in 2015.4
In 2000, for example, there were 9.8 million annual deaths of children <5 years of age.5 Pooled estimates
for 42 countries that included >90% of all such deaths identified leading causes as:
○ neonatal conditions (33%),
○ diarrhea (22%),
○ pneumonia (21%),

importance of newborn survival in ○ malaria (9%), and

○ HIV (3%)5
reducing child mortality. Strategies
In 2013, mortality rates reduced to 5.9 million deaths per year6 with a major shift in the causes:
to address newborn survival1 will ○ 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 deaths7;
and child health goals within ○ pneumonia (15%),

the United Nations’ Sustainable ○ diarrhea (9%),

Development Goal 3 for health
and well-being.2 Although global
burden of disease data have typically
focused on children <5 years of age,
more recent evidence points to a
continued burden of morbidity and
ill health among older children and
adolescents.3
Increasingly, 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.9 In addition, reductions
in child mortality have not been
universally realized and significant
disparities exist for marginalized
populations.10 According to the
2016 Global Nutrition Report,
159 million children have stunted
growth worldwide, reflecting a
rate of reduction that is far lower
than the targets set by the World
Health Assembly.11 The data suggest
that, notwithstanding the leading
infectious disease–associated
deaths, iron deficiency anemia was
the leading cause of years lived
with disability among children and
adolescents, affecting 619 million
children in 2013.3 Not only are
developmental deficits important
consequences of conditions
associated with a higher risk of
mortality (such as intrauterine
growth restriction, prematurity,
and birth asphyxia),12 but they may
also be associated with a range of
factors related to living conditions
○ malaria (7%), and
○ AIDS (2%) deaths have declined in relative terms, and even more so in absolute terms.8
(eg, sanitation), poverty, and
undernutrition.13 More recently, the
association of Zika virus infection
during pregnancy and microcephaly
highlights the importance of
emerging infectious diseases and the
risks of adverse neurodevelopmental
outcomes.14 By using Early Child
Development Index data from
Demographic and Health Surveys
as well as Multiple Indicator Cluster
Surveys in 35 low- and middle-
income countries, estimates of the
prevalence of neurodevelopmental
deficits have recently been published,
indicating that 14.6% of children had
low Early Child Development Index
scores in the cognitive domain, 26.2%
had low socioemotional scores, and
36.8% performed poorly in either
or both domains.15 Risk factors for
such deficits should be considered in
the context of sensitive time periods
in fetal and childhood physical
and neurodevelopment. For the
purposes of this journal supplement,
neurodevelopment is defined as the
dynamic interrelationship between
environment, genes, and the brain
whereby the brain develops across
time to establish sensory, motor,
cognitive, socioemotional, cultural,
and behavioral adaptive functions.
This definition has been modified
for this effort from an earlier version
recently published in Nature.16
As will be explored more fully below
and throughout this supplement,
the implications of potential insults
are compounded by their timing
(ie, during critical and sensitive
periods of neurodevelopment).
A sensitive period is a time in
development during which the brain
is particularly responsive to stimuli
or insults followed by an extended
period of ongoing responsiveness,
but to a lesser degree (eg, language
development); by contrast, a
critical period refers to a time in
development when the presence or
absence of an experience results in
irreversible change (eg, binocular
vision).17,18 Figure 1 depicts neural
network development from the
prenatal period into adulthood,
including key time periods, sensitive
and critical, for specific domains. An
example of the former might be the
formation of a healthy attachment
between infant and caregiver, which
requires an adult who is invested in
the child’s needs during the first 2
years of life. An example of the latter
is the need to treat children born
with cataracts in the first few months
of life for children to ever develop
normal vison. For most aspects of
human behavioral development, the
concept of sensitive periods is the
most applicable, given the prolonged
course of brain development and
the enormous range of experiences
to which children from different
cultures and societies are exposed.
Although not all developmental

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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 specific domains.
