Iron for Human Brain Development: A Fulfill Strategy in the First

1,000 Days of Life

Qodri Santosa

Department of Child Health, Faculty of Medicine, Universitas Jenderal Soedirman Purwokerto, Indonesia

Keywords: iron, brain, development, the first 1,000 days of life

Abstract: Every child has the right to live, survive, and optimal growth and development. Iron has a fundamental role

in brain development. Iron deficiency (ID) in the first two years of life harms the child's long-term

development (possibly irreversible), even though ID has been corrected. For optimal child development, the

first two years of life are a crucial period. Iron deficiency during pregnancy can cause adverse pregnancy

outcomes, both maternal and newborn, resulting in long-term disruption to the child's growth and development.

We must pay special attention to the adequacy of iron needs from conception to two years of age. This article

describes the importance of iron for human brain development and what should we do to ensure iron adequacy,

especially in the first 1,000 days of life.

1 INTRODUCTION

Every fetus in pregnancy and the baby (after birth)

has the right to live, survive, and has optimal growth

and development (ILO, 1999). Children are the next

generation of a nation and have a strategic role in

ensuring the nation's existence and continuity (UU RI

23, 2002).

The successful development of children,

especially the brain, determines the future fate of the

country. The first 1,000 days period, from conception

to her child's second birthday, offers a brief critical

brain's window of opportunity (as the golden period)

(Bellieni, 2016) to shape the development of children.

The fulfilment of both macro and micronutrient

nutrients is very fundamental for the successful

development of a child.

Iron, as an essential micronutrient, has a strategic

role in developing the human brain. Iron deficiency/

iron deficiency anaemia (ID/IDA) at the end of the

fetal period and early in the infant period can cause

decreased cellular respiration in the hippocampus and

frontal cortex. It also may lead to abnormal

neurotransmitter concentrations, altered fatty acid

profiles, and impaired myelination, potentially

disrupting infant growth and development (Georgieff,

2007).

https://orcid.org/0000-0001-7712-2549

Poorly child fares of iron fulfil in this period,

potentially causing neurological disorders (Georgieff,

2007), interfering with the child's long-term

development (Mattei & Pietrobelli, 2019; Pietrobelli

et al., 2017)

and might irreversible, across the lifespan

(Lozoff, 2006; Halterman, 2009). The success of

nutrition management in the first 1,000 lives provides

a vast opportunity to improve human resources with

transgenerational impacts (Martorell, 2017). It should

be a priority not only for the government but also for

all community groups and individuals, including

academics. This article describes the importance of

iron for human brain development and what we

should do to ensure iron adequacy, especially in the

first 1,000 days of life.

2 THE HUMAN BRAIN

DEVELOPMENT

The human brain develops from the prenatal and

continues to the postnatal period. The brain structures

are designed gradually and begin in the third

gestational week with the differentiation of the neural

progenitor cells (Thompson & Nelson, 2001); (Stiles

& Jernigan, 2010) (See figure 1). Approximately 22

days after conception, the neural plate begins to fold

214

Santosa, Q.

Iron for Human Brain Development: A Fulﬁll Strategy in the First 1,000 Days of Life.

DOI: 10.5220/0010490302140222

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 214-222

ISBN: 978-989-758-499-2

inward, forming the neural tube, which eventually

becomes the brain and spinal cord (Prado & Dewey,

2014). In the prenatal period, neurulation (i.e., the

formation of the neural tube from which eventually

evolves the central nervous system) occurred at 18-24

prenatal days, followed by the generation,

proliferation, migration, and, finally, differentiation

of neurons. Seven weeks after conception, cell

division begins within the neural tube, creating nerve

cells (neurons) and glial cells (cells that support

neurons). After a neuron is made, it migrates to its

place in the brain, where it then grows axons and

dendrites projecting out from its cell body (Prado &

Dewey, 2014).

At the beginning of the last (third) trimester of

fetal life, both myelinations (the fatty insulation of

neurons) runs up to 5-10 years of age. It is continuing

into adult life, and also the synaptogenesis (forming

relationships between cells) continues up to the age

of 15 -18 years). These events are essential to

developing the functional architecture of the brain

(Thompson & Nelson, 2001; Stiles & Jernigan, 2010;

Mattei & Pietrobelli, 2019).

