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SUPPLEMENT ARTICLEPEDIATRICS Volume 139 , Number s1 , April 2017 :e 20162828

Executive Summary: Research Gaps at the Intersection of Pediatric Neurodevelopment, Nutrition, and Inflammation in Low-Resource SettingsVesna Kutlesic, PhD, Margaret Brewinski Isaacs, MD, MPH, Lisa S. Freund, PhD, Rohan Hazra, MD, Daniel J. Raiten, PhD

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland

Dr Kutlesic conceptualized the article, coordinated the author team, compiled and drafted the initial manuscript, and drafted the fi nal manuscript; Dr Brewinski

Isaacs conceptualized the article, helped coordinate the author team, helped compile and draft the initial manuscript, and revised the fi nal manuscript; Drs Freund,

Hazra, and Raiten conceptualized the article and revised the initial and fi nal manuscripts; and all authors approved the fi nal manuscript as submitted and are

accountable for all aspects of the work.

DOI: 10.1542/peds.2016-2828C

Accepted for publication Dec 21, 2016

Address correspondence to Vesna Kutlesic, PhD, Offi ce of Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B

Rockledge Dr, MSC 7002, Bethesda, MD 20892. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275); published in the public domain 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.

A growing and compelling body of evidence demonstrates that children born into poverty, whether

in high-, middle-, or low-income countries, 1 are at heightened risk for compromised health and

developmental outcomes throughout the life course. 2 – 6 It is estimated that 80.8 million children

ages 3 and 4 years in low- and middle-income countries experienced low cognitive and/or

socioemotional development in 2010 based on Early Childhood Development Index scores, with

the largest number of affected children in sub-Saharan Africa, South Asia, and the East Asia and

Pacific region. 6 Recent evidence has also underscored the importance of interventions to foster

healthy neurodevelopment from preconception through adolescence in light of findings that

the early years of life are a sensitive period for countering adverse exposures that threaten the

integrity of neural, neuroendocrine, and immune systems. 7

Consequently, there is an increasing recognition by the global health community of the need to

expand initiatives to address not only the ongoing need for reduced child mortality, but also to

decrease child morbidity and adverse exposures toward improving health and developmental

outcomes. The bridging of the child survival and child development fields has recently been

prioritized by the World Health Organization (WHO) and other agencies as being essential for

optimizing global health, equity, and sustainable development. 8 In fact, a recent review found

significant overlap between public health strategies for improving child survival and child

development interventions, the latter of which typically include enriching learning components. 9

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KUTLESIC et al

The newly developed United Nations

Sustainable Development Goals

(SDGs) for 2015 to 2030 additionally

reinforce that human development

is essential for sustainable global

development. 10 In April 2016, an

alliance was established by the

World Bank and the United Nations

Children’s Fund (UNICEF) to make

gains on these SDGs by supporting

country-led efforts to invest in

nutrition, early stimulation, learning,

and protection for every child. 11

The WHO has also recommended

several essential interventions

worldwide for child survival, growth,

and development. 7, 12 However,

research is needed on the extent

to which these interventions can

be applied and/or adapted to

diverse populations as well as

implementation science on the

optimal approaches for scaling up

these interventions, particularly in

low-resource settings (LRS).

Furthermore, for children living

in poverty, there are a host of

adverse exposures that dramatically

increase the risk for altering the

course of neurodevelopment.

Paramount among these is the

intersection between nutrition

and inflammation (ie, acute and

chronic), a hallmark of both

infectious and noncommunicable

diseases. Neurodevelopmental

outcomes are of particular interest

to the global community given

their implications for long-term

individual and population health

and prosperity, as the current

Zika virus outbreak demonstrates.

Although some evidence exists

linking pediatric neurodevelopment,

nutrition, and inflammation,

much remains to be learned about

underlying mechanisms, biomarkers,

assessment, interventions, and risk

and protective factors, among other

considerations. At the forefront, it

is essential to develop tools for the

assessment of neurodevelopment

and the nutritional, inflammatory,

and other influencing factors that

impact it, that are readily deployable

in the field, particularly in culturally

diverse LRS.

