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Neurodevelopment: The Impact of

Nutrition and Inflammation During


Infancy in Low-Resource Settings
Nancy F. Krebs, MD, MS,a Betsy Lozoff, MD,b,c Michael K. Georgieff, MDd

abstract Infancy and early childhood (ie, birth through age 24 months) represent a period of life with
both exquisite opportunity and vulnerability for neurodevelopment. This is due to rapid
brain development, both anatomic and functional, as well as to high nutrient requirements
during a time of dependence on human milk and complementary foods. Complex interactions
exist among nutrition, social, and physical environments and exposures. The newborn
brain also reflects maternal exposures that occurred as the product of many interacting
forces during gestation. Connections between nutrient use and acute and chronic
inflammation are increasingly recognized, but the evidence base linking both nutrition and
inflammation to neurodevelopment is relatively modest and quite limited for this young
age group specifically. This article provides an overview of key interactions of nutritional
requirements relevant to brain development and function; nutritional vulnerabilities related
to maternal nutritional status and function; and the impact of environmental exposures
and inflammation on nutrient homeostasis and neurodevelopment during this critical
developmental window.

aDepartment of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; bCenter for Human Growth and Development and cDepartment of Pediatrics and Communicable
Diseases, University of Michigan, Ann Arbor, Michigan; and dDivision of Neonatology, University of Minnesota School of Medicine, Minneapolis, Minnesota

Dr Krebs was a panelist at the original Eunice Kennedy Shriver National Institute of Child Health and Human Development 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; Drs Lozoff and Georgieff 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.2016-2828G
Accepted for publication Dec 21, 2016
Address correspondence to Nancy F. Krebs, MD, MS, Department of Pediatrics, University of Colorado School of Medicine, 12700 East 19th Ave, Research Complex 2,
Room 5025, Box C225, Aurora, CO 80045. E-mail: nancy.krebs@ucdenver.edu
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
Estimates of the burden of neurodevelopment is only modest Developmental Progression of
neurodevelopmental impairments and even more limited for this Physical and Anatomic Maturation
in low- and middle-income young age group specifically. This During Infancy and Early Childhood
countries (LMIC) are limited and article in the supplement will The brain is not a homogenous
highly variable, but are generally provide an overview of key aspects organ. Rather, it is composed of
reported to be higher than in high- of interactions that are particularly discrete regions (eg, hippocampus,
resource settings. In all settings, the relevant to the infant and young child striatum, cortex, cerebellum) and
prevalence of mild impairments is during this critical developmental processes (eg, myelination, release
higher than severe disability.1,2 stage. The underlying framework and reuptake of neurotransmitters)
Among several factors identified reflecting these interrelationships that have different developmental
as contributors to developmental and the issues particular to infants trajectories. In the article
disabilities in LMIC, infections and in low-resource settings (LRS) are in this supplement titled,
malnutrition, including micronutrient depicted in Fig 1. Furthermore, "Neurodevelopment, Nutrition,
deficiencies, are particularly emphasis will be placed on these and Inflammation: The Evolving
important and potentially
sectors as they exist in, and are Global Child Health Landscape,"
modifiable.3
impacted by, environments in LRS. Fig 1 demonstrates when these
Infancy and early childhood (ie, birth To advance the field, knowledge trajectories begin, peak, and end. The
through age 24 months) represent gaps and research priorities will be vulnerability of any of these regions
a period of life with both exquisite highlighted. to a nutrient deficit will depend on
opportunity and vulnerability for the timing of the event, based on the
neurodevelopment. Not only are region’s requirement for the nutrient
many aspects of brain development at that time. This basic principle
KEY NEURODEVELOPMENTAL exists from conception through
undergoing rapid anatomic and
CONSIDERATIONS DURING INFANCY the end of brain development, but
functional expansion during this
postnatal component of the “1000 is particularly accentuated during
days critical window,” but nutrient The concept of neurodevelopment periods of rapid brain growth and
requirements are also high due for the infant and young child differentiation. One such period is
to rapid physical growth and includes multiple behavioral infancy and young childhood.
maturation. The complex interactions domains: motor, mental, sensory,
and socioemotional. It is important The postnatal periods of infancy and
that exist among nutritional status
to understand that these behaviors early childhood are characterized
(deficits and surfeits) as well as the
are the expression of the brain’s by rapid differentiation of brain
social and physical environments
activity. Thus, understanding brain regions, such as the visual, auditory,
and exposures they entail are
and motor cortices; the limbic
particularly potent during this period development and the roles that
system, including the hippocampus;
of rapid change. Furthermore, the nutrients and inflammation play
and the cerebellum. These regions
interactions are bidirectional, such in shaping its development and
mediate fundamental behaviors,
that the developing infant not only function are critical for effective
such as seeing, hearing, movement,
responds to his/her environment child health practice and policy
declarative memory, and mixed
but also, in ideal circumstances, recommendations. The young brain
motor/cognitive functions,
elicits responses from adult care in particular is highly susceptible to
respectively. Just as importantly,
providers that additionally stimulate early life experiences, both positive the integrity of these fundamental
more inputs. The newborn brain and negative, and thus attention structures is key for the construction
also reflects maternal exposures that should be paid to the elements that of connections to later maturing
occurred as the product of many support brain development. Although structures (eg, the frontal cortex) that
interacting forces during gestation. the young brain is highly plastic and support more complex processing
The connections between nutrient demonstrates potential for recovery behavior, such as working memory
use (absorption, excretion, and from early life insults, the bulk of and executive function. Indeed,
retention) and acute and chronic research evidence suggests that its although the frontal cortex begins
inflammation and stress are vulnerability outweighs its plasticity.5 to show differentiation as early as
increasingly recognized.4 Recent Thus, support of normal development infancy, its developmental trajectory
reviews have addressed selected (eg, through proper nutrition) is far is more protracted through young
aspects of this sensitive period, more efficient than trying to restore a adulthood and thus is vulnerable to
but the evidence base linking both neurodevelopmental trajectory after nutritional insults both in infancy
nutrition and inflammation to a period of deprivation. and later in childhood. Examples

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PEDIATRICS Volume 139, Number s1, April 2017 S51
FIGURE 1
Relationships among individual and environmental risk factors, inflammation, nutrition, and neurodevelopment for infants in LRS. TB, tuberculosis.

of brainwide processes that are cascades, such as the mammalian particularly critical for infants in LRS
rapidly progressing in infants and target of rapamycin system, dictate where the risk of exposures to enteric
toddlers include myelination, which rates of protein synthesis and actin pathogens from contaminated human
proceeds at a brisk pace from 32 polymerization in neurons, which milk substitutes, fluids and foods
weeks’ gestation through 2 to 3 years in turn are related to dendritic is very high. The recommendation
of age; synaptogenesis, which begins complexity and neuronal functional in 2001 from the World Health
prenatally and continues throughout capacity.7,8 Thus, deficiencies of Organization for exclusive
childhood; and the dopamine these nutrients have more profound breastfeeding for the first 6 months
neurotransmitter system. negative effects on the brain than of life9 emphasized the protective
other nutrients. effects against gastrointestinal
Rapid development of the brain is a
disease. Importantly, however,
highly metabolically taxing process.
the statement acknowledged that
The young brain accounts for 60%
THE IMPACT OF NUTRITION ON the evidence base was insufficient
of the body’s energy consumption,6
NEURODEVELOPMENT DURING INFANCY to exclude the potential for
a figure that contrasts with the
micronutrient deficiencies and
adult value of ∼20%. Nutrients that Human Milk and Breastfeeding insufficient intake, especially for
support this cellular metabolic rate (0–6 months) infants born with low birth weight
include glucose, protein (especially
and/or to undernourished mothers.
branched-chain amino acids), At the very time when brain
oxygen, iron (for cytochromes), development is rapidly progressing, Recent research has raised caution
zinc, selenium, and iodine (through the young infant is uniquely about the robustness of human
regulation of the thyroid). Their dependent on a single food. Exclusive milk micronutrient composition,
integration through signaling breastfeeding for young infants is particularly for those nutrients in