Especially in the third trimester and the first two

years after birth, the brain faces extraordinary growth,

increasing its dimension, differentiating gradually in

a highly specialized organ, and slowly losing

plasticity. It is known that the higher rate of growth

in this period, the greater the risk of damage due to

insufficient nutrients (Fox et al., 2010; Mattei &

Pietrobelli, 2019). The brain has unique

developmental trajectories and a set of nutrient

requirements, so we must pay more attention to it.

The brain regions or processes have

developmental trajectories that begin and accelerate

in fetal life or shortly after birth. Every area of the

brain and every process has two crucial moments, (i)

the critical period and (ii) the sensitive period.

Conceptually, they can be defined as follows: the

former is an early life period where irreversible long-

term consequences follow insults. The latter

represents broader periods when the brain is more

susceptible to environmental factors, such as nutrient

deficiencies (including iron), but the effect is not

inevitably permanent (Mattei & Pietrobelli, 2019).

The logical consequences of failure to construct a

brain region during its critical period can lead to

permanent disorders, such as residual structural

defects (Jorgenson et al., 2003), persistent

neurochemical and electrophysiological

abnormalities, and even altered gene expression

(Tyagi, 2015; Barks et al., 2018; Mattei & Pietrobelli,

2019;). Thus, ensuring adequate nutrient, especially

iron, is necessary to allow a time-coordinated brain

development and create an integrated healthy

working brain structure.

In the human biological system, the brain is the

most complex organ. It contains 100 billion neurons

(information processing cells) and between neuron

cells make connections with other neuron cells

(through synapses) to create the information

processing networks responsible for all of our

thoughts, sensations, feelings, and actions. Since each

neuron has more than 1,000 other neurons, the adult

brain is estimated to have more than 60 trillion

neuronal connections (synapses) (Stiles & Jernigan,

2010).

Figure 1. Development course of the human brain (Thompson & Nelson, 2001)

Iron for Human Brain Development: A Fulﬁll Strategy in the First 1,000 Days of Life

215

Neuron populations are linked by fibres extending

from individual neurons' cell bodies, namely

dendrites and axons (see Figure 2). Dendrites are

short visible fibres like the branches of a tree, which

function to receive electrochemical input signals from

other neurons. In contrast, axons are long connecting

fibres that extend over great distances and make

connections with other neurons (often at the

dendrites) to send electrochemical signals to neurons

located at distant locations (Stiles & Jernigan, 2010).

Figure 2. Schematically illustration of a neuron (Stiles & Jernigan, 2010)

Individual axon collections from many different

neurons (in one brain region) form fibre channels that

extend to and make connections with groups of

neurons in the other areas of the brain, developing

information-processing networks. The axons are

encased in a fatty substance called myelin, like the

insolation in telephone wires, making the

transmission of electrochemical signals between

regions efficient (Stiles & Jernigan, 2010). The

efficiency of information transmission in the

pathways is greatly enhanced by myelin, which

unsheathes the axons. This myelination process needs

iron so that ID during the rapid growth period (the

first 1,000 days of life) will harm the child's future.

3 HOW DOES IRON

DEFICIENCY INTERFERE

WITH BRAIN

DEVELOPMENT?

Iron deficiency is the most prevalent nutritional

deficiencies in the world (Bastian, 2020)

Iron is an

essential micronutrient for normal cellular function in

roles as varied as oxygen transportation, energy

metabolism/energy production, cellular respiration,

cell signalling, gene expression/ DNA synthesis and

the regulation of cell growth and differentiation, and

more (Musallam & Taher, 2019; Ferreira et al., 2019).

Heme is an iron complex with protoporphyrin IX,

which is essential for all aerobic cells' function. Cells

need heme as a prosthetic part for key hemoprotein,

including haemoglobin, cytochromes, and

myoglobin. Another ones are catalase, peroxidases,

and nonheme-containing enzymes involved multiple

metabolic activities. The dominance function of iron

as the cofactor for intracellular processes is due to the

chemistry and redox properties of iron, which enable

it to bind oxygen, transfer electrons and catalyze

various reactions (Aisen, 2001; Musallam & Taher,

2019; Ferreira et al., 2019). In case the brain, as a

metabolically active organ, is susceptible to iron

homeostasis changes, there is still much uncertainty

(Ferreira et al., 2019).

Cells in the brain do not directly access nutrients,

including iron, in the systemic circulation because the

blood-brain barrier and the blood–cerebrospinal fluid

barrier separate the CNS from the systemic

circulation (Ferreira et, 2019). The iron can cross the

blood-brain border by binding to transferrin. The

transferrin-iron complex will attach to the transferrin

receptor on the capillary endothelium. It results in

further internalization by forming endocytic vesicles.