To address these knowledge gaps

and identify the next set of research

priorities, a global health meeting

was held by the Eunice Kennedy Shriver National Institute of Child

Health and Human Development

(NICHD) on February 11th and 12th,

2015 on the Bethesda, Maryland

campus of the United States

National Institutes of Health (NIH).

This meeting, entitled “Research

Gaps at the Intersection of Child

Neurodevelopment, Nutrition, and

Inflammation in Low-Resource

Settings, ” included 80 academic

researchers and representatives from

multiple organizations, including:

several offices and institutes from the

United States Department of Health

and Human Services (HHS), including

the NIH, HHS Office of Global

Affairs, and United States Centers

for Disease Control and Prevention

(CDC); the United States Agency for

International Development (USAID);

National Academy of Sciences (NAS);

the WHO; World Bank; the Bill and

Melinda Gates Foundation (BMGF);

Grand Challenges Canada; and the

Sackler Institute for Nutrition Science

at the New York Academy of Sciences.

The primary objective of this NICHD

Global Health Meeting was to identify

research priorities that are key to

understanding the interrelationships

and impact of nutritional status

and inflammation due to specific

infections or noncommunicable

diseases on child neurodevelopment

and brain function from fetal

life through adolescence in LRS.

Multidisciplinary panels, with

experts in child neurodevelopment,

nutrition, and infectious disease/

inflammation, identified research

gaps and assessment needs

during 4 developmental periods:

(1) pregnancy/fetal life, (2) infancy

(birth to 2 years of age), (3) early to

middle childhood (age 3 to 12 years),

and (4) adolescence (age 13 to

18 years).

After these panel presentations,

multidisciplinary working groups,

4 focused on targeted developmental

periods and a fifth on assessment

needs, were charged with responding

to the 5 thematic areas in Table 1 and

considering (1) existing knowledge,

(2) evidence gaps, and (3) research

priorities, as well as developing

outlines for the articles contained in

this supplement. The working groups

were also encouraged to break down

existing silos between disciplines

in child neurodevelopment,

nutrition, and inflammation (ie,

due to infectious and noninfectious

causes) to identify an integrated,

multidisciplinary approach for

conducting research, implementing

programs, and developing policies.

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TABLE 1 Five Thematic Areas Addressed by NICHD Global Health Meeting Working Groups

I. What is the existing knowledge and what are the evidence gaps and research priorities related to the

impact of:

a. nutritional status on nerodevelopment and brain function?

b. infl ammation on neurodevelopment and brain function?

c. interactions between infl ammation and nutritional status on neurodevelopment and brain function?

d. protective factors (including environmental and behavioral), plasticity, and resilience on

neurodevelopmental outcomes?

II. What underlying mechanisms help explain the complex interactions among neurodevelopment,

infl ammation, and nutritional status?

III. What types of measures, metrics, biomarkers, and tools are needed to evaluate the relationships of

neurodevelopment/brain function, nutritional status, and infl ammation?

IV. What is the potential impact of therapeutics that target infl ammation (ie, the effects of nutrients and

drugs considered individually as well as their interactions) on neurodevelopment/brain function

during childhood?

V. Identify important considerations throughout the continuum from basic research and mechanisms to

translational research and clinical care (including environmental, cultural, family, community, etc).


PEDIATRICS Volume 139 , number s1 , April 2017

During the second meeting day, a

policy roundtable was held that

focused on translational research,

program implementation, and

policy implications targeting child

neurodevelopment, nutrition, and

infectious diseases/inflammation.

Roundtable participants included

representatives from several

domestic (HHS Office of Global

Affairs, NIH, CDC, USAID, NAS) and

international (WHO, World Bank,

BMGF, Grand Challenges Canada,

Sackler Institute) agencies that were

supporting research, programs, or

policies on key global health topics.