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S52 KREBS et al
human milk that are responsive populations, and generally meet acids could be considered exceptions.
to maternal dietary intake and the term infant’s needs for the first Iodine is often added as a fortificant
status: vitamins B6 and B12, choline, several months of postnatal life. The to salt, rather than consumed within
iodine, and selenium,10 all of which adequacy of the zinc from human a specific food.14 Due to both limited
are directly involved in brain milk alone for low birth weight and availability (eg cost constraints) and
development and function, namely, premature infants has not been to tradition, animal flesh foods are
neurogenesis, differentiation, systematically addressed in LRS, often not offered as complementary
migration, myelination, and but some intervention trials suggest foods to young children, and
neurotransmitter-related processes.5 a benefit of zinc supplements.13 even more infrequently to infants
Maternal vitamin B12 depletion, Folate concentrations in human between 6 and 12 months of age.15,16
whether due to dietary inadequacy milk, unlike the other B vitamins, Primary reliance on unfortified,
or to impaired absorption, has been are maintained independently of plant-based staple foods during
associated with the development of maternal folate status. Infants in the complementary feeding period,
vitamin B12 deficiency in exclusively both high- and low-resource settings even with continued breastfeeding,
breastfed infants. Neurologic who have been exclusively breastfed often results in inadequate intake
symptoms of deficiency appeared for ∼6 months have been observed of several critical micronutrients.16
midway through the first year of to have normal circulating folate Additionally, lower bioavailability of
life and included cerebral atrophy, concentrations whether mothers some micronutrients from primarily
loss of developmental milestones, were well-nourished or had marginal plant sources (except for some
and behavioral and developmental nutritional status.10 The demand beans) may additionally compromise
delays. Notably, the deficits were for all 3 of these nutrients for the the adequacy of the intake of a
reversible with supplementation in undernourished lactating mother given micronutrient. Undoubtedly,
only about half of the cases.11 Low is met by her own tissues, and she suboptimal complementary feeding
iodine concentrations in human milk may become depleted if her dietary quality and quantity contribute to
have also been observed in regions intake is inadequate to support poor linear growth, even though
with a high prevalence of goiter, and the amounts secreted in milk. In total energy intake may be adequate.
the prevalence of cretinism has been such circumstances, maternal The combination, along with the
reported in 5% to 15% of breastfed supplementation benefits the mother impact of prenatal factors and
infants in such regions.12 rather than the infant directly. The austere environments associated
impact (direct or indirect) on infant with poor hygiene and chronic
For folate, iron, and zinc, 3 growth and development through immune stimulation, results in a high
micronutrients that are critical to improvement in maternal nutritional prevalence of stunting, with wasting
brain development and function,5 status during the demanding process being less common.17,18 Many of
breast milk concentrations are of lactation, especially during the the same factors that contribute to
relatively unaffected by maternal early postpartum months, has stunting are also likely to impact
intake or status. In the case of received relatively little investigation neurodevelopment during the period
iron concentrations, human milk and represents an important of complementary feeding, although
is uniformly low, and the young research gap. trials to specifically isolate and
infant depends primarily on non- quantify the impact of each factor are
dietary factors, such as the use of Complementary Feeding Period lacking.3
stores accrued prenatally, delayed (∼6–24 months)
cord clamping, and gradual use of By ∼6 months postpartum, exclusive Feeding Context and Environment
iron from the erythron over the breastfeeding is no longer adequate
early postnatal months. Current to meet micronutrient needs, and In addition to the quantity of energy
estimates of iron requirements of the quality of complementary foods and nutrient intakes, the quality of
young breastfed infants may not is critical for the young child’s the feeding process and caregiver
pertain to LMIC, where many infants optimal growth and development. responsiveness are also critical
may be born with a low endowment This represents another period of for optimal infant and young child
and yet, in an increasing number great vulnerability. Nearly all of the development (Fig 1). However,
of settings, are doubling or tripling micronutrients highlighted above as interventions that have investigated
in birth weight more rapidly than being critical for brain development the impact of improving the quality of
ever before. In the case of zinc, the are found primarily, or in some cases the complementary feeding process
concentration in early milk and exclusively, in animal-source foods, specifically on neurodevelopment are
thus daily transfer to the infant especially flesh foods. Iodine and limited in LRS. One study in Malawi
are quite high, are similar across long-chain polyunsaturated fatty that employed lipid-based nutrient

