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PEDIATRICS Volume 139 , Number s1 , April 2017 :e 20162828 SUPPLEMENT ARTICLE

Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child Health LandscapeZulfi qar A. Bhutta, MBBS, FRCPCH, FAAP, PhD, a, b Richard L. Guerrant, MD, c Charles A. Nelson III, PhDd, e, f

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) 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.

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.

abstract

by guest on June 26, 2020www.aappublications.org/newsDownloaded from

PEDIATRICS Volume 139 , Number s1 , April 2017 S13

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

importance of newborn survival in

reducing child mortality. Strategies

to address newborn survival 1 will

also be a critical part of the maternal

and child health goals within

the United Nations’ Sustainable

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

(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

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 identifi ed leading causes as:

○ neonatal conditions (33%),

○ diarrhea (22%),

○ pneumonia (21%),

○ malaria (9%), and

○ HIV (3%) 5

In 2013, mortality rates reduced to 5.9 million deaths per year 6 with a major shift in the causes:

○ preterm birth complications cause 15% of all under-5 deaths and, along with other neonatal causes,

represent 44% of all deaths 7;

○ pneumonia (15%),

○ diarrhea (9%),

○ malaria (7%), and

○ AIDS (2%) deaths have declined in relative terms, and even more so in absolute terms. 8


BHUTTA et al S14

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

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 mortality 23

FIGURE 1The 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. Available at: http:// ngm. nationalgeographi c. com/ 2015/ 01/ baby- brains/ bhattacharjee- text.)



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

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 attention 27

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 al 32 have

reported decreased scores on the

Bayley Scales of Infant and Toddler

Development 33 in association with

FIGURE 2Early 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.


BHUTTA et al S16

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

neural 34, 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

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 survival 44 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

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



However, nutritional intervention

in the first 2 years of life has been

reported to be associated with as

much as a 10% higher IQ score and

46% higher wages in later life. 53

Given the close nexus between

poverty and undernutrition, it

is not surprising that significant

correlations between poverty and

brain development have been

demonstrated. 54, 55 Other research

looking at factors associated with

neurodevelopment and poverty

has focused on the toxic effects of

violence, abuse, and exposure to

conflict. Data from the recent Lancet

series on early child development 56

also suggest that by using conjoint

estimates of poverty and stunting,

some 200 million children

worldwide are at risk for suboptimal

development with huge economic

costs over their lifetimes and

potentially across generations. These

data do not, as yet, take into account

the number of families and young

children affected by violence, abuse,

and exposure to conflict. It is now

estimated that at least 40% of the

global burden of maternal and child

mortality lies in countries affected

by national or subnational conflict

and population displacement. 57

The growing knowledge of the

biology of typical and atypical child

and brain development, and the

potential impact of interventions

during sensitive periods of brain

development may ameliorate the

global burden of adversity and risk.

The key focus on the first 1000 days

of life points to the importance of the

period of fetal development, during

which the adverse effects on brain

development and linear growth

are maximal and the potential for

interventions is at a maximum.