There was general consensus among

roundtable participants that it is

important to maintain an ongoing

dialogue between researchers,

program implementers, and policy

makers to ensure that research

priority-setting is informed by

current global health challenges in

the field and, in turn, for research

evidence to inform program and

policy development. Furthermore,

in light of the complex global health

landscape and extensive needs in

LRS, the value of public–private

partnerships was underscored.

During the policy roundtable

discussion, ideas for linking research

evidence to program and policy

development included: promoting

research capacity building in LRS;

pooling data for meta-analyses;

conducting implementation science;

facilitating open access; sharing

research protocols, data, and plans;

linking the results of cohort studies

to well-framed policy statements;

studying the effectiveness of

integrated delivery of interventions;

establishing professional standards

of care; including economic analyses

when framing research plans and

findings; and developing guidelines

for governments for selecting

and scaling up evidence-based

interventions.

This NICHD Global Health Meeting

also aimed to build on research

findings and related work of NIH-led

interagency research platforms,

which are referred to in several

articles within this supplement.

These include: the NICHD Biomarkers

of Nutrition for Development (BOND)

study 13; the Biomarkers Reflecting

Inflammation and Nutritional

Determinants of Anemia (BRINDA)

study 14; the Inflammation and

Nutritional Science for Programs/

Policies and Interpretation of

Research Evidence (INSPIRE)

project 15; the NICHD Global Network

for Women’s and Children’s

Research 16; the Interactions of

Malnutrition and Enteric Infections:

Consequences for Child Health and

Development (MAL-ED) study17;

and the Fogarty International

Center (FIC) Global Brain Disorders

Program, 18 among others. Working

definitions for key science areas

addressed in this journal supplement

were extracted from and/or at least

in part developed based on the work

of these ongoing NIH-led research

collaborations. A more detailed

summary of definitions related to

this journal supplement can be found

in Table 1 of the article “Assessment

of Neurodevelopment, Nutrition,

and Inflammation From Fetal Life

to Adolescence in Low-Resource

Settings.”

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. 19

Nutrition is defined as the science

of food, the nutrients and other

substances therein, their action,

interaction, and balance in relation

to health and disease, and the

processes of ingestion, absorption,

use, and excretion. 20 Furthermore,

malnutrition has 3 principal

constituents: undernutrition (ie,

poor growth, including underweight,

stunting, and wasting), overnutrition

(ie, overweight/obesity), and

deficiencies in micronutrients. 20, 21

Finally, both infection and

inflammation are addressed

within the articles of this journal

supplement. The term “infection”

describes the interaction between the

action of microbial invasion and the

reaction of the body’s inflammatory

defensive response; the 2

components are considered together

when discussing an infection, and

the word infection is used to imply

a microbial invasive cause for the

observed inflammatory reaction. 22

In contrast, inflammation is the

stereotypical physiologic response to

infections, tissue injury, psychological

stress, and other insults. 23, 24

It is also important to distinguish

between acute and chronic

inflammation. Inflammation,

as characterized by the acute

phase response, is an innate

body defense that triggers a

sequence of physiologic changes in

response to a myriad of stressors,

including microbial invasion, tissue

injury, immunologic reactions,

and inflammatory processes. 15

Inflammation is generally protective

to the host because it removes

injurious stimuli and promotes the

healing of damaged tissue. However,

chronic inflammation may result

when there is overproduction of

inflammatory mediators that may

amplify the acute phase response

on an ongoing basis and become

detrimental to the host. 23 For the

purposes of this journal supplement,

the term “inflammation” will include

both infectious and noninfectious

as well as acute and chronic causes

of inflammation, unless otherwise

specified.

Figure 1 conceptualizes examples of

individual and environmental factors

on both nutrition and inflammation

that, separately and collectively,

affect child neurodevelopment, the

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KUTLESIC et al

focus of this overview. Examples

of important variables include

caregiver factors, such as education,

physical and mental health, and the

environment in which children grow

up, including the effects of poverty,

violence, toxic stress, pathogen

and toxin exposure, and the level

of nurturance, enrichment, and

education provided to the child.