The iron is then pumped out via the expression

divalent metal transporter 1 (DMT1) in the "ferrous"

form. In the cytosol, ceruloplasmin oxidase Ferro to

ferric form. It releases to the extracellular space by

ferroportin (Rouault, 2013).

Disruption of iron homeostasis in the brain

significantly impairs oxidative metabolism of neural

cells, with dramatic consequences for synaptic

plasticity, myelination, and synthesis of

neurotransmitters (Beard & Connor, 2003; Nnah &

Wessling-Resnick, 2018). Iron is a double-edged

sword, "deficiency" and "overload" of iron lead to

detrimental consequences. It means that both

deficiency and iron overload are associated with

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

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216

disruption of neurophysiological mechanisms

previously associated with impaired cognition,

altered social behaviour, and other brain functions

(Ferreira et al., 2019). Iron deficiency further

threatens the body's physiological processes during

the fast-growing life period.

During pregnancy and the early phases of human

life (first 1,000 days of life), the needs for macro and

micronutrients (including iron), energy, and other

resources increase. The effects of ID are profound on

cells with the highest metabolic rates, possibly

because ID disrupts mitochondrial and cellular

energy (Beard & Connor, 2003). Mitochondrial

function can be severely impaired because iron is a

cofactor for both heme and nonheme-containing

enzymes in the mitochondrial electron transport chain

(Georgieff et al., 2019). The consequences of ID are

more significant during development when the

oxygen consumption rates of cells are highest, driven

by the energy demands of growth and differentiation

(Kuzawa, 1998; Georgieff et al., 2019), such as

during the late stages of pregnancy and early life.

As an illustration, the total-body oxygen

consumption of a neonate is three to four times

greater than that of an adult. The infant's brain is

estimated to consume 50–60% of the total metabolic

expenditure. The neonatal human brain alone utilizes

60% oxygen consumption, compared with 20% in the

adult brain (Kuzawa, 1998; Georgieff et al., 2019). As

a result, because of the high use of iron in rapid brain

development, the early life period is the most

susceptible to ID.

Potential mechanisms contributing to this

disorder include deficits in brain energy metabolism,

nerve transmission, and myelination. A

comprehensive review shows the brain's reduced

energetic capacity as a mechanical driver of impaired

neurobehavioral development due to fetal-neonatal

ID. Permanent metabolic reprogramming, which

occurs during the ID period, results in chronic

disruption of neuronal energy and mitochondrial

capacity in adulthood, limiting neuroplasticity and

neuro-behaviour in adults (Bastian et al., 2020).

Unfortunately, ID in the late fetal and early life period

can cause abnormal cognitive performance and

emotional regulation, which can persist into

adulthood despite iron repletion.

4 STRATEGY FULFILL IRON

NEED 1,000 DAYS OF LIFE

The strategy to fulfil the iron need in the first 1,000

days of life is a meaningful way to prevent the adverse

effects of ID that harms the child's long-term

development, even though ID has been corrected. So,

clear that prevention is the best solution.

General ID Prevention Strategies Approaches

In principle, ID prevention must involve various

sectors, both government and non-government

organizations. Individual preventive approaches will

not have an impact on the broader community.

General strategies approach of ID prevention is

including food-based procedures, infection disease

control program, and iron supplementation (WHO,

2001).

1. Food-based approaches

a. Dietary improvement

Add substances that enhance iron absorption and

remove inhibitors of iron absorption substances in the

diet menu (WHO, 2001). Iron absorption enhancers

(such as ascorbic acid, Muscle tissue)

(Seriki et al.,

2017; Cappellini et al., 2020) or inhibitors (such as

calcium, phytates [cereals], polyphenols [black tea],

tannins [tea and coffee], proteins [milk proteins, egg

proteins]) should also be aware of when supplying

iron-rich food menus (WHO, 2001; Seriki et al.,

2017; Cappellini et al., 2020).

b. Provide a diet menu that is heme iron-rich food

sources

Low dietary intake of bioavailable iron is an essential

factor in the development of ID. Increased access to

and consumption of iron-rich foods should always be

a priority (WHO, 2018a; Cappellini et al., 2020).