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PEDIATRICS Volume 139, Number s1, April 2017 S53
as can environmental influences.
Such effects would be expected with
other common nutrient deficits
in infancy and early childhood,
particularly involving those nutrients
that affect brain chemistry, anatomy,
and metabolism.5
FIGURE 2
Iron deficiency and brain development, illustrating connections among iron-dependent changes Initial studies linking fetal and
in brain architecture during development, with examples of altered gene and protein profiles that
may regulate these CNS processes. (Reprinted with permission from Lozoff B, Georgieff MK. Iron
neonatal iron deficiency involved
deficiency and brain development. Semin Pediatr Neurol. 2006;13(3):159.) neonates with other risk factors for
compromised development, such as
supplements or a micronutrient- Iron as an Example of prematurity, maternal diabetes, or
fortified corn–soy flour reported no Nutrient Deficits and Impaired intrauterine growth restriction.24
difference in developmental scores in Neurodevelopment The handful of studies involving
18-month-old children after a year- term infants of uncomplicated
This section concludes with an pregnancies suggest short- and
long intervention, but length-for-age
additional discussion of iron and long-term effects.25–29 The different
z score gain and maternal education
neurodevelopment, because this neurodevelopmental impacts of
were both significant predictors
micronutrient has the richest fetal–neonatal versus postnatal
of developmental outcomes,
evidence base to illustrate several iron deficiency in humans are
supporting the interconnectedness
broadly applicable general concepts: unknown, but the time course of
of child development, nutritional
powerful interconnections in brain brain development suggests there
intake, growth status, and maternal
and behavior development; roles would be differential effects. That
factors.19 In a clinical trial studying
of timing, duration, and severity is, outcomes would be worse when
Indian toddlers, improved
of deficiency; and cooccurrence of a nutrient deficiency starts earlier,
complementary feeding alone did
nutritional deficiencies with other lasts longer, or is more severe. The
not affect development, but guidance
disadvantages. Iron deficiency sole study of adult outcomes involved
around complementary feeding
is not only the most prevalent iron deficiency that was probably
practices in addition to psychosocial
micronutrient deficiency in this age chronic during infancy, because iron
stimulation had a significant
group, but its eradication has been deficiency anemia was detected
positive effect on the toddlers’
challenging and is, as yet, incomplete. (and treated) at 12 to 23 months of
neurodevelopment.20 These findings
age in a sample of infants in Costa
support the critical importance of Iron is required for many central
Rica. There were poorer functional
maternal education for fostering nervous system (CNS) processes
outcomes at 25 years of age, despite
enhanced child psychosocial that are rapidly maturing in infancy
correction of iron deficiency anemia
stimulation, improved feeding and early childhood. Thus, both
in infancy. Specifically, previously
practices, and improved nutritional diffuse and subtle effects would be
iron-deficient individuals were less
status on child development, with expected with iron deficiency. The
likely to complete secondary school,
or without a substantial impact conceptual framework in Fig 223
to have pursued additional training,
on linear growth.21 In addition to emphasizes the interconnectedness
or to have married.30
the physiologic impact of maternal of iron-dependent changes in brain
undernutrition on the mother’s architecture and physiologic “wiring” Human studies have also turned
health and that of her offspring, during development (myelin/ to randomized controlled
nutritional deficiencies have dendrites, neurotransmitters, trials (RCTs) of prophylactic
potential adverse effects on maternal and neurometabolism in specific iron supplementation (rather
cognition and mental status, which brain regions) and includes altered than treatment) to strengthen
in turn exacerbate the risk for gene and protein profiles that may causal inferences. The effects
low infant stimulation and limited regulate these CNS processes. For on neurodevelopment are less
maternal–child responsiveness. behavioral development, changes in consistent or pronounced in such
Potential interactions between sensory, motor, cognitive, language, trials versus in studies that compare
maternal stress and poor nutrition and socioemotional functioning neurodevelopment in infants with
have also recently been reviewed, related to iron deficiency are also or without iron deficiency. In fact,
but the relative contributions of each interconnected. As noted above and some meta-analyses conclude
factor have not yet been elucidated indicated in the Fig 2, brain and that there are no effects of iron
by rigorous field studies.22 behavior effects can be bidirectional, supplementation,31,32 in contrast

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S54 KREBS et al
TABLE 1 Recommendations for Research Initiatives To Address Knowledge Gaps
Problem or Question Studies Needed
1. Gaps in knowledge related to nutrition and neurodevelopment/brain function
during infancy
What are the critical interactions of nutrient deficiencies and inflammation/ Testing in animal models brain and behavioral effects of nutrient deficiencies,
infection on brain development and neurodevelopment? What is the inflammation/infection, and their interactions.
impact of timing of such insults on outcomes?
How can micronutrients critical to the developing brain reach the relevant Investigations of novel micronutrient delivery systems on neural systems.
brain regions more effectively?
To what extent does maternal malnutrition impact human milk composition Characterize the maternal sensitive micronutrient profile in human milk in
and infant brain development? vulnerable populations.
Conduct interventions in pregnant and lactating women to mitigate the risk of
human milk –transmitted deficiencies in young infants in vulnerable settings.
2. Gaps in knowledge related to inflammation, infection, and neurodevelopment/
brain function during infancy
Need to better understand the roles and interaction of the microbiome, Develop strategies to mitigate gut inflammation and dysbiosis.
micronutrient availability, inflammation, and neurodevelopment. Identify microbiota profiles associated with improved micronutrient
bioavailability and functional neurodevelopmental outcomes.
3. Gaps in knowledge related to interactions of nutrition, inflammation,
neurodevelopment, and other influencing factors during infancy
Current assessment tools are not sufficiently sensitive to detect subtle Develop field-friendly, brain-based measures that can, especially in LRS,
deficits in neurodevelopment in infants and young children. meaningfully assess multiple domains in the infant and young child and yield
predictive value for later function and benefit of early intervention.
What is the functional significance of diffuse but mild deficits in Conduct long-term follow-up studies to refine prognostic understanding of early
neurodevelopment? deficits.
What is the balance between environmental exposures and genetic Investigate effects of potentially toxic environmental exposures and their
vulnerability and protection against micronutrient deficiencies? interactions with micronutrient deficiencies on neurodevelopment.
4. Gaps in knowledge related to evidence-based interventions for optimal
neurodevelopmental outcomes during infancy
Multiple insults are likely to adversely impact neurodevelopment. Conduct studies designed and powered to assess for multiple insults (eg,
micronutrient deficiency, neurotoxins, stress, inflammation).
Develop “bundled” interventions to evaluate impact on global
neurodevelopment.
What are the epigenetic effects of interventions? Incorporate evaluation of epigenetic modifications (eg, methylation) in
intervention studies in mothers, infants, and young children.

to several studies showing poorer supplementation on fetal–neonatal and noninfectious causes, on


outcomes in iron-deficient iron status. A recent RCT in China neurodevelopment is even more
infants.24,33–36 Additional showed marked improvements limited than that for nutrient use.
considerations help us understand in maternal iron status with The recent outbreak of Zika virus
this apparent paradox. RCTs in supplemental iron, but many infection has drawn attention to
populations where iron deficiency women were still iron deficient the striking effects of infection
is uncommon may require huge at or near term, and there was no occurring early in gestation, notably
sample sizes to detect statistically effect on cord blood measures of manifest as severe microcephaly. In
and clinically meaningful effects. fetal–neonatal iron status.37 In this a prospective study, 29% of women
RCTs in populations where iron same trial, iron supplementation found to have become infected at
deficiency is widespread may not during infancy was associated with various time points throughout
provide sufficient iron if prophylactic significantly improved motor scores pregnancy had adverse effects
doses are used, and supplementation compared with placebo or with that extended beyond the most
may begin after neurodevelopment supplementation during pregnancy severe brain insults to also include
has already been compromised alone.38 placental insufficiency, intrauterine
by lack of iron for many infants. growth restriction, and milder
Consequently, improved analytic central nervous system injury.39
methods and study designs are Thus, the full extent of infection
THE IMPACT OF INFLAMMATION ON
needed to investigate these during gestation on offspring
NEURODEVELOPMENT DURING INFANCY
intersecting scientific areas. neurodevelopmental outcomes
The evidence base for the is unknown, but early findings
Few studies to date have considered direct impact of inflammation, suggest that this may represent
the impact of maternal iron resulting from both infectious an important additional burden