It is important to note that factors

affecting neurodevelopment are

often bidirectional and include

both direct and indirect effects,

highlighting opportunities to

evaluate interventions. A detailed

review of all factors affecting child

neurodevelopment is beyond

the scope of this supplement,

which will specifically focus on

the interrelationships among

nutrition, inflammation, and

neurodevelopment, as described

in more detail in subsequent

supplement articles.

EMERGING RESEARCH AREAS

This section summarizes emerging

research areas at the intersection of

child neurodevelopment, nutrition,

and inflammation in LRS, first

discussed at the aforementioned

February 2015 NICHD Global Health

Meeting and explored in more depth

within the articles contained in this

journal supplement. They are listed

below in no particular order of

priority.

1. Need for an integrated approach. Determine how

nutritional and inflammatory

status, independently and

in relationship with each

other, impact brain and

neurodevelopment from

preconception (including

maternal and paternal factors)

through gestation, infancy,

childhood, adolescence, and

beyond and what interventions

can favorably alter these

processes. Children living in

impoverished settings are

at risk for exposure to early

and compounding adversities

that dramatically increase

the potential for altered

neurodevelopment. 2 –6 Nutrition

and inflammation play essential

roles throughout early brain

development, and, in the face

of adversities, children may

experience lasting deficits to

their growth and development.

For example, micronutrient

deficiency, infection, and

inflammation interact in complex

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FIGURE 1Relationships among individual and environmental factors, infl ammation, nutrition, and neurodevelopment.



ways. Micronutrient deficiency

may predispose children to or

protect them from infection or

inflammation, but, conversely,

inflammation and infection

may lead to micronutrient

deficiency. Over time, as a child

is distanced from a specific

insult or experiences ongoing

adversities, environmental and

contextual factors become even

more important. Integrated

interventions that combine

nutrients with opportunities

for responsive caregiving

and early learning have been

recommended, 25 and evidence

suggests that trials that include

both early education and

nutrition are more likely to

result in cognitive benefits than

single intervention trials, 26 but

relatively few integrated trials or

programs have been evaluated

systematically. 27

2. New tools for neurodevelopmental assessment. Develop

tools for the assessment of

neurodevelopment (ie, birth

to adolescence) that are field-

friendly in LRS for diverse

populations. There is a lack

of standardized, validated

neurodevelopmental assessment

tools for children from birth

through adolescence that

are field-friendly in LRS for

diverse populations. Currently

available tools are relatively

coarse behavioral measures

(eg, developmental exams) that

lack sensitivity to underlying

neural mechanisms, cannot be

used early in life given limited

behavioral repertoires, and are

largely developed in western,

high-resource countries. Cutting-

edge tools are needed, including

brain imaging, which can provide

a more direct assessment of

the physical development of

the brain and can be combined

with behavioral measures

for a more comprehensive

assessment. Generally,

neurocognitive assessment tools

have included less emphasis

on executive functions, such

as socioemotional regulation,

impulse control, and the ability

to sustain attention, 28 although

these areas of neurodevelopment

may be particularly affected

by nutritional deficiencies or

inflammatory responses.

3. Standardized norms for neurodevelopment. Establish whether there is

a standardized “norm” by

sex for neurodevelopment

that is applicable across

diverse populations. If

it were determined that

neurodevelopment unfolds in a

universally consistent manner

in girls and boys across cultural,

socioeconomic, and geographic

contexts, this would provide

support for neurodevelopmental

assessment measures developed

in high-resource countries, in

a valid and consistent manner,

being reasonably adapted for

use in LRS. However, if the

ecological and cultural context

or differences in biological

factors overshadow the

more universal dimensions

of child neurodevelopment,

then more time and effort

would be required to develop

local, context-specific

neurodevelopmental measures.