(Reprinted with permission from Bhattacharjee Y. Baby Brains – The First Year. National Geographic. Available at: http://ngm.nationalgeographic.com/
2015/01/baby-brains/bhattacharjee-text.)
domains follow sensitive periods,
of those that do, most sensitive
periods occur during the first few
years of life. Importantly, not all
sensitive periods are the same, even
within the same general domain.
For example, the acquisition of
syntax likely follows a much more
compressed time table than the
acquisition of vocabulary, which
may extend throughout much of the
lifespan. Similarly, the formation of
attachments likely follows a different
time table than the acquisition of
executive functions (ie, cognitive
control), which, like vocabulary, is
apt to be broadly tuned.
During sensitive periods, when
there is maximal brain plasticity,
experiences can “cut both ways.”
That is, positive experiences are
likely to direct development along a
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S14
typical trajectory, whereas negative
experiences can undermine this
trajectory. This association is
particularly true if such negative
experiences continue beyond the
sensitive period. Accordingly,
interventions are more likely to be
met with success when implemented
early, when many brain regions and
circuits are at their peak of plasticity.
However, effective interventions
are also needed throughout the life-
course from early childhood through
young adulthood to achieve the best
possible outcomes for those who
did not receive appropriate support
at earlier time points. For example,
recent advances in understanding
the molecular signals that regulate
the opening and closing of sensitive
periods, such as those reported
in animal models by Hensch
and colleagues,19–21 may prove
particularly helpful in developing
new “late-onset” interventions.
Although healthy debates continue
about the data quality, complexity of
causality, and mechanisms involved,
multiple lines of evidence link
impaired early-life development
with later health impairment.
Examples that provoke challenging
genetic, epigenetic, microbiologic,
and metabolomic models for
understanding include potential
development and metabolic
consequences of diseases of poverty,
such as repeated enteric infections
in early childhood in impoverished
areas.22 The associations of key
prenatal factors and being small
for gestational age (SGA) with
an increased risk of mortality23
BHUTTA et al
and subsequent stunting are well
recognized.13
RISK FACTORS FOR IMPAIRED
NEURODEVELOPMENT
The fact that a range of
periconceptual, fetal, and
postnatal factors affect health and
neurodevelopmental outcomes
in an interconnected manner is
well established. Increasingly, at
both the population and individual
level, there is a cooccurrence of
malnutrition (ie, both overnutrition
and undernutrition) and infectious
and noncommunicable diseases,
each of which has strong nutritional
and inflammatory components
that impact and are impacted by
neurodevelopment, particularly
in the context of pregnancy,
birth outcomes, infant feeding,
and maternal health, including
adolescents. A host of environmental
factors have been identified in low-
resource settings (LRS) that increase
the risk for altering the course of
FIGURE 2
Early adversity causal model: Interactions between early childhood adversity, biological changes, and long-term outcomes. Reprinted and adapted with
permission from Annie E. Berens, medical student, Harvard Medical School. IUGR, intrauterine growth restriction; LBW, low birth weight; SGA, small for
gestational age.
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PEDIATRICS Volume 139, Number s1, April 2017
neurodevelopment.24,25 Figure 2
illustrates an early adversity causal
model of the interactions between
early childhood adversity, biological
changes, and long-term outcomes.
Specific examples of early-life insults
and adversities that are of particular
relevance to LRS include:
• Prematurity: Preterm birth,
particularly in LRS where fewer
interventions and services
are available, can lead to both
short- and long-term deficits in
neurodevelopment,26 including
specific impairments in attention27
and higher-order cognitive skills.28
Although multifactorial in origin,
prematurity risks include maternal
undernutrition, micronutrient
deficiencies, as well as subclinical
infections and inflammation;
these risks may vary in different
populations and are affected
by genetic influences. Given the
prevalence of prematurity in the
United States and globally, it is
fortunate that some progress on
solutions to the health care of
such children worldwide has been
made,29 such as with recently
developed nutritional guidelines
for preterm infants.30
• Nutrition: Malnutrition,
including both undernutrition
and overnutrition, clearly has
implications for all aspects of
child development. An abundance
of evidence exists implicating
undernutrition as an independent
causal factor in altering physical
and neurologic development,
with both short- and long-term
implications for health and quality
of life.31
• Infectious disease and
inflammation: It is well known
that chronic diarrheal illness, often
due to poor sanitation, food safety,
and water quality, is associated
with chronic inflammation. In
a cohort of Bangladeshi infants
living in poverty, Jiang et al32 have
reported decreased scores on the
Bayley Scales of Infant and Toddler
Development33 in association with
S15
 febrile illness as a clinical marker
of inflammation and a variety of
proinflammatory cytokines. This
is an impressive demonstration
that children experiencing early
inflammatory processes are at
risk for diminished or delayed
development. Whether there is
catch-up later in life is unknown.