Complementary foods should not forget to provide

animal food sources rich in heme iron which is easily

absorbed.

c. Food fortification

The food fortification (or enrichment of food) is

adding micronutrients (including iron) to food. It is

usually considered the deliberate addition of one or

more micronutrients to particular foods to increase

these micronutrient (s) intake to prevent or correct a

demonstrated deficiency (WHO & FAO, 2006). For

Iron for Human Brain Development: A Fulﬁll Strategy in the First 1,000 Days of Life

217

example, enrichment of food (rice, maize flour,

cornmeal) with iron. Food manufacturers can carry it

out (or by governments as a public health policy) to

reduce the number of people with a low iron diet and

risk of ID within a population (WHO & FAO, 2006).

2. Infection disease control program

In particular, this effort to hookworm,

schistosomiasis, and malaria control, can enhance

IDA control program effectiveness in a population

with moderate to severe levels of infection (WHO,

2001).

3. Iron supplementation

Supplementation is the most common strategy

currently and often used to treat existing IDA (WHO,

2001). Iron supplementation program has

successfully reduced the prevalence of ID/ However,

we must realize that iron is a "double-edged sword,"

deficiency and iron overload lead to detrimental

consequences (Georgieff, 2007).

The WHO (2016) recommends iron

supplementation (without screening) to prevent DI /

IDA in a population where the prevalence of anaemia

is 40% or higher (: children 6–23 months (10–12.5

mg elemental iron daily), three consecutive months in

a year), 24–59 months (30 mg elemental iron daily),

three straight months in a year), 5–12 years (30–60

mg essential iron daily), three consecutive months in

a year) (WHO, 2016).

Recommendation from WHO, pregnant women

are given a daily oral iron and folic acid

supplementation with 30 - 60 mg of elemental iron

and 400 g (0.4 mg) of folic acid to prevent maternal

anaemia, puerperal sepsis, low birth weight, and

preterm birth (WHO, 2018c).

When daily iron is not acceptable due to side-

effects, and in populations with anaemia prevalence

among pregnant women of less than 20%,

intermittent oral iron and folic acid supplementation

with 120 mg of elemental iron and 2800 µg (2.8 mg)

of folic acid once weekly (WHO, 2018b).

Controversy Iron Supplementation of Pregnant

Women and Children

Although iron supplementation programs have

successfully reduced ID prevalence, blindly iron

supplementation without detecting iron status is still

controversial. Iron has a narrower adequacy range, so

iron supplementation might even cause health

problems regardless of iron status. Iron

supplementation to iron-sufficient individuals is

likely unnecessary or has a little additional benefit

and may carry health risks for iron-sufficient

individuals and potentially some iron-deficient

populations (Georgieff, 2007; Georgieff et al., 2019).

However, emerging and preliminary evidence

shows a U-shaped risk at both deficiency and iron

status overload for birth and infant adverse health

outcomes (Dewey & Oaks, 2017). This fact raises

questions about the effects of high iron intakes

through supplementation or food fortification during

pregnancy and infancy, particularly in iron-replete

individuals (Brannon & Taylor, 2017). However, the

inability to reliably distinguish total-body iron status

from three iron-replete states of haemoglobin in

nonanemic women (namely: nonanemic ID, optimal

iron status, and iron overload) raises a significant

problem in determining the "benefit-risk analysis"

since the effects of iron supplementation on these

three states likely differ (Georgieff et al., 2019).

During pregnancy, high iron status is associated with

increased risk for maternal and fetal adverse

outcomes, related to preterm birth, low birth weight

and small for gestational babies (Brannon & Taylor,

2017; Breymann, 2015).

There is preliminary

evidence that supplementation or high iron status is

associated with gestational diabetes mellitus (Zhang

& Rawal, 2017). Iron supplementation on iron-

replete children increased the risk of vomiting and

fever (Pasricha et al., 2013), impaired linear growth

(Lönnerdal, 2017), and disturbing microbiome

profiles (Brannon & Taylor, 2017; Paganini &

Zimmermann, 2017). Iron supplementation without

screening is allowed by WHO in populations wit a

high prevalence of ID / IDA. The implications of this

risk of iron supplementation deserve serious

discussion relative to screening and supplementation

in these "vulnerable" populations (which are likely

iron-replete) (Brannon & Taylor, 2017), not only

population in developed countries but also every iron-

replete individuals.

The Phase of Human Life, Associated With a

Vicious Cycle of Iron Deficiency

Neonates women born to iron deficient mothers will

potentially grow up to be children, adolescents, and

women of childbearing age with ID and subsequently

become pregnant women with ID, thus giving birth to

babies with ID. Continuity of care is not only

necessary throughout the lifecycle (adolescence,

pregnancy, childbirth, the postnatal period, and

childhood) but also between places of caregiving

(including households and communities, outpatient

and outreach services, and clinical-care settings)

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(Kerber et al., 2007). It is like a vicious cycle, so to

prevent the ID / IDA must cut it at every phase of

human life and need an effective continuum of care.