Toward developing standardized

norms for neurodevelopment,

a large-scale longitudinal

study that tracks the

neurodevelopment of “healthy”

children in multiple countries is

recommended.

4. Critical and sensitive periods. Build on recent advances

in neurobiology related to

critical and sensitive periods

to determine whether they can

be rescued later in life. Adverse

environmental exposures

are most deleterious to the

developing brain when they

occur during a sensitive or

critical period of development. 29, 30

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). Although

the young brain is resilient

and demonstrates potential

for recovery, early-life insults,

particularly during sensitive or

critical periods of development,

can result in long-term deficits

and adverse outcomes later

in life. 31 However, studies of

resilience and recent advances

in the neurobiology of sensitive

periods may lead to new

discoveries that enable the

rescue of sensitive periods

through targeted interventions

later in life. 32

5. Mild but diffuse deficits in neurodevelopment. Explore

the functional significance

of mild but diffuse deficits in

neurodevelopment. Although

reliable estimates are not

readily available, the global

burden of mild but diffuse

neurodevelopmental deficits

is likely to be substantial.

Additional research is needed,

including long-term follow-up

studies, to better understand

etiologies and prognoses of mild

deficits in neurodevelopment

toward developing effective

preventive and therapeutic

interventions (eg, behavioral and

family programs, trauma care,

educational initiatives).

6. More precise biomarkers for nutrition and inflammation.


KUTLESIC et al

Identify field-friendly,

standardized, and cost-effective

biomarkers for nutritional,

inflammatory, and other

influencing factors linked to

specific health outcomes across

the life span. There is a need

for the development of low-

cost, point-of-care, accurate

diagnostics for nutrition,

infection, and inflammation

in LRS. A biomarker is a

characteristic that is objectively

measured and evaluated as an

indicator of normal biological

processes, pathogenic processes,

or pharmacologic responses to

a therapeutic intervention. 33

Although biomarkers may have

biological use, their measures

should ideally also be of use

in clinical or programmatic

settings. There is a need for field-

friendly, age-standardized norms

for nutritional and inflammatory

biomarkers. Ideally, nutrient-

driven alterations in brain

function that are measureable

(ie, signature effects that may

vary by nutrient and age of the

subject) should be determined.

Better markers of inflammation,

tissue injury, and host response,

including noninvasive surrogate

markers of central nervous

system (CNS) infection,

inflammation, and injury are

needed.

7. Impact of malnutrition (ie, undernutrition, overnutrition, and micronutrient deficiency) on neurodevelopment. Characterize the magnitude

and duration of the effects

of nutritional status on

neurodevelopmental outcomes.

The vulnerability of a brain

region to a nutrient deficit will

depend on the timing of the

event, based on the region’s

requirement for the nutrient at

that time. 31 This basic principle

exists from conception through

the end of brain development,

but is particularly accentuated

during periods of rapid brain

growth and differentiation.

Poor nutrition and growth (ie,

intrauterine growth restriction,

small for gestational age, and

stunting) are associated with

impaired neurodevelopmental

outcomes. 3, 34 – 37 Moreover,

most of the research linking

nutrition with inflammation

and neurodevelopment

focuses on undernutrition

and overnutrition, including

maternal and childhood

obesity, that have also become

a global concern. Obesity begins

early in life, increases during

childhood and adolescence,

and has been associated

with impaired cognition. 38

Possible mechanisms include

inflammation, oxidative stress,

decreased motor performance

associated with a degraded

musculoskeletal system, and

alterations in brain structure,

leptin/insulin regulation,

cerebrovascular function, and/or

blood-brain barrier function.

8. Infections, inflammation, and neurodevelopment. Elucidate

the role of and mechanisms

through which infectious

diseases and inflammation

impact neurodevelopment.