• Violence: Child maltreatment
increases the risk of both adverse
neural34,35 and cardiovascular
outcomes.36 A recent systematic
review of population-based
surveys, including data for 96
countries, estimates that 1 billion
children ages 2 to 17 years,
representing over half of all
children globally, experienced
violence in the past year.37 This
pervasive exposure to conflict and
violence in early childhood can
have far-reaching consequences for
the physical and mental health of
future generations.38
• Toxic stress: For the purposes
of this article, toxic stress
will be defined by using key
concepts introduced by the
National Scientific Council on
the Developing Child, which
described toxic stress as being the
excessive or prolonged activation
of the physiologic stress response
systems in the absence of the
buffering protection afforded by
stable, responsive relationships
and the result of cumulative
adverse childhood experiences.39
There is now extensive evidence
from neuroscience, molecular
biology, and epigenetics illustrating
that increases in heart rate, blood
pressure, and serum glucose,
coupled with elevations in stress
hormones and inflammatory
cytokines fuel the fight or flight
response to deal with acute
threat.39–42 Furthermore, excessive
or prolonged activation of stress
response systems can lead to
long-term disruptions in brain
development, immune status,
metabolic systems, cardiovascular
S16
function, and gene expression.
Animal and human studies have
found associations between early-
life adversity and toxic stress to
changes in brain architecture
and gene expression, potentially
resulting in long-term and even
intergenerational physical and
mental health consequences.
Importantly, toxic stress is most
deleterious to the developing
brain when it occurs during a
sensitive or critical period of
development and may have lifelong
effects. Consequently, toxic stress
is an important concept with
implications for the research,
clinical, and policy arenas.
THE IMPACT OF NUTRITION ON
NEURODEVELOPMENT
The evidence to support the intimate
and inextricable role of food and
nutrition, including in mortality and
human development is compelling.13
Suboptimal nutrition, associated with
fetal growth restriction, stunting,
wasting, and deficiencies of vitamin
A and zinc, along with suboptimal
breastfeeding, is associated with
∼45% of all deaths of children
<5 years of age.13 The Pelotas
cohort of 3500 infants followed
up to 30 years of age, adjusted for
potential confounders, showed that
participants who were breastfed for
at least 12 months, as compared with
<1 month, scored on average 3.76
points higher on IQ tests, achieved
0.91 extra years of education, and
earned higher monthly incomes.43
These effects are especially notable
given the known benefits of exclusive
breastfeeding for newborn and
child survival44 and the impacts
on the burden of morbidity due to
gastrointestinal and respiratory
infections.45 Stunting is included
among the 2013 World Health
Assembly nutrition targets, but the
world is off track for achieving the
global target of reducing stunting
prevalence by 40% by 2025.11
As per the latest estimates,46 the
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median prevalence of stunting in
the 65 countdown countries with
data from 2009 or later is 32%, and
ranges from 9% in China to 58% in
Burundi. Progress in these domains
has been relatively slow, despite the
calls for action at the World Health
Assembly and through The Lancet
Undernutrition Series in 2013.13,44
Few countries have launched
comprehensive programs integrating
child survival and nutrition at
scale.11,46
A significant advance in recent years
is the recognition of the relationship
between maternal undernutrition,
indeed even preconceptional factors,
such as maternal height, and fetal
growth restriction, resulting in SGA
births.47 Not only has SGA been
shown to compound the risk of
neonatal mortality, especially among
preterm infants,47 but it has also been
shown to account for at least a fifth of
all stunting in children at 18 months
of age.13 This association could be
stronger in South Asia, which has
significantly higher rates of maternal
malnutrition and SGA births. To
illustrate, both maternal height and
BMI were found to be independently
associated with childhood stunting in
Pakistan,48 and similar relationships
have been shown from an analysis of
data from the National Family Health
Survey of India.49,50
Stunting has been associated with
impaired cognitive development,