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PEDIATRICS Volume 139, Number s1, April 2017 S55
for LRS. The acute and long-term stunting observed in LMIC.43 IMPLICATIONS FOR RESEARCH,
consequences of new Zika virus Although stunting is undoubtedly PROGRAM, AND POLICY DEVELOPMENT
infection in infancy are unknown, multifactorial and includes chronic The period from birth through
but pose a theoretical risk for malnutrition, environmental enteric 24 months of age represents a
neurodevelopmental sequelae. dysfunction, a chronic inflammatory strongly compelling illustration
The connection between stunting, condition of the intestinal tract of the interactions among
which is mediated in part by that starts in early infancy,44,45 maternal and infant nutritional
chronic inflammation, and impaired is increasingly recognized to status, environmental exposures,
child development has clearly impact nutrient use, growth, and inflammation, and the rapidly
been documented, particularly in neurodevelopment. For example, developing brain. A list of knowledge
older children. Such associations the central role of hepcidin in the gaps and research priorities is
include less exploratory behavior, regulation of iron homeostasis provided in Table 1. Although this
poorer cognitive achievement, powerfully illustrates a biological complexity mandates multisectoral
more anxiety, and lower school balance between the need for interventions to maximize benefits,
performance.18 A recent large adequate intake of an essential the evidence base is more than
prospective observational study nutrient and the countering effect adequate to prioritize selected
in Bangladesh directly assessed of immune stimulation to inhibit nutrition-specific and nutrition-
the association of biomarkers of iron absorption and use. Although sensitive elements, especially
inflammation at 6 months of age a similar “master regulator” in the most socioeconomically
on motor and cognitive function analogous to hepcidin has not been deprived settings.21,49 Despite the
at 12 and 24 months of age. In this identified for other micronutrients, numerous vulnerabilities for infants
cohort, fever and inflammation data are emerging to suggest and young children highlighted
were strongly associated with adverse effects of environmental in this paper, highest yields for
significantly lower scores on enteric dysfunction and improved neurodevelopment seem
language, cognitive, and motor inflammation on zinc absorption likely to be realized by bundled
tests.40 In the same cohort, high and homeostasis.13,46,47 Another interventions that focus on improved
rates of anemia and zinc deficiency mechanism by which disrupted gut maternal nutritional status through
were also observed, with rates health may impact development the entire reproductive cycle,
being highest in the first year is through alterations in the including lactation; promoting and
of life when processes of brain gut microbiota which, through supporting exclusive breastfeeding
maturation are particularly interaction with the developing for nutritional benefits and for
active.41 New insights regarding innate immune system, can drive limiting infant contaminant
the links between inflammation elevations in proinflammatory and exposures; enhancing the quality of
and neurodevelopment will antiinflammatory cytokines and complementary foods as well as the
undoubtedly emerge in coming influence brain function.48 Such feeding process; enabling maternal
years, as prospective data linking early and enduring inflammatory education to improve parenting and
growth, feeding, and nutrient- stimuli have also been linked infant stimulation (among numerous
intake patterns, gut function and to a risk of systemic metabolic other benefits); and improving
the microbiota, inflammation, and disease associated with later hygiene and sanitation to reduce
developmental testing from other noncommunicable diseases, the drivers of high-inflammatory
high-risk populations become particularly in settings where burdens. As multidimensional
available.41,42 access to more abundant caloric programs aiming to broadly improve
intake is emerging. In recent infant and young child feeding
years, this constellation has been are developed, rigorous process
THE INTERACTION OF NUTRITION, termed the “stunting syndrome,”18 evaluation should be a cornerstone
INFLAMMATION, NEURODEVELOPMENT, reflecting the multifactorial to enable identification of the key
AND OTHER INFLUENCING FACTORS and self-perpetuating nature of effective components. Examples of
DURING INFANCY the condition. Such recognition program impact evaluation have
now underpins consideration recently been published.50,51 Thus,
The pervasive and substantial of effective interventions that beyond traditional research trials to
exposures to environments with encompass approaches well beyond examine biological outcomes, such
contaminated water and to poor nutrient intakes alone and that dissemination and implementation
hygiene are increasingly recognized attempt to mitigate other negative studies are critical to move from
to contribute to the early postnatal environmental factors and host identification of best practices to
linear growth faltering and exposures.4,49 best programs and policies. With

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S56 KREBS et al
progress in each of these domains, 9. World Health Organization. The optimal year of complementary feeding with
the potential benefits in human duration of exclusive breastfeeding: lipid-based nutrient supplements or
capital would be realized for both report of an expert consultation. corn-soy flour. Matern Child Nutr.
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of_exc_bfeeding_report_eng.pdf.
Accessed June 6, 2016 et al. Cluster-randomized trial on
complementary and responsive
ABBREVIATIONS 10. Allen LH. B vitamins in breast milk: feeding education to caregivers
relative importance of maternal found improved dietary intake,
CNS: central nervous system status and intake, and effects on growth and development among rural
LMIC: low- and middle-income infant status and function. Adv Nutr. Indian toddlers. Matern Child Nutr.
countries 2012;3(3):362–369 2013;9(1):99–117
LRS: low-resource setting 11. Dror DK, Allen LH. Effect of vitamin
RCT: randomized controlled trial 21. Bhutta ZA, Das JK, Rizvi A, et al;
B12 deficiency on neurodevelopment
Lancet Nutrition Interventions
in infants: current knowledge and
Review Group; Maternal and Child
possible mechanisms. Nutr Rev.
Nutrition Study Group. Evidence-based
2008;66(5):250–255
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Lancet. 2013;382(9890):427–451 gestational age infants. J Pediatr.
perspective. Am J Phys Anthropol.
1998;(suppl 27):177–209 18. Prendergast AJ, Humphrey JH. The 2013;163(5):1267–1271
7. Wullschleger S, Loewith R, Hall MN. TOR stunting syndrome in developing 28. Geng F, Mai X, Zhan J, et al. Impact
signaling in growth and metabolism. countries. Paediatr Int Child Health. of fetal-neonatal iron deficiency on
Cell. 2006;124(3):471–484 2014;34(4):250–265 recognition memory at 2 months of
age. J Pediatr. 2015;167(6):1226–1232
8. Fretham SJ, Carlson ES, Georgieff 19. Phuka JC, Gladstone M, Maleta K, et al.
MK. The role of iron in learning and Developmental outcomes among 29. Christian P, Murray-Kolb LE, Khatry
memory. Adv Nutr. 2011;2(2):112–121 18-month-old Malawians after a SK, et al. Prenatal micronutrient