See figure 3.

Figure 3. The phase of human life, associated with a vicious cycle of ID

All life periods need to get attention to fulfil

human iron needs for brain growth and development

in the golden period, the first 1,000 days of life.

Throughout the journey of life, infancy, childhood,

adolescence, and women of childbearing age,

especially during pregnancy, they are the ID risk

period due to their high iron requirements. Children

(women) who grow up to be anaemic adolescents will

become anaemic pregnant women someday. For the

success of optimal children's brain development, all

ID problems, including chronic inflammation

problems, must be cut off and overcome in all human

stage life cycles. We must break this vicious cycle of

ID.

5 PLACENTAL TRANSFUSION:

IMPORTANT BUT

OVERLOOKED IN ID

PREVENTION

The general prevention strategies of ID (including

iron supplementation) can be practised from infants

aged six months until pregnant women. However, in

infants under six months is quite complicated, and

there is still a controversy regarding supplementation

in exclusive breastfeeding infants. Then, what is the

ID/ IDA preventive solution for children aged 0-6

months?

An inexpensive and easy preventive ID/ IDA

solution for infants 0-6 months has been provided by

delaying cord clamping at birth. In the first few

minutes after the baby is born, there is still circulation

from the newborn's placenta. Blood flow from the

neonate to the placenta (through the umbilical artery)

only occurs during the first 20-25 seconds after the

baby is born. Otherwise, the closure of blood flow in

the umbilical vein (from the placenta to neonate) can

last up to the first 3 minutes, and after that, the blood

flow is minimal and meaningless (Dewey &

Chaparro, 2007).

The debate about umbilical cord clamping time

has occurred for more than two centuries (Philip &

Saigal, 2004). The Pan American Health

Organization believes that the optimal timing of

umbilical cord clamping for all babies (regardless of

gestational age or weight) is when the cord circulation

stops, usually about 3 minutes or more after the baby

is born (Chaparro et al., 2007). The American College

of Obstetricians and Gynecologists (ACOG) argues

that delayed clamping for the mother does not affect

postpartum haemorrhage incidence. In contrast, for

term infants, there is not enough evidence of benefit

for them, and the risk of hyperbilirubinemia should be

considered (Committee on Obstetric Practice ACOG,

2012).

WHO recommend clamping the umbilical cord at

1-3 minutes after birth for all deliveries in 2012

(WHO, 2012a). They did not suggest an early

clamping (<1 minute) unless the neonate is

Iron for Human Brain Development: A Fulﬁll Strategy in the First 1,000 Days of Life

219

asphyxiated and requires immediate resuscitation

(WHO 2012a; WHO, 2012b). Delayed umbilical cord

clamping (1-3 minutes) is recommended for

improved maternal and infant health and nutrition

outcomes (WHO, 2014). The care protocol for

expected delivery in Indonesia, Jaringan Nasional

Pelatihan Klinik-Kesehatan Reproduksi (JNPK-KR,

2017), recommends clamping of the umbilical cord 2-

3 minutes after birth if there is no need for

resuscitation of the baby (JNPK-KR, 2017). Due to

the importance of delayed cord clamping, WHO gives

remarks that for basic neonatal resuscitation, if the

baby rescue team in the delivery process has

experience providing adequate positive-pressure

ventilation without cutting the umbilical cord,

actually ventilation can be initiated before cutting the

cord (WHO, 2014).

Delaying to clamp the umbilical cord for 2–3 min,

or until cord pulsations cease, facilitates a

physiological blood transfer of placental blood to the

infant (called "placental transfusion"), the majority of

which occurs within 3 min. The placental transfusion

provides sufficient iron reserves for the growth and

development of the baby's brain in the first 6–8

months of human life and prevents or delays the

development of ID until other interventions – such as

the use of iron-fortified foods– can be implemented

after exclusive breastfeeding period (WHO, 2016).

6 SUMMARY

This article describes brain development and the

crucial role played by iron. As an essential

micronutrient in human brain development, fulfil iron

needs in the first 1,000 days of life is a fundamental

step to achieve optimal child development in the

future. However, both deficiency and iron overload

harm maternal and neonatal outcomes. Iron

deficiency in the first two years of life impairs the

child's long-term development (possibly irreversible),

even though ID has been corrected. ID prevention is

essential—general ID prevention strategies approach,

including food-based approaches, infection disease

control program, and iron supplementation.