A recent review of infections that

affect the nervous system noted

that, for most pathogens, reliable

estimates of the incidence of

infection and infection-related

neurodevelopmental impairment

are not currently available. 39 The

burden of neurodevelopmental

impairment from specific

infectious agents and/or the

accompanying inflammatory

response, and how exposure

at a given time point impacts

later neurodevelopment, need

to be explored. For infectious

diseases and a variety of other

early nutritional, inflammatory,

or toxic environmental insults,

duration and severity may be as

important as timing. Infection

may lead to neurodevelopmental

impairment through direct

CNS injury by the infectious

pathogen or through pathways

that may involve inflammation

as 1 component, but may not

be traditionally defined as

inflammation. 40

9. Noninfectious inflammation and neurodevelopment. Describe the role of and

mechanisms through which

noninfectious inflammation

(eg, chronic diseases, exposure

to environmental toxins, and

psychological stress) impacts

neurodevelopment. The evidence

base for the direct impact of

noninfectious inflammation

on neurodevelopment is even

more limited than for infectious

causes of inflammation.

Nonetheless, growing evidence

indicates that a variety of early-

life stresses can contribute

to enduring abnormalities

in brain organization and

structure, as well as in endocrine

regulatory processes, among

other consequences. 41 – 44 These

life stressors contribute to a

physiologic response referred

to as toxic stress by the

National Scientific Council on

the Developing Child, defined

as 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. 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. Additionally,

longitudinal studies have shown

that early malnutrition has

effects on inflammatory status in

adulthood.

10. Environmental enteropathy. Define the pathways by which

environmental enteropathy

leads to neurodevelopmental

impairments and interacts

with the microbiome. Children

in LRS are at higher risk for


caused by fecal–oral

contamination, which results

in the blunting of intestinal

villi and inflammation. 45 This

can lead to chronic intestinal

problems with absorbing

nutrients, which may result in

malnutrition, growth stunting,

and other developmental deficits

in children. 46 Environmental

enteropathy, involving

intestinal inflammation

without overt diarrhea, also

seems to affect the risk of both

malnutrition and impaired child

neurodevelopment. 45 In fact,


may contribute to the failure

of nutritional interventions

and oral vaccines in LRS.

Furthermore, environmental

enteropathy and alterations

in the microbiome interact to

increase microbial translocation

and cause inflammation in

the CNS in animals 47– 49 and

humans, 49, 50 as evidenced by

findings that markers in gut

inflammation are associated

with schizophrenia and other

psychiatric disorders. 51– 53

11. Microbiome. Identify

microbiome profiles

associated with improved

micronutrient bioavailability,

inflammatory status, functional

neurodevelopmental outcomes,

and psychiatric disorders. We

need improved understanding of

the role of the microbiome along

the life span, including prenatal

life, on child neurodevelopment.

Research has shown that

inflammation and malnutrition

can alter the microbiome, and,

conversely, that the microbiome

can affect both nutrition and

systemic inflammation. 54

Changes in the microbiome

have been hypothesized to

potentially influence child

neurodevelopment and behavior

through the “microbiome-

gut–brain axis.” 55 Alterations

in the microbiome are very

likely to occur in environmental

enteropathy and indeed might

be part of the pathogenesis.

Future research studies should

assess how both conditions may

affect child neurodevelopment,

how each condition affects the

other, and how inflammation,

malnutrition, and micronutrient

deficiency contribute to and

interact with the microbiome

and environmental enteropathy.

12. Epigenetic mechanisms and intergenerational effects. Understand

epigenetic mechanisms and

potential intergenerational

effects whereby adverse life

experiences are biologically

embedded to tailor interventions

to specific neural and behavioral

systems. Areas in which there

is interesting preliminary data,

but for which additional studies

are needed, include the role

of genetic factors in terms of

susceptibility to infections as

well as the role of infections,

nutrition, stress, and other

factors in modulating gene

expression through epigenetic

changes in DNA, including the

role of DNA methylation 53 and

modifications of DNA binding

proteins, such as histones. 56, 57

The Barbados Nutrition

Study is elucidating some

intergenerational effects of

infant malnutrition due to

DNA methylation. 56 Epigenetic

changes have been found in

the first and second generation

of study participants and the

imprinted genes are seen in both

generations. The gut microbiome

in pregnancy also presents an

epigenetic pattern that affects

inflammatory trajectories.