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supplementation and intellectual maternal anemia, iron deficiency, chronic inflammation in Zimbabwean
and motor function in early school- and iron deficiency anemia in a infants. PLoS One. 2014;9(2):e86928
aged children in Nepal. JAMA. randomized clinical trial in rural 45. Kosek M, Haque R, Lima A, et al; MAL-ED
2010;304(24):2716–2723 china, but iron deficiency remains network. Fecal markers of intestinal
30. Lozoff B, Smith JB, Kaciroti N, Clark widespread in mothers and neonates. inflammation and permeability
KM, Guevara S, Jimenez E. Functional J Nutr. 2015;145(8):1916–1923 associated with the subsequent
significance of early-life iron 38. Angulo-Barroso RM, Li M, Santos acquisition of linear growth deficits
deficiency: outcomes at 25 years. DC, et al. Iron supplementation in in infants. Am J Trop Med Hyg.
J Pediatr. 2013;163(5):1260–1266 pregnancy or infancy and motor 2013;88(2):390–396
31. McDonagh MS, Blazina I, Dana T, development: a randomized controlled 46. Esamai F, Liechty E, Ikemeri J, et al.
Cantor A, Bougatsos C. Screening trial. Pediatrics. 2016;137(4): Zinc absorption from micronutrient
and routine supplementation for iron e20153547 powder is low but is not affected by
deficiency anemia: a systematic review. 39. Brasil P, Pereira JP Jr, Moreira ME, iron in Kenyan infants. Nutrients.
Pediatrics. 2015;135(4):723–733 et al. Zika virus infection in pregnant 2014;6(12):5636–5651
32. Pasricha SR, Hayes E, Kalumba women in Rio de Janeiro. N Engl J Med. 47. Manary MJ, Abrams SA, Griffin IJ,
K, Biggs BA. Effect of daily iron 2016;375(24):2321–2334 et al. Perturbed zinc homeostasis
supplementation on health in children 40. Jiang NM, Tofail F, Moonah SN, et al. in rural 3-5-y-old Malawian children
aged 4-23 months: a systematic review Febrile illness and pro-inflammatory is associated with abnormalities in
and meta-analysis of randomised cytokines are associated with lower intestinal permeability attributed to
controlled trials. Lancet Glob Health. neurodevelopmental scores in tropical enteropathy. Pediatr Res.
2013;1(2):e77–e86 Bangladeshi infants living in poverty. 2010;67(6):671–675
33. Berglund SK, Westrup B, Hägglöf B, BMC Pediatr. 2014;14:50 48. Cryan JF, Dinan TG. Mind-altering
Hernell O, Domellöf M. Effects of iron 41. Lang D; MAL-ED Network Investigators. microorganisms: the impact of the gut
supplementation of LBW infants on Opportunities to assess factors microbiota on brain and behaviour. Nat
cognition and behavior at 3 years. contributing to the development of the Rev Neurosci. 2012;13(10):701–712
Pediatrics. 2013;131(1):47–55 intestinal microbiota in infants living 49. Ahmed T, Auble D, Berkley JA, et al. An
34. Shafir T, Angulo-Barroso R, Jing Y, in developing countries. Microb Ecol evolving perspective about the origins
Angelilli ML, Jacobson SW, Lozoff Health Dis. 2015;26:28316 of childhood undernutrition and
B. Iron deficiency and infant motor 42. Arnold BF, Null C, Luby SP, et al. nutritional interventions that includes
development. Early Hum Dev. Cluster-randomised controlled trials the gut microbiome. Ann N Y Acad Sci.
2008;84(7):479–485 of individual and combined water, 2014;1332(1):22–38
35. Lozoff B, Clark KM, Jing Y, Armony- sanitation, hygiene and nutritional 50. Menon P, Rawat R, Ruel M. Bringing
Sivan R, Angelilli ML, Jacobson SW. interventions in rural Bangladesh rigor to evaluations of large-scale
Dose-response relationships between and Kenya: the WASH Benefits study programs to improve infant and
iron deficiency with or without anemia design and rationale. BMJ Open. young child feeding and nutrition:
and infant social-emotional behavior. 2013;3(8):e003476 the evaluation designs for the Alive
J Pediatr. 2008;152(5):696–702, 31–33 43. Victora CG, de Onis M, Hallal PC, & Thrive initiative. Food Nutr Bull.
36. Siddappa AM, Georgieff MK, Wewerka Blössner M, Shrimpton R. Worldwide 2013;34(3 suppl):S195–S211
S, Worwa C, Nelson CA, Deregnier timing of growth faltering: revisiting 51. Rawat R, Nguyen PH, Ali D, et al.
RA. Iron deficiency alters auditory implications for interventions. Learning how programs achieve
recognition memory in newborn Pediatrics. 2010;125(3). Available at: their impact: embedding theory-
infants of diabetic mothers. Pediatr www.pediatrics.org/cgi/content/full/ driven process evaluation and other
Res. 2004;55(6):1034–1041 125/3/e473 program learning mechanisms in alive
37. Zhao G, Xu G, Zhou M, et al. Prenatal 44. Prendergast AJ, Rukobo S, Chasekwa & thrive. Food Nutr Bull. 2013;34(3
iron supplementation reduces B, et al. Stunting is characterized by suppl):S212–S225

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S58 KREBS et al
Estimates of the burden of neurodevelopmental impairments in low- and middle-income
countries (LMIC) are limited and highly variable, but are generally reported to be higher than in
high-resource settings. In all settings, the prevalence of mild impairments is higher than severe
disability.1,2 Among several factors identified as contributors to developmental disabilities in LMIC,
infections and malnutrition, including micronutrient deficiencies, are particularly important and
potentially modifiable.3
Infancy and early childhood (ie, birth through age 24 months) represent a period of life with
both exquisite opportunity and vulnerability for neurodevelopment. Not only are many aspects
of brain development undergoing rapid anatomic and functional expansion during this postnatal
component of the “1000 days critical window,” but nutrient requirements are also high due to
rapid physical growth and maturation. The complex interactions that exist among nutritional
status (deficits and surfeits) as well as the social and physical environments and exposures they
entail are particularly potent during this period of rapid change. Furthermore, the interactions are
bidirectional, such that the developing infant not only responds to his/her environment but also,
in ideal circumstances, elicits responses from adult care providers that additionally stimulate more
inputs. The newborn brain also reflects maternal exposures that occurred as the product of many
interacting forces during gestation.
The connections between nutrient use (absorption, excretion, and retention) and acute and chronic
inflammation and stress are increasingly recognized.4 Recent reviews have addressed selected
aspects of this sensitive period, but the evidence base linking both nutrition and inflammation to
neurodevelopment is only modest and even more limited for this young age group specifically.
This article in the supplement will provide an overview of key aspects of interactions that are

aDepartment of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; bCenter for Human Growth and Development and cDepartment of Pediatrics and Communicable
Diseases, University of Michigan, Ann Arbor, Michigan; and dDivision of Neonatology, University of Minnesota School of Medicine, Minneapolis, Minnesota

Dr Krebs was a panelist at the original National Institute of Child Health and Human Development 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; Drs Lozoff
and Georgieff was a panelist at the original National Institute of Child Health and Human Development 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.2016-2828G
Accepted for publication Dec 21, 2016
Address correspondence to Nancy F. Krebs, MD, MS, Department of Pediatrics, University of Colorado School of Medicine, 12700 East 19th Ave, Research Complex 2,
Room 5025, Box C225, Aurora, CO 80045. E-mail: nancy.krebs@ucdenver.edu
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
FIGURE 1
Relationships among individual and environmental risk factors, inflammation, nutrition, and neurodevelopment for infants in LRS. TB, tuberculosis.

particularly relevant to the infant to understand that these behaviors neurodevelopmental trajectory after
and young child during this critical are the expression of the brain’s a period of deprivation.
developmental stage. The underlying activity. Thus, understanding brain
framework reflecting these development and the roles that
Developmental Progression of
interrelationships and the issues nutrients and inflammation play
Physical and Anatomic Maturation
particular to infants in low-resource in shaping its development and During Infancy and Early Childhood
settings (LRS) are depicted in Fig 1. function are critical for effective
Furthermore, emphasis will be placed child health practice and policy
on these sectors as they exist in, and The brain is not a homogenous
recommendations. The young brain
are impacted by, environments in organ. Rather, it is composed of
in particular is highly susceptible to
LRS. To advance the field, knowledge discrete regions (eg, hippocampus,
early life experiences, both positive
gaps and research priorities will be striatum, cortex, cerebellum) and
and negative, and thus attention
highlighted. processes (eg, myelination, release,
should be paid to the elements that
and reuptake of neurotransmitters)
support brain development. Although
that have different developmental
the young brain is highly plastic and
KEY NEURODEVELOPMENTAL trajectories. In the article
demonstrates potential for recovery
CONSIDERATIONS DURING INFANCY in this supplement titled,
from early life insults, the bulk of
"Neurodevelopment, Nutrition,
The concept of neurodevelopment research evidence suggests that its
and Inflammation: The Evolving
for the infant and young child vulnerability outweighs its plasticity.5
Global Child Health Landscape,
includes multiple behavioral Thus, support of normal development
" Fig 1 demonstrates when these
domains: motor, mental, sensory, (eg, through proper nutrition) is far
trajectories begin, peak, and end. The
and socioemotional. It is important more efficient than trying to restore a