Complementary foods should provide animal food

sources that are rich in heme-iron, which is easily

absorbed. Children (girl) who grow up to be anaemic

adolescents will become anaemic pregnant women

someday, so all ID problems must be cut off and

overcome in all human life cycles. We must break this

vicious cycle of ID. Especially for exclusively

breastfed babies in the 0-6 month period, the delay of

umbilical cord clamping (about 2-3 minutes) after

birth provides sufficient iron reserves for the baby's

life for 6-8 months.

REFERENCES

Aisen P, Enns C, and Wessling-Resnick M. (2001)

'Chemistry and biology of eukaryotic iron metabolism'.

Int J Biochem Cell Biol., 33(10):940-959. DOI:

10.1016/s1357-2725(01)00063-2.

Barks A, SJB F, Georgieff MK, and Tran PV. (2018) 'Early-

life neuronal-specific iron deficiency alters the adult

mouse hippocampal transcriptome". J Nutr.

148(10):1521–1528. DOI: 10.1093/jn/nxy125.

Bastian TW, Rao R, Tran PV and Georgieff MK. (2020)

'The effects of early-life iron deficiency on brain energy

metabolism'. Neurosci Insights., 15:1-12. DOI:

10.1177/2633105520935104.

Bastian TW, von Hohenberg WC, Mickelson DJ, Lanier

LM, and Georgieff MK. (2016) 'Iron deficiency impairs

developing hippocampal neuron gene expression,

energy metabolism and dendrite complexity'. Dev.

Neurosci., 38(4):264–276. DOI: 10.1159/000448514.

Beard JL and Connor JR. (2003) 'Iron status and neural

functioning'. Annu. Rev. Nutr., 23:41–58. DOI:

10.1146/annurev.nutr.23.020102.075739.

Bellieni CV. (2016) 'The Golden 1,000 Days'. J Gen

Practice. 4(2): 250. DOI:10.4172/2329-9126.1000250.

Brannon PM, and Taylor CL. (2017) 'Iron supplementation

during pregnancy and infancy: uncertainties and

implications for research and policy'. Nutrients.

9(12):1327. DOI: 10.3390/nu9121327.

Breymann C. (2015) 'Iron deficiency anemia in pregnancy'.

Semin. Hematol. 52(4):339–347. DOI:

10.1053/j.seminhematol.2015.07.003.

Cappellini MD, Musallam KM, and Taher AT. (2020) 'Iron

deficiency anaemia revisited". J Intern Med.,

287(2):153–170. DOI: 10.1111/joim.13004.

Chaparro C, Lutter C, and Hubner AVC. (2007) 'Essential

delivery care practices for maternal and newborn health

and nutrition'. Pan American Health Organization,

Reginal office of the Word Health Organization and

USAID.

Committee on Obstetric Practice American College of

Obstetricians and Gynecologists. (2012) 'Committee

Opinion No.543: Timing of umbilical cord clamping

after birth'. Obstet Gynecol. 120(6): 1522-1526.

Dewey KG, and Chaparro CM. (2007) 'Mineral metabolism

and body composition iron status of breastfed infants'.

Proc Nutr Soc., 66(3):412–422. DOI:

10.1017/S002966510700568X.

Dewey KG, and Oaks BM. (2017) 'U-shaped curve for risk

associated with maternal iron status or

supplementation'. Am J Clin Nutr. 106(Suppl

6):1694S–1702S. DOI: 10.3945/ajcn.117.156075.

Ferreira A, Neves P and Gozzelino R. (2019) 'Multilevel

impacts of iron in the brain: the cross talk between

neurophysiological mechanisms, cognition, and social

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

220

behavior'. Pharmaceuticals, 12(3):126;

DOI:10.3390/ph12030126.

Fox SE, Levitt P, and Nelson CA. (2010) 'How the timing

and quality of early experiences influence the

development of brain architecture'. Child Dev.,

81(1):28–40. DOI: 10.1111/j.1467-8624.2009.01380.x.

Halterman JS, Kaczorowski C, Aligne A, Auinger P, and

Szilagyi PG. (2001) 'Iron deficiency and cognitive

achievement among school-aged children and

adolescents in the United States'. Pediatrics.;107:1381-

1386.