Malnutrition, the microbiome,

and inflammation can all lead

to epigenetic changes that can

be transmitted to subsequent

generations.

13. Sleep, immune function, and neurodevelopment. Determine

how sleep deprivation or

altered sleep schedules

(circadian rhythm) affect

immune function, inflammation,

and neurodevelopmental

outcomes. The importance

of the relationship between

healthy sleep duration and

quality and neurodevelopment

is increasingly being recognized

across the life span. 58, 59 Sleep

represents an important

modifiable risk factor that can

impact neurodevelopment

and overall health or

chronic disease progression,

including gene expression. 60

Populations in LRS may be

disproportionately affected

by poor sleep due to various

environmental and cultural

factors, such as noise, hunger,

insect or rodent infestation,

or psychological stress. Poor

sleep parameters may also exert

a role on neurodevelopment

through alterations in nutrient

use, immune function, and

inflammation, particularly

during sensitive or critical

periods of brain development.

A better understanding of these

mechanisms and interactions is

necessary to develop and target

evidence-based interventions.


KUTLESIC et al

14. Resiliency and protective factors. Identify exposures,

influences, and interventions

that contribute to resiliency.

The chronic exposure of millions

of children to early childhood

malnutrition, infections, and

environmental insults creates

an even more urgent need

for studies of resilience and

protective factors in these

settings. This research needs to

include longitudinal studies and

data collection at the individual,

family, and societal levels. The

sex of the child and ethnic or

cultural identity also need to be

considered because they may

modify the benefits attributable

to any protective factor. In

addition, modern genetic,

epigenetic, and neuroimaging

techniques may help us to better

identify unique variability and

characteristics of individuals

displaying greater resilience and

change the concepts of “critical

and sensitive periods” and have

implications for interventions.

Furthermore, because nearly

one-third of all women globally

undergo pregnancy during their

adolescent years, interventions

during this period of life not

only impact the adolescents

themselves, but also have

substantial effects on the well-

being of the next generation.

SUMMARY AND NEXT STEPS

The subsequent articles in this

supplement will additionally explore

and develop the concepts and

themes introduced in this executive

summary from preconception

through adolescence. An introductory

article describes the current

global child health context with an

emphasis on neurodevelopment and

the impact and interrelationships

of nutrition and inflammation.

A second article considers available

assessment methodologies and

tools in these 3 scientific areas. Four

subsequent articles address specific

developmental considerations for

these topics during fetal life, infancy,

childhood, and adolescence. Within

each article, the existing knowledge,

evidence gaps, and research

priorities are explored.

ACKNOWLEDGMENTS

The NICHD Global Health Meeting

held on February 11th and 12th,

2015 was organized by the Office

of Global Health and sponsored

by the Office of the Director and

several branches at NICHD, which

included both financial support and

valuable scientific input. The Office

of Dietary Supplements in the NIH

Office of the Director also made a

generous financial contribution and

had a representative at this NICHD

Meeting.