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PEDIATRICS Volume 139, number s1, April 2017 S3
vulnerability of any of these regions include glucose, protein (especially development and function, namely,
to a nutrient deficit will depend on branched-chain amino acids), neurogenesis, differentiation,
the timing of the event, based on the oxygen, iron (for cytochromes), migration, myelination, and
region’s requirement for the nutrient zinc, selenium, and iodine (through neurotransmitter-related processes.5
at that time. This basic principle regulation of the thyroid). Their Maternal vitamin B12 depletion,
exists from conception through integration through signaling whether due to dietary inadequacy
the end of brain development, but cascades, such as the mammalian or to impaired absorption, has been
is particularly accentuated during target of rapamycin system, dictate associated with the development of
periods of rapid brain growth and rates of protein synthesis and actin vitamin B12 deficiency in exclusively
differentiation. One such period is polymerization in neurons, which breastfed infants. Neurologic
infancy and young childhood. in turn are related to dendritic symptoms of deficiency appeared
complexity and neuronal functional midway through the first year of
The postnatal periods of infancy and
capacity.7,8 Thus, deficiencies of life and included cerebral atrophy,
early childhood are characterized
these nutrients have more profound loss of developmental milestones,
by rapid differentiation of brain
negative effects on the brain than and behavioral and developmental
regions, such as the visual, auditory,
other nutrients. delays. Notably, the deficits were
and motor cortices; the limbic
reversible with supplementation in
system, including the hippocampus;
only about half of the cases.11 Low
and the cerebellum. These regions THE IMPACT OF NUTRITION ON iodine concentrations in human milk
mediate fundamental behaviors, NEURODEVELOPMENT DURING INFANCY have also been observed in regions
such as seeing, hearing, movement,
Human Milk and Breastfeeding (0–6 with a high prevalence of goiter, and
declarative memory, and mixed
months) the prevalence of cretinism has been
motor/cognitive functions,
reported in 5% to 15% of breastfed
respectively. Just as importantly, At the very time when brain infants in such regions.12
the integrity of these fundamental development is rapidly progressing,
structures is key for the construction the young infant is uniquely
of connections to later maturing For folate, iron, and zinc, 3
dependent on a single food. Exclusive micronutrients that are critical to
structures (eg, the frontal cortex) that breastfeeding for young infants is
support more complex processing brain development and function,
particularly critical for infants in LRS 5 breast milk concentrations are
behavior, such as working memory where the risk of exposures to enteric
and executive function. Indeed, relatively unaffected by maternal
pathogens from contaminated human intake or status. In the case of
although the frontal cortex begins milk substitutes, fluids and foods
to show differentiation as early as iron concentrations, human milk
is very high. The recommendation is uniformly low, and the young
infancy, its developmental trajectory in 2001 from the World Health
is more protracted through young infant depends primarily on non-
Organization for exclusive dietary factors, such as the use of
adulthood and thus is vulnerable to breastfeeding for the first 6 months
nutritional insults both in infancy stores accrued prenatally, delayed
of life9 emphasized the protective cord clamping, and gradual use of
and later in childhood. Examples effects against gastrointestinal
of brainwide processes that are iron from the erythron over the
disease. Importantly, however, early postnatal months. Current
rapidly progressing in infants and the statement acknowledged that
toddlers include myelination, which estimates of iron requirements of
the evidence base was insufficient young breastfed infants may not
proceeds at a brisk pace from 32 to exclude the potential for
weeks’ gestation through 2 to 3 years pertain to LMIC, where many infants
micronutrient deficiencies and may be born with a low endowment
of age; synaptogenesis, which begins insufficient intake, especially for
prenatally and continues throughout and yet, in an increasing number
infants born with low birth weight of settings, are doubling or tripling
childhood; and the dopamine and/or to undernourished mothers.
neurotransmitter system. in birth weight more rapidly than
Recent research has raised caution ever before. In the case of zinc, the
about the robustness of human concentration in early milk and
Rapid development of the brain is a
milk micronutrient composition, thus daily transfer to the infant
highly metabolically taxing process.
particularly for those nutrients in are quite high, are similar across
The young brain accounts for 60%
human milk that are responsive populations, and generally meet
of the body’s energy consumption,
6 a figure that contrasts with the to maternal dietary intake and the term infant’s needs for the first
status: vitamins B6 and B12, choline, several months of postnatal life. The
adult value of ∼20%. Nutrients that
iodine, and selenium,10 all of which adequacy of the zinc from human
support this cellular metabolic rate
are directly involved in brain milk alone for low birth weight and