Georgieff MK. (2007) 'Nutrition and the developing brain:

nutrient priorities and measurement'. Am J Clin Nutr.,

85(2):614S–620S. DOI: 10.1093/ajcn/85.2.614S.

Georgieff MK, Krebs NF and Cusick SE. (2019) 'The

benefits and risks of iron supplementation in pregnancy

and childhood'. Annu. Rev. Nutr. 39:121-146. DOI:

10.1146/annurev-nutr-082018-124213.

Harvey L J, Berti C, Casgrain A, Cetin I, Collings R,

Gurinovic M, Hermoso M, Hooper L, Hurst R,

Koletzko B, Ngo J, Vinas BR, Vollhardt C, Vucic V,

and Fairweather-Tait SJ. (2013) 'Estimating iron

requirements for deriving dietary reference values'. Crit

Rev Food Sci Nutr. 53(10), pp.1064-1076. DOI:

10.1080/10408398.2012.742860.

ILO Convention No. 182. (1999). Concerning the

Prohibition and Immediate Action for the Elimination

of The Worst Forms of Child Labour.

JNPK-KR. (2017) Asuhan Persalinan Normal. Asuhan

esensial bagi ibu bersalin dan bayi baru lahir serta

penatalaksanaan komplikasi segera pasca persalinan

dan nifas. Buku Acuan.

Jorgenson LA, Wobken JD, and Georgieff MK. (2003)

'Perinatal iron deficiency alters apical dendritic growth

in hippocampal CA1 pyramidal neurons'. Dev

Neurosci., 25(6), pp.412–420. DOI:

10.1159/000075667.

Kerber KJ, de Graft-Johnson JE, qar A Bhutta Z, Okong P,

Starrs A, and Lawn JE. (2007) 'Continuum of care for

maternal, newborn, and child health: from slogan to

service delivery'. Lancet.;370(9595):1358–1369. DOI:

10.1016/S0140-6736(07)61578-5.

Kuzawa CW. (1998) 'Adipose tissue in human infancy and

childhood: an evolutionary perspective'. Am. J. Phys.

Anthropol; 107(Suppl. 27), pp.177–209. DOI:

10.1002/(sici)1096-8644(1998)107:27+<177::aid-

ajpa7>3.0.co;2-b

Lönnerdal B. (2017) Excess iron intake as a factor in

growth, infections and development of infants and

young children. Am J Clin Nutr. 106(Suppl 6):1681S–

1687S. DOI: 10.3945/ajcn.117.156042.

Lozoff B, Jimenez E, and Smith JB. (2006) 'Double burden

of iron deficiency in infancy and low Socioeconomic

status: a longitudinal analysis of cognitive test scores to

age 19 years'. Arch Pediatr Adolesc Med.

160(11):1108-1113. DOI:

10.1001/archpedi.160.11.1108.

Martorell R. (2017) 'Improved nutrition in the first 1000

days and adult human capital and health'. Am J Hum

Biol., 29(2). DOI:10.1002/ajhb.22952.

Mattei D and Pietrobelli A. (2019 ) 'Micronutrients and

brain development'. Curr Nutr Rep., 8(2), pp.99-107.

DOI: 10.1007/s13668-019-0268-z.

McCann A, Amadó MP and Moore SE. (2020) 'The role of

iron in brain development: a systematic review'.

Nutrients,12(7), 2001. DOI: 10.3390/nu12072001.

Musallam KM, and Taher AT. (2018) 'Iron deficiency

beyond erythropoiesis: should we be concerned?' Curr

Med Res Opin., 34(1), pp. 81-93. DOI:

10.1080/03007995.2017.1394833.

Nnah IC and Wessling-Resnick M. (2018) 'Brain iron

homeostasis: a focus on microglialiron'.

Pharmaceuticals, 11(4):129. DOI:

10.3390/ph11040129.

Paganini D and Zimmermann MB. (2017) 'The effects of

iron fortification and supplementation on the gut

microbiome and diarrhea in infants and children: A

review'. Am J Clin Nutr. 106(Suppl 6):1688S–1693S.

DOI: 10.3945/ajcn.117.156067.

Pasricha SR, Hayes E, Kalumba K, and Biggs BA. (2013)

'Effect of daily iron supplementation on health in

children aged 4–23 months: A systematic review and

meta-analysis of randomized controlled trials'. Lancet

Glob. Health., 1(2):e77–e86. DOI: 10.1016/S2214-

109X(13)70046-9.