During the second day of the

NICHD Global Health Meeting and

2 subsequent conference calls, 5

working groups (ie, Assessment,

Pregnancy/Fetal Development,

Infancy, Early/Middle Childhood,

and Adolescence) convened to

brainstorm existing research

evidence and knowledge gaps

related to the intersection of child

neurodevelopment, nutrition,

and inflammation in low resource

settings. These working groups

were chaired by the panelists at the

NICHD Global Health Meeting, who

subsequently served as the lead

and co-authors of the manuscripts

in this supplement. We would

like to acknowledge the valuable

contribution of these working

group members, who are listed in

alphabetical order: Jere Behrman

(University of Pennsylvania), Sharon

Bergquist (BMGF), Robert Black

(Johns Hopkins Bloomberg School

of Public Health), Kimber Bogard

(National Academy of Medicine),

Pim Brouwers (NIMH/NIH),

Germaine Buck Louis (NICHD/NIH),

Rebecca Clark (NICHD/NIH), Cindy

Davis (ODS/NIH), Tarun Dua (WHO),

Linda Duffy (NCCIH/NIH), Eleanore

Edson (BMGF), Henry Falk (CDC),

Sarah Glavin (NICHD/NIH), Devasena

Gnanashanmugam (NIAID/NIH),

Lynne Haverkos (NICHD/NIH), Yiwu

He (BMGF), Van Hubbard (NIDDK/

NIH), Terrie Inder (Brigham and

Women’s Hospital), Elizabeth Jordan-

Bell (USAID), Alice Kau (NICHD/NIH),

Patrick Kelley (National Academies of

Sciences, Engineering, and Medicine),

Marion Koso-Thomas (NICHD/NIH),

Danuta Krotoski (NICHD/NIH), Ty

Lawson (OD/NIH), Anne ML Lee

(Brigham and Women’s Hospital,

Harvard Medical School), Sonia

Lee (NICHD/NIH), Daniel Marks

(BMGF), Mireille Seneclauze Mclean

(Sackler Institute for Nutrition

Science at the New York Academy

of Sciences), Dominique McMahon

(Grand Challenges Canada), Kathleen

Michels (FIC/NIH), Jeffrey Murray

(BMGF), Melissa Parisi (NICHD/NIH),

Cristina Rabadan-Diehl (HHS), Tonse

Raju (NICHD/NIH), Zeba Rasmussen

(FIC/NIH), Dianne Rausch (NIMH/

NIH), Rebecca Scharf (University of

Virginia Children’s Hospital), Meera

Shekar (World Bank), George Siberry

(NICHD/NIH), Caroline Signore

(NICHD/NIH), Donald Silberberg

(University of Pennsylvania Medical

Center), Rachel Sturke (FIC/NIH),

David Weinberg (NICHD/NIH), Linda

Wright (NICHD/NIH), Edwina Yeung

(NICHD/NIH).

We thank Ty Lawson and Rosalina

Bray at NICHD/NIH for their

assistance with meeting preparations

for the February 2015 NICHD Global

Health Meeting; Annie E. Berens at

the Harvard Medical School for her

development of the "Early Adversity

Causal Model" included in the article,

"Neurodevelopment, Nutrition, and

Inflammation: The Evolving Global

Child Health Landscape"; and Arielle

G. Rabinowitz at the Yale School of

Medicine and Rebecca S. Hock at

the Massachusetts General Hospital

and Harvard Medical School for



their assistance with manuscript

preparation.

ABBREVIATIONS

BMGF: Bill and Melinda Gates

Foundation

CDC: United States Centers for

Disease Control and

Prevention

CNS: central nervous system

FIC: John E. Fogarty

International Center

HHS: United States Department

of Health and Human

Services

LRS: low-resource setting

NAS: National Academy of

Sciences

NICHD: Eunice Kennedy Shriver

National Institute of

Child Health and Human

Development

NIH: United States National

Institutes of Health

SDGs: United Nations Sustainable

Development Goals

UNICEF: United Nations

Children's Fund

USAID: United States Agency for

International

Development

WHO: World Health Organization

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DOI: 10.1542/peds.2016-2828C2017;139;S1Pediatrics

J. RaitenVesna Kutlesic, Margaret Brewinski Isaacs, Lisa S. Freund, Rohan Hazra and Daniel

Neurodevelopment, Nutrition, and Inflammation in Low-Resource SettingsExecutive Summary: Research Gaps at the Intersection of Pediatric

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Neurodevelopment, Nutrition, and Inflammation in Low-Resource SettingsExecutive Summary: Research Gaps at the Intersection of Pediatric

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