THE IMPACT OF INFLAMMATION ON NEURODEVELOPMENT

Our appreciation of the interaction

between inflammation associated

with chronic infection and various

aspects of child development

has been greatly informed by the

recognition of both the prevalence

and nature of “environmental

enteropathy” (EE). 58 EE with

disrupted intestinal barrier function,

intestinal inflammation, and impaired

absorptive function is postulated to

impair early childhood growth and

neurodevelopment. The fact that

inflammation during key life periods

may play a critical role in affecting

nutrition, EE, and development has

been well recognized for well over

2 decades 59 and was convincingly

demonstrated in a series of studies

in Malawi and Zimbabwe. 60 –62 These

indicate that low-grade exposure

to environmental pathogens

may create an environment of

immunostimulation and may relate

to changes in the microbiome 63 or the

insulinlike growth factor axis. 64 In

separate studies, children in Kenya or

Jamaica who received treatment with

the antihelminthic drug albendazole

compared with placebo had

significantly better growth, fitness,

and cognitive function. 65, 66

Despite surprisingly comparable

growth curves in the first few

months of life, the fall from the

expected growth trajectory from

4 to 24 months of age in children

living in impoverished areas of

Asia, Africa, and Latin America

has been remarkably consistent in

decade-plus reviews as well as in

current multisite studies. 3, 67 The

extent to which stunted growth is a

reflection of intestinal parasitic or

other infections or is predictive of

impaired cognitive development,

or that the latter may occur with an

EE independent of stunted growth,

has been and remains the topic of

many studies ranging from work

in Guatemala, 53 the Philippines, 51

Kenya, 63 Jamaica, 64, 67 Peru, 68, 69 and

Brazil70, 71 to the current work by

the Interactions of Malnutrition and

Enteric Infections: Consequences

for Child Health and Development

consortium. 72

Evidence continues to mount that

enteric infections and enteric or

systemic inflammation in early

childhood or prenatally can impair

growth and development and

perhaps even increase later life

associations with obesity, metabolic

syndrome or cardiovascular

disease. 22, 32, 73 Murine models also

confirm that infection can impair

growth and undernutrition can

greatly worsen infection burdens

and their growth impairment,

documenting a potential

“vicious cycle” with such enteric

pathogens as cryptosporidium or

enteroaggregative Escherichia coli. 74, 75

Although stunting may be an

increasingly imperfect surrogate

for the long-term effects of early life

enteric infections, Victora et al 43 have

noted that the height-for-age z score

around the second birthday can be

the best predictor of “human capital”

in terms of educational attainment,

economic productivity, and even the

weight of future offspring.

Diarrheal illnesses, a surrogate for

enteric infections, EE, and stunting or

impaired “catch-up growth” 68 have

also been associated with impaired

cognitive development. Specifically,

the cognitive impairment most

affected appears to be semantic

(versus phonemic) fluency and

higher executive function, somewhat

analogous to the cognitive deficits

seen in Alzheimer’s disease. 76

Because of this, a specific allele of

the Apo-lipoprotein E (ApoE4),

which has been associated with

an increased risk of late-onset

Alzheimer’s disease, has been

examined and, surprisingly, has been

found to be protective against the

cognitive deficits seen in children

with heavy diarrhea burdens. 77 Table

2 provides some highlights of this

seminal research. Taken together,

these findings of a potential benefit

of the ApoE4 allele in protecting the

cognitive development of children (or

enteropathy in mice)78 with repeated

diarrhea or enteropathy in early


BHUTTA et al S18

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

innovative interventions to optimize

these critical determinants in

early childhood. The critical roles

of the microbiota in influencing

susceptibility to (and being

influenced by) malnutrition and

enteric and other infections are

rapidly growing areas of research

and are beyond the scope of this

overview. 85, 86 Similarly, relevant

metabolic and other biomarkers of

intestinal barrier function, microbial

translocation, inflammatory and

immunologic signaling, and local and

systemic inflammation are important

areas of research and clinical

application. 87, 88

IMPLICATIONS FOR RESEARCH, PROGRAM, AND POLICY DEVELOPMENT

Based on what we know about

the effects of early-life adversity

and sensitive or critical periods

in development, what should our

research priorities be? First, we need

to improve our understanding of the

dose, timing, and duration of early

adversity. For example, which forms

of adversity, at which levels, and at

which time periods exert the greatest

impact on development? Why and

how does susceptibility to stress

vary with age, especially during

sensitive periods of heightened

or diminished sensitivity to

environmental influences? Are these

sensitive periods limited to early

childhood or could there be windows

of opportunity even later, especially

in adolescence or adult life? If this

can be established, this information

will be critical for developing and

targeting interventions. More

recently, a systematic review of

key interventions that can impact

maternal, newborn, and child health

and nutrition outcomes has shown

the potential of integrating strategies

for health, nutrition, and nurturing

care across the life course 89 with

much potential for intergenerational

benefits. 56

Second, much more needs to be

known about how experience is

biologically embedded. Acquiring

this knowledge will require in-depth

research into potential mechanisms

that link various stress and protective

pathways to tailor interventions

to different neural and behavioral

systems. To address the burden of

impaired neurodevelopment and

develop strategies that include an

appreciation of individual biological

differences, it is critically important

to link basic molecular research

with complementary translational

and clinical research and evidence-

based service delivery. Such efforts

must include an appreciation of host

genetic, microbiologic, metabolic,

and environmental (including

cultural, family, and community)

factors. A systems biology approach

and characterization of gene

networks in the assessment of

neurodevelopmental disorders

is emerging as a potential future

approach to assessing individual

variations in neural network

configuration and differential

vulnerabilities to neurocognitive

deficits.

TABLE 2 Potential Role of ApoE4 in Cognition

A specifi c 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 defi cits 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 work 79, 80 showing that:

these mice exhibit increased expression of cationic amino acid transporter-1 that is responsible for

arginine uptake



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

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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