effects that are only partially
mitigated by schooling.51 In addition,
although the magnitude and duration
of effects in the postnatal period and
infancy remain controversial, relative
to the importance of maternal and
fetal effects, some studies have
provided intriguing insight into
critical opportunities for benefit. In
a large study in rural Pakistan with
community health workers providing
integrated nutrition and child
development messaging, although
there were developmental benefits
at 24 months of age, there was no
impact on nutritional outcomes.52
BHUTTA et al
However, nutritional intervention aspects of child development Evidence continues to mount that
in the first 2 years of life has been has been greatly informed by the enteric infections and enteric or
reported to be associated with as recognition of both the prevalence systemic inflammation in early
much as a 10% higher IQ score and and nature of “environmental childhood or prenatally can impair
46% higher wages in later life.53 enteropathy” (EE).58 EE with growth and development and
disrupted intestinal barrier function, perhaps even increase later life
Given the close nexus between
intestinal inflammation, and impaired associations with obesity, metabolic
poverty and undernutrition, it
absorptive function is postulated to syndrome or cardiovascular
is not surprising that significant
impair early childhood growth and disease.22,32,73 Murine models also
correlations between poverty and
neurodevelopment. The fact that confirm that infection can impair
brain development have been
inflammation during key life periods growth and undernutrition can
demonstrated.54,55 Other research
may play a critical role in affecting greatly worsen infection burdens
looking at factors associated with
nutrition, EE, and development has and their growth impairment,
neurodevelopment and poverty
been well recognized for well over documenting a potential
has focused on the toxic effects of
2 decades59 and was convincingly “vicious cycle” with such enteric
violence, abuse, and exposure to
demonstrated in a series of studies pathogens as cryptosporidium or
conflict. Data from the recent Lancet
in Malawi and Zimbabwe.60–62 These enteroaggregative Escherichia coli.74,75
series on early child development56
indicate that low-grade exposure Although stunting may be an
also suggest that by using conjoint
to environmental pathogens increasingly imperfect surrogate
estimates of poverty and stunting,
may create an environment of for the long-term effects of early life
some 200 million children
immunostimulation and may relate enteric infections, Victora et al43 have
worldwide are at risk for suboptimal
to changes in the microbiome63 or the noted that the height-for-age z score
development with huge economic
insulinlike growth factor axis.64 In around the second birthday can be
costs over their lifetimes and
separate studies, children in Kenya or the best predictor of “human capital”
potentially across generations. These
Jamaica who received treatment with in terms of educational attainment,
data do not, as yet, take into account
the antihelminthic drug albendazole economic productivity, and even the
the number of families and young
compared with placebo had weight of future offspring.
children affected by violence, abuse,
significantly better growth, fitness,
and exposure to conflict. It is now
and cognitive function.65,66 Diarrheal illnesses, a surrogate for
estimated that at least 40% of the
enteric infections, EE, and stunting or
global burden of maternal and child
Despite surprisingly comparable impaired “catch-up growth”68 have
mortality lies in countries affected
growth curves in the first few also been associated with impaired
by national or subnational conflict
months of life, the fall from the cognitive development. Specifically,
and population displacement.57
expected growth trajectory from the cognitive impairment most
The growing knowledge of the
4 to 24 months of age in children affected appears to be semantic
biology of typical and atypical child
living in impoverished areas of (versus phonemic) fluency and
and brain development, and the
Asia, Africa, and Latin America higher executive function, somewhat
potential impact of interventions
has been remarkably consistent in analogous to the cognitive deficits
during sensitive periods of brain
decade-plus reviews as well as in seen in Alzheimer’s disease.76
development may ameliorate the
current multisite studies.3,67 The Because of this, a specific allele of
global burden of adversity and risk.