Pietrobelli A, Agosti M, and MeNu Group. (2017)

'Nutrition in the first 1000 days: ten practices to

minimize obesity emerging from published science'. Int

J Environ Res Public Health. 14(12):1491. DOI:

10.3390/ijerph14121491.

Philip AGS, and Saigal S. (2004) 'When should we clamp

the umbilical cord?' Neo Reviews. 5(4):e142-e154.

DOI: https://doi.org/10.1542/neo.5-4-e142.

Rouault TA. (2013) 'Iron metabolism in the CNS:

implications for neurodegenerative diseases'. Nat. Rev.

Neurosci. 14(8):551–564. DOI: 10.1038/nrn3453.

Prado EL, and Dewey KG. (2014) 'Nutrition and brain

development in early life'. Nutr Rev. 72(4):267–284.

DOI: 10.1111/nure.12102.

Seriki SA, Adebayo OF, and Odetola AO. (2017) 'Iron:

From dietary sources to utilization in the body'. Glob J

Nanomed. 3(3), pp. 85-91. doi:

10.19080/GJN.2017.03.555615.

Stiles J, and Jernigan TL. (2010) 'The basics of brain

development'. Neuropsychol Rev. 20(4), pp.327–348.

DOI: 10.1007/s11065-010-9148-4.

Thompson RA, and Nelson CA. (2001) 'Developmental

science and the media: early brain development'. Am

Psychol., 56(1), pp.5-15. DOI: 10.1037/0003-

066x.56.1.5.

Tyagi E, Zhuang Y, Agrawal R, Ying Z, and Gomez-Pinilla

F. (2015) 'Interactive actions of Bdnf methylation and

cell metabolism for building neural resilience under the

influence of diet'. Neurobiol Dis. 73:307–18. DOI:

10.1016/j.nbd.2014.09.014.

Undang-Undang Republik Indonesia 23. (2002)

‘Perlindungan Anak’

WHO. (2001) 'Iron deficiency anaemia assessment,

prevention, and control. A guide for programme

managers'.

Iron for Human Brain Development: A Fulﬁll Strategy in the First 1,000 Days of Life

221

https://www.who.int/nutrition/publications/en/ida_asse

ssment_prevention_control.pdf

WHO. (2004) 'Focusing on anaemia: Towards an integrated

approach for effective anaemia control'.

https://www.who.int/medical_devices/publications/en/

WHO_UNICEF-anaemiastatement.pdf?ua=1

WHO. (2012a) 'WHO recommendations for the prevention

and treatment of postpartum haemorrhage'.

https://www.who.int/iris/bitstream/10665/75411/1/978

9241548502_eng.pdf?ua=1.

WHO. (2012b) 'Guidelines on basic newborn resuscitation.

Genewa'.

http://apps.who.int/iris/bitstream/10665/75157/1/9789

241503693_eng.pdf?ua=1

WHO. (2014) 'Guideline: Delayed umbilical cord clamping

for improved maternal and infant health and nutrition

outcomes.

https://www.who.int/nutrition/publications/guidelines/

cord_clamping/en/.

WHO. (2016) 'Guideline: daily iron supplementation in

infants and children'.

http://apps.who.int/iris/bitstream/10665/204712/1/978

9241549523_eng.pdf?ua=1&ua=1

WHO. (2018a) 'Guideline: Fortification of rice with

vitamins and minerals as a public health strategy'.

Geneva: World Health Organization,

https://apps.who.int/iris/bitstream/handle/10665/27253

5/9789241550291-eng.pdf?sequence=1&isAllowed=y

WHO. (2018b) 'WHO recommendation on intermittent oral

iron and folic acid supplementation'.

https://extranet.who.int/rhl/topics/preconception-

pregnancy-childbirth-and-postpartum-care/antenatal-

care/who-recommendation-intermittent-oral-iron-and-

folic-acid-supplementation

WHO. (2018c) 'WHO recommendation on daily oral iron

and folic acid supplementation'.

https://extranet.who.int/rhl/topics/preconception-

pregnancy-childbirth-and-postpartum-care/antenatal-

care/who-recommendation-daily-oral-iron-and-folic-

acid-supplementation

WHO, and FAO. (2006) 'Guidelines on food fortification

with micronutrients'.

https://www.who.int/nutrition/publications/guide_food

_fortification_micronutrients.pdf

Zhang C, and Rawal S. (2017) Dietary iron intake, iron

status and gestational diabetes. Am J Clin Nutr.,

106(Suppl 6): 1672S–1680S. DOI:

10.3945/ajcn.117.156034.

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