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S4 KREBS et al
premature infants has not been to tradition, animal flesh foods are z score gain and maternal education
systematically addressed in LRS, often not offered as complementary were both significant predictors
but some intervention trials suggest foods to young children, and of developmental outcomes,
a benefit of zinc supplements.13 even more infrequently to infants supporting the interconnectedness
Folate concentrations in human between 6 and 12 months of age.15, of child development, nutritional
milk, unlike the other B vitamins, 16 Primary reliance on unfortified, intake, growth status, and maternal
are maintained independently of plant-based staple foods during factors.19 In a clinical trial studying
maternal folate status. Infants in the complementary feeding period, Indian toddlers, improved
both high- and low-resource settings even with continued breastfeeding, complementary feeding alone did
who have been exclusively breastfed often results in inadequate intake not affect development, but guidance
for ∼6 months have been observed of several critical micronutrients.16 around complementary feeding
to have normal circulating folate Additionally, lower bioavailability of practices in addition to psychosocial
concentrations whether mothers some micronutrients from primarily stimulation had a significant
were well-nourished or had marginal plant sources (except for some positive effect on the toddlers’
nutritional status.10 The demand beans) may additionally compromise neurodevelopment.20 These findings
for all 3 of these nutrients for the the adequacy of the intake of a support the critical importance of
undernourished lactating mother given micronutrient. Undoubtedly, maternal education for fostering
is met by her own tissues, and she suboptimal complementary feeding enhanced child psychosocial
may become depleted if her dietary quality and quantity contribute to stimulation, improved feeding
intake is inadequate to support poor linear growth, even though practices, and improved nutritional
the amounts secreted in milk. In total energy intake may be adequate. status on child development, with
such circumstances, maternal The combination, along with the or without a substantial impact
supplementation benefits the mother impact of prenatal factors and on linear growth.21 In addition to
rather than the infant directly. The austere environments associated the physiologic impact of maternal
impact (direct or indirect) on infant with poor hygiene and chronic undernutrition on the mother’s
growth and development through immune stimulation, results in a high health and that of her offspring,
improvement in maternal nutritional prevalence of stunting, with wasting nutritional deficiencies have
status during the demanding process being less common.17,18 Many of potential adverse effects on maternal
of lactation, especially during the the same factors that contribute to cognition and mental status, which
early postpartum months, has stunting are also likely to impact in turn exacerbate the risk for
received relatively little investigation neurodevelopment during the period low infant stimulation and limited
and represents an important of complementary feeding, although maternal–child responsiveness.
research gap. trials to specifically isolate and Potential interactions between
quantify the impact of each factor are maternal stress and poor nutrition
Complementary Feeding Period lacking.3 have also recently been reviewed,
(∼6–24 months) but the relative contributions of each
By ∼6 months postpartum, exclusive Feeding Context and Environment factor have not yet been elucidated
breastfeeding is no longer adequate by rigorous field studies.22
to meet micronutrient needs, and In addition to the quantity of energy
the quality of complementary foods and nutrient intakes, the quality of Iron as an Example of
is critical for the young child’s the feeding process and caregiver Nutrient Deficits and Impaired
optimal growth and development. responsiveness are also critical Neurodevelopment
This represents another period of for optimal infant and young child This section concludes with an
great vulnerability. Nearly all of the development (Fig 1). However, additional discussion of iron and
micronutrients highlighted above as interventions that have investigated neurodevelopment, because this
being critical for brain development the impact of improving the quality of micronutrient has the richest
are found primarily, or in some cases the complementary feeding process evidence base to illustrate several
exclusively, in animal-source foods, specifically on neurodevelopment are broadly applicable general concepts:
especially flesh foods. Iodine and limited in LRS. One study in Malawi powerful interconnections in brain
long-chain polyunsaturated fatty that employed lipid-based nutrient and behavior development; roles
acids could be considered exceptions. supplements or a micronutrient- of timing, duration, and severity
Iodine is often added as a fortificant fortified corn–soy flour reported no of deficiency; and cooccurrence of
to salt, rather than consumed within difference in developmental scores in nutritional deficiencies with other
a specific food.14 Due to both limited 18-month-old children after a year- disadvantages. Iron deficiency
availability (eg cost constraints) and long intervention, but length-for-age

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PEDIATRICS Volume 139, number s1, April 2017 S5
is not only the most prevalent
micronutrient deficiency in this age
group, but its eradication has been
challenging and is, as yet, incomplete.

Iron is required for many central


nervous system (CNS) processes
that are rapidly maturing in infancy FIGURE 2
and early childhood. Thus, both Iron deficiency and brain development, illustrating connections among iron-dependent changes
in brain architecture during development, with examples of altered gene and protein profiles that
diffuse and subtle effects would be may regulate these CNS processes. (Reprinted with permission from Lozoff B, Georgieff MK. Iron
expected with iron deficiency. The deficiency and brain development. Semin Pediatr Neurol. 2006;13(3):159.)
conceptual framework in Fig 223
emphasizes the interconnectedness sole study of adult outcomes involved for many infants. Consequently,
of iron-dependent changes in brain iron deficiency that was probably improved analytic methods and study
architecture and physiologic “wiring” chronic during infancy, because iron designs are needed to investigate
during development (myelin/ deficiency anemia was detected these intersecting scientific areas.
dendrites, neurotransmitters, (and treated) at 12 to 23 months of
and neurometabolism in specific Few studies to date have considered
age in a sample of infants in Costa
brain regions) and includes altered the impact of maternal iron
Rica. There were poorer functional
gene and protein profiles that may supplementation on fetal–neonatal
outcomes at 25 years of age, despite
regulate these CNS processes. For iron status. A recent RCT in China
correction of iron deficiency anemia
behavioral development, changes in showed marked improvements
in infancy. Specifically, previously
sensory, motor, cognitive, language, in maternal iron status with
iron-deficient individuals were less
and socioemotional functioning supplemental iron, but many
likely to complete secondary school,
related to iron deficiency are also women were still iron deficient
to have pursued additional training,
interconnected. As noted above and at or near term, and there was no
or to have married.30
indicated in the Fig 2, brain and effect on cord blood measures of
behavior effects can be bidirectional, fetal–neonatal iron status.37 In this
Human studies have also turned to same trial, iron supplementation
as can environmental influences. randomized controlled trials (RCTs)
Such effects would be expected with during infancy was associated with
of prophylactic iron supplementation significantly improved motor scores
other common nutrient deficits (rather than treatment) to strengthen
in infancy and early childhood, compared with placebo or with
causal inferences. The effects supplementation during pregnancy
particularly involving those nutrients on neurodevelopment are less
that affect brain chemistry, anatomy, alone.38
consistent or pronounced in such
and metabolism.5 trials versus in studies that compare
neurodevelopment in infants with THE IMPACT OF INFLAMMATION ON
Initial studies linking fetal and or without iron deficiency. In fact, NEURODEVELOPMENT DURING INFANCY
neonatal iron deficiency involved some meta-analyses conclude
neonates with other risk factors for that there are no effects of iron The evidence base for the
compromised development, such as supplementation,31,32 in contrast direct impact of inflammation,
prematurity, maternal diabetes, or to several studies showing poorer resulting from both infectious
intrauterine growth restriction.24 outcomes in iron-deficient infants.24, and noninfectious causes, on
The handful of studies involving 33–36 Additional considerations neurodevelopment is even more
term infants of uncomplicated help us understand this apparent limited than that for nutrient use.
pregnancies suggest short- and paradox. RCTs in populations where The recent outbreak of Zika virus
long-term effects.25–29 The different iron deficiency is uncommon may infection has drawn attention to
neurodevelopmental impacts of require huge sample sizes to detect the striking effects of infection
fetal–neonatal versus postnatal statistically and clinically meaningful occurring early in gestation, notably
iron deficiency in humans are effects. RCTs in populations where manifest as severe microcephaly. In
unknown, but the time course of iron deficiency is widespread a prospective study, 29% of women
brain development suggests there may not provide sufficient iron if found to have become infected at
would be differential effects. That prophylactic doses are used, and various time points throughout
is, outcomes would be worse when supplementation may begin after pregnancy had adverse effects
a nutrient deficiency starts earlier, neurodevelopment has already that extended beyond the most
lasts longer, or is more severe. The been compromised by lack of iron severe brain insults to also include