extent to which stunted growth is a the Apo-lipoprotein E (ApoE4),
The key focus on the first 1000 days
reflection of intestinal parasitic or which has been associated with
of life points to the importance of the
other infections or is predictive of an increased risk of late-onset
period of fetal development, during
impaired cognitive development, Alzheimer’s disease, has been
which the adverse effects on brain
or that the latter may occur with an examined and, surprisingly, has been
development and linear growth
EE independent of stunted growth, found to be protective against the
are maximal and the potential for
has been and remains the topic of cognitive deficits seen in children
interventions is at a maximum.
many studies ranging from work with heavy diarrhea burdens.77 Table
in Guatemala,53 the Philippines,51 2 provides some highlights of this
Kenya,63 Jamaica,64,67 Peru,68,69 and seminal research. Taken together,
THE IMPACT OF INFLAMMATION ON
Brazil70,71 to the current work by these findings of a potential benefit
NEURODEVELOPMENT
the Interactions of Malnutrition and of the ApoE4 allele in protecting the
Our appreciation of the interaction Enteric Infections: Consequences cognitive development of children (or
between inflammation associated for Child Health and Development enteropathy in mice)78 with repeated
with chronic infection and various consortium.72 diarrhea or enteropathy in early

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PEDIATRICS Volume 139, Number s1, April 2017 S17
childhood (or specific infections in
mice) could help explain a potential
selective advantage for this ApoE4
allele despite its clear association with
an increased risk for Alzheimer’s
disease in later life (an effect that has
been termed “antagonistic pleiotropy,”
or when a single gene controls more
than a single trait, ≥1 of which
has beneficial and ≥1 of which has
detrimental effects on the fitness
of the host). Thus, the evolutionary
benefit of ApoE4 (perhaps like
other genes, such as the sickle cell
trait gene) may only persist in the
presence of such health threats as
diarrhea or enteropathy (or malaria).
As conditions improve, one could
imagine the changing “evolutionary
value” of different traits over time.
The long-term and even
transgenerational effects of early
childhood infectious, inflammatory,
or nutritional challenges increase
the human and health system costs.
These costs may be compounded
by potential epigenetic mechanisms
that may be involved, leading to
long-term intergenerational effects.
Military recruits whose mothers
were pregnant with them in the
Dutch hunger winter of 1944 to
1945 were more likely to be obese
and, in later life, had problems with
certain cognitive functions.81,82
Potential mechanisms could involve
leptin promoter methylation, which
has been shown to occur during
postzygotic development in mice
and in humans.83 Indeed, leptin
promoter methylation has been
shown in recruits who were exposed
periconceptionally to the Dutch
hunger winter.83,84
Thus, translating basic laboratory
research and models into relevance
to child nutrition, inflammation, and
neurodevelopment holds promise
for elucidating not only host and
microbiome determinants of the
metabolic pathways involved, but
also potential practical biomarkers
of risk. These biomarkers could be
used to assess the effectiveness of
S18
TABLE 2 Potential Role of ApoE4 in Cognition
A specific allele of ApoE4, which has been associated with an increased risk of late-onset Alzheimer’s
disease, has been found to be protective against the cognitive deficits seen in children with heavy
diarrhea burdens.77
The potential link between ApoE4 and cognition has been extended to targeted transgenic mice
expressing the human ApoE4 allele. Findings include:
protected intestinal villus morphometry,
improved growth trajectories, and
reduced shedding of Cryptosporidium parasites in experimental infections with malnutrition.78
The bridge with basic studies may lie in Colton and Czapiga’s work79,80 showing that:
these mice exhibit increased expression of cationic amino acid transporter-1 that is responsible for
arginine uptake
innovative interventions to optimize targeting interventions. More
these critical determinants in recently, a systematic review of
early childhood. The critical roles key interventions that can impact
of the microbiota in influencing maternal, newborn, and child health
susceptibility to (and being and nutrition outcomes has shown
influenced by) malnutrition and the potential of integrating strategies
enteric and other infections are for health, nutrition, and nurturing
rapidly growing areas of research care across the life course89 with
and are beyond the scope of this much potential for intergenerational
overview.85,86 Similarly, relevant benefits.56