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S6 KREBS et al
placental insufficiency, intrauterine THE INTERACTION OF NUTRITION, ”18 reflecting the multifactorial
growth restriction, and milder INFLAMMATION, NEURODEVELOPMENT, and self-perpetuating nature of
central nervous system injury.39 AND OTHER INFLUENCING FACTORS the condition. Such recognition
Thus, the full extent of infection DURING INFANCY now underpins consideration
during gestation on offspring The pervasive and substantial of effective interventions that
neurodevelopmental outcomes is exposures to environments encompass approaches well beyond
unknown, but early findings suggest with contaminated water and to nutrient intakes alone and that
that this may represent an important poor hygiene are increasingly attempt to mitigate other negative
additional burden for LRS. The acute recognized to contribute to the environmental factors and host
and long-term consequences of new early postnatal linear growth exposures.4,49
Zika virus infection in infancy are faltering and stunting observed
unknown, but pose a theoretical risk in LMIC.43 Although stunting is
for neurodevelopmental sequelae. IMPLICATIONS FOR RESEARCH,
undoubtedly multifactorial and
PROGRAM, AND POLICY DEVELOPMENT
The connection between stunting, includes chronic malnutrition,
which is mediated in part by chronic environmental enteric dysfunction, The period from birth through
inflammation, and impaired child a chronic inflammatory condition 24 months of age represents a
development has clearly been of the intestinal tract that starts in strongly compelling illustration
documented, particularly in older early infancy,44,45 is increasingly of the interactions among
children. Such associations include recognized to impact nutrient use, maternal and infant nutritional
less exploratory behavior, poorer growth, and neurodevelopment. status, environmental exposures,
cognitive achievement, more anxiety, For example, the central role of inflammation, and the rapidly
and lower school performance.18 hepcidin in the regulation of iron developing brain. A list of knowledge
A recent large prospective homeostasis powerfully illustrates a gaps and research priorities is
observational study in Bangladesh biological balance between the need provided in Table 1. Although this
directly assessed the association for adequate intake of an essential complexity mandates multisectoral
of biomarkers of inflammation at 6 nutrient and the countering effect interventions to maximize benefits,
months of age on motor and cognitive of immune stimulation to inhibit the evidence base is more than
function at 12 and 24 months of age. iron absorption and use. Although a adequate to prioritize selected
In this cohort, fever and inflammation similar “master regulator” analogous nutrition-specific and nutrition-
were strongly associated with to hepcidin has not been identified sensitive elements, especially
significantly lower scores on for other micronutrients, data in the most socioeconomically
language, cognitive, and motor are emerging to suggest adverse deprived settings.21,49 Despite the
tests.40 In the same cohort, high effects of environmental enteric numerous vulnerabilities for infants
rates of anemia and zinc deficiency dysfunction and inflammation on and young children highlighted
were also observed, with rates being zinc absorption and homeostasis.13, in this paper, highest yields for
highest in the first year of life when 46,47 Another mechanism by which improved neurodevelopment seem
processes of brain maturation are disrupted gut health may impact likely to be realized by bundled
particularly active.41 New insights development is through alterations interventions that focus on improved
regarding the links between in the gut microbiota which, through maternal nutritional status through
inflammation and neurodevelopment interaction with the developing the entire reproductive cycle,
will undoubtedly emerge in coming innate immune system, can drive including lactation; promoting and
years, as prospective data linking elevations in proinflammatory and supporting exclusive breastfeeding
growth, feeding, and nutrient- antiinflammatory cytokines and for nutritional benefits and for
intake patterns, gut function and influence brain function.48 Such limiting infant contaminant
the microbiota, inflammation, and early and enduring inflammatory exposures; enhancing the quality of
developmental testing from other stimuli have also been linked complementary foods as well as the
high-risk populations become to a risk of systemic metabolic feeding process; enabling maternal
available.41,42 disease associated with later education to improve parenting and
noncommunicable diseases, infant stimulation (among numerous
particularly in settings where other benefits); and improving
access to more abundant caloric hygiene and sanitation to reduce
intake is emerging. In recent the drivers of high-inflammatory
years, this constellation has been burdens. As multidimensional
termed the “stunting syndrome, programs aiming to broadly improve
infant and young child feeding

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PEDIATRICS Volume 139, number s1, April 2017 S7
TABLE 1 Recommendations for Research Initiatives To Address Knowledge Gaps
Problem or Question Studies Needed
1. Gaps in knowledge related to nutrition and neurodevelopment/brain function
during infancy
What are the critical interactions of nutrient deficiencies and inflammation/ Testing in animal models brain and behavioral effects of nutrient deficiencies,
infection on brain development and neurodevelopment? What is the inflammation/infection, and their interactions.
impact of timing of such insults on outcomes?
How can micronutrients critical to the developing brain reach the relevant Investigations of novel micronutrient delivery systems on neural systems.
brain regions more effectively?
To what extent does maternal malnutrition impact human milk composition Characterize the maternal sensitive micronutrient profile in human milk in
and infant brain development? vulnerable populations.
Conduct interventions in pregnant and lactating women to mitigate the risk of
human milk –ransmitted deficiencies in young infants in vulnerable settings.
2. Gaps in knowledge related to inflammation, infection, and neurodevelopment/
brain function during infancy
Need to better understand the roles and interaction of the microbiome, Develop strategies to mitigate gut inflammation and dysbiosis.
micronutrient availability, inflammation, and neurodevelopment. Identify microbiota profiles associated with improved micronutrient
bioavailability and functional neurodevelopmental outcomes.
3. Gaps in knowledge related to interactions of nutrition, inflammation,
neurodevelopment, and other influencing factors during infancy
Current assessment tools are not sufficiently sensitive to detect subtle Develop field-friendly, brain-based measures that can, especially in resource
deficits in neurodevelopment in infants and young children. limited settings:
meaningfully assess multiple domains in the infant and young child;
yield predictive value for later function and benefit of early intervention
What is the functional significance of diffuse but mild deficits in Conduct long-term follow-up studies to refine prognostic understanding of early
neurodevelopment? deficits.
What is the balance between environmental exposures and genetic Investigate effects of potentially toxic environmental exposures and their
vulnerability and protection against micronutrient deficiencies? interactions with micronutrient deficiencies on neurodevelopment.
4. Gaps in knowledge related to evidence-based interventions for optimal
neurodevelopmental outcomes during infancy
Multiple insults are likely to adversely impact neurodevelopment. Conduct studies designed and powered to assess for multiple insults (eg,
micronutrient deficiency, neurotoxins, stress, inflammation).
Develop “bundled” interventions to evaluate impact on global
neurodevelopment.
What are the epigenetic effects of interventions? Incorporate evaluation of epigenetic modifications (eg, methylation) in
intervention studies in mothers, infants, and young children.

are developed, rigorous process


evaluation should be a cornerstone
to enable identification of the key ABBREVIATIONS
effective components. Examples of CNS: central nervous system
program impact evaluation have LMIC: low- and middle-income
recently been published.50,51 Thus, countries
beyond traditional research trials to LRS: low-resource setting
examine biological outcomes, such RCT: randomized controlled trial
dissemination and implementation
studies are critical to move from
identification of best practices to
best programs and policies. With
progress in each of these domains,
the potential benefits in human
capital would be realized for both
individuals and populations in both
short- and long-term time frames.

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S8 KREBS et al
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S10 KREBS et al
Neurodevelopment: The Impact of Nutrition and Inflammation During Infancy
in Low-Resource Settings
Nancy F. Krebs, Betsy Lozoff and Michael K. Georgieff
Pediatrics 2017;139;S50
DOI: 10.1542/peds.2016-2828G
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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
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Neurodevelopment: The Impact of Nutrition and Inflammation During Infancy
in Low-Resource Settings
Nancy F. Krebs, Betsy Lozoff and Michael K. Georgieff
Pediatrics 2017;139;S50
DOI: 10.1542/peds.2016-2828G

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/139/Supplement_1/S50.full.html

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
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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