metabolic and other biomarkers of
intestinal barrier function, microbial
Second, much more needs to be
translocation, inflammatory and
known about how experience is
immunologic signaling, and local and
biologically embedded. Acquiring
systemic inflammation are important
this knowledge will require in-depth
areas of research and clinical
research into potential mechanisms
application.87,88
that link various stress and protective
pathways to tailor interventions
IMPLICATIONS FOR RESEARCH, to different neural and behavioral
PROGRAM, AND POLICY DEVELOPMENT systems. To address the burden of
impaired neurodevelopment and
Based on what we know about
develop strategies that include an
the effects of early-life adversity
appreciation of individual biological
and sensitive or critical periods
differences, it is critically important
in development, what should our
to link basic molecular research
research priorities be? First, we need
with complementary translational
to improve our understanding of the
and clinical research and evidence-
dose, timing, and duration of early
based service delivery. Such efforts
adversity. For example, which forms
must include an appreciation of host
of adversity, at which levels, and at
genetic, microbiologic, metabolic,
which time periods exert the greatest
and environmental (including
impact on development? Why and
cultural, family, and community)
how does susceptibility to stress
vary with age, especially during factors. A systems biology approach
sensitive periods of heightened and characterization of gene
or diminished sensitivity to networks in the assessment of
environmental influences? Are these neurodevelopmental disorders
sensitive periods limited to early is emerging as a potential future
childhood or could there be windows approach to assessing individual
of opportunity even later, especially variations in neural network
in adolescence or adult life? If this configuration and differential
can be established, this information vulnerabilities to neurocognitive
will be critical for developing and deficits.
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BHUTTA et al
Third, it is imperative that we
improve our armamentarium of tools
that can be used to assess the impact
of early adversity. Currently, the
most widely used tools are relatively
coarse behavioral measures (eg,
developmental exams) that lack
sensitivity to underlying neural
mechanisms, cannot be used early
in life given the infant’s limited
behavioral repertoire, and are largely
developed in Western, high-resource
countries. There are now many more
promising models as well as genetic
and metabolomic tools available
to us that may help us understand
mechanisms and develop biomarkers
and interventions.
Finally, as mentioned previously,
advances in the neurobiology of
sensitive or critical periods will likely
lead to new discoveries in ways to
rescue or reopen these important
time periods in brain development.
If we were able to rescue a sensitive
period later in life, without neural
circuitry becoming unstable (ie,
sensitive periods may exist in the
first place because newly formed
neural systems crave stability), then
we may be able to develop targeted
interventions much later in life that
have comparable efficacy to those
implemented early in life. Work
on all these fronts should vastly
improve our knowledge of how to
intervene in the lives of children
exposed to early-life adversity and
must receive adequate support and
funding for research. And while we
wait for the science to improve the
understanding and pathogenesis
of neurodevelopmental risks and
deficits, we know enough about
evidence-based practices that
can ameliorate the effect of such
adversities during sensitive time
periods to prioritize this for action.
What is needed is an integrated and
accelerated strategy for research in
this field that prioritizes action across
the discovery, development, and
delivery pathways with concomitant
PEDIATRICS Volume 139, Number s1, April 2017
investments in monitoring and
evaluation.
ABBREVIATIONS
ApoE4: apolipoprotein E4
EE: environmental enteropathy
LRS: low-resource setting
SGA: small for gestational age
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Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child
Health Landscape
Zulfiqar A. Bhutta, Richard L. Guerrant and Charles A. Nelson III
Pediatrics 2017;139;S12
DOI: 10.1542/peds.2016-2828D
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child
Health Landscape
Zulfiqar A. Bhutta, Richard L. Guerrant and Charles A. Nelson III
Pediatrics 2017;139;S12
DOI: 10.1542/peds.2016-2828D

The online version of this article, along with updated information and services, is
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2017 by the American Academy
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