Diet and cognitive performance in early life

Question 1

What is the link between nutrition and neurocognitive development?

Answer 1

Neurodevelopmentaldisorders are impairments of the growth and development of the brain and/or central nervous system

Morphological = structural changes = detected using imigary, size of brain, number or size of neurons in brain

Functional changes = behavioural outcomes = measured in the way of lang/memory

Question 2

Children failing to fulfil neurocognitive development potential (Grantham-McGregor et al, 2007; McCoy et al, 2017)

Answer 2

Estimated 200 million children under 5 in low- and middle-income countries are at risk of failing to reach potential in cognitive development.

Around 80.8 million of the ~240 million preschool-aged children (3-4 years) in the world’s low- and middle-income countries fail to develop a core set of age-appropriate skills that allow them to maintain attention, understand and follow simple directions, communicate and get along with others, control aggression, and solve progressively complex problems

Question 3

Adequate nutrition is important for cognitive development (Prado & Dewey, 2014)

Answer 3

Nutrition is especially important during pregnancy and infancy, which are crucial periods for the formation of the brain

Question 4

An overview of brain development… (Prado & dewy, 2014)

Answer 4

Neural Tube Formation
~22 days after conception the neural tube is formed which eventually becomes the brain and spinal cord.

Neuron proliferation
~7 weeks after conception, cell division begins within the neural tube, creating nerve cells (neurons) and glial cells (cells that support neurons)

Axon and Dendrite growth
After a neuron is created, it migrates to its place in the brain, where it then grows axons and dendrites projecting out from its cell body.

Synapse formation
These branching projections make connections with
other cells, called synapses, through which nerve signals
travel from one cell to another.

Myelination
Covering of axons with myelin (fatty sheath that accelerates the nerve impulses travelling from one nerve to another

Neuron Apoptosis & pruning
Groups of neurons
form pathways, which are refined through the programmed
elimination of cells and connections. Synapses are also overproduced and then selectively
eliminated. Cells and
connections that are activated are retained and strengthened
while those that are not used are eliminated

Question 5

Dietary influences and cognitive development (Prado & Dewy, 2014)

Answer 5

Folate, B6 and B12
e.g. Maternal deficiency in folic acid and B12 associated with neural tube defects

Iron deficiency and Iron deficiency anaemia

Breastfeeding Practices
e.g. both the composition and experience of breastfeeding.

Zinc deficiency
e.g. Animal models show maternal and infant deficiency causes deficits in attention, activity, learning and memory

Iodine deficiency
e.g. Gestational iodine deficiency results in reduced dendritic branching in the cerebral cortex in animal studies

Fatty Acids
e.g. DHA and AA are important part of the brain tissue, including cell membranes and myelin. Therefore, Neurogenesis requires the synthesis of large amounts of membrane phospholipid from fatty acids.

Question 6

Adequate nutrition and the developing brain

Answer 6

Gestation and infancy are periods of rapid brain development

Inadequate availability of nutrients during gestation and infancy affects structural and functional development of the brain.

Question 7

how a child’s experience (illness) acts as a mediator between nutritional status and cognitive development (Taken from Prado & Dewey, 2014)

Answer 7

Childs early life experiences count towards development for later in life

Nutrition status = ill = more fussy = withdrawn from environment = less physical activity = doesn’t explore environment as much

Question 8

An introduction to Iron deficiency

Answer 8

Whilst iron deficiency (ID) is not perceived as a life-threatening disorder, it is the most prevalent single-nutrient deficiency in the world (Black et al., 2011).

ID is estimated to affect 2.5-5 billion people (Youdim, 2008).

Iron-deficiency Anaemia (IDA) affects an estimated 1 -2 billion people worldwide (WHO, 2007; Pasricha et al., 2013).
The prevalence is highest in preschool children, especially those aged 4–23 months.

Question 9

Food sources of Iron

Answer 9

Dietary iron is found in two basic forms:

Haem-iron – meat products rich in two major haem containing proteins,
haemoglobin and myoglobin

Non-haem iron – found in iron storage proteins, such as ferritin.

Main form of iron in all diet is non-haem iron found in cereals, vegetables, pulses, beans, fruits, etc….

Cereals contribute approx. half of our daily iron intake.

Since 1950’s all wheat flours (other than wholemeal) have been fortified with iron by law (1.65mg iron/100g) in the UK.

Breakfast cereals and infant foods also fortified with iron in UK.

Question 10

Why do we need Iron in the body?

Answer 10

Iron is an essential trace element and plays numerous biochemical roles in the body, including:

Oxygen binding in haemoglobin.

Acting as an important catalytic centre for many enzymes.

Body iron levels must be tightly regulated to avoid pathologies associated with iron deficiency and overload.

Question 11

Iron deficiency

Answer 11

Iron deficiency (ID)
Occurs when the body’s iron demand is not met by iron absorption from the diet (Killip et al., 2007; WHO, 2007; SACN, 2010).

Question 12

iron deficiency anaemia

Answer 12

Iron deficiency anaemia (IDA)
Occurs in the more severe stages of iron deficiency when the body is iron deficient to the degree that the red blood cell production is reduced (WHO, 2007; SACN, 2010).

Question 13

What groups of the population are particularly at risk of IDA?

Answer 13

Women (particularly pregnant women) and children (particularly infants and preschool-aged children)

Question 14

Population sub-groups at risk of IDA

Answer 14

Anaemia is a serious global public health problem that particularly affects young children and pregnant women:

“Globally, almost half of preschool-aged children and pregnant women and close to one-third of non-pregnant women have IDA.” (Osendarp et al., 2010)

Question 15

Risk factors for ID and IDA

Answer 15

Low dietary intake of iron

Poor iron absorption

Dietary inhibitors

Period of life where iron requirements are high (e.g. growth and pregnancy)

Menstruation (blood loss)

Infections

Presence of other nutrient deficiencies

Question 16

Inhibitors of non-haem iron absorption (SACN, 2010)

Answer 16

Tannins e.g. tea can reduce absorption by 50% if consumed with half an hour of the meal

Phytates e.g. in wholemeal cereals and fibre

Oxalates e.g. in spinach, dark green leaves

Calcium

Phosphates e.g. in eggs

Zinc and copper

Question 17

Why does childhood IDA exist in the UK?

Answer 17

Prevalence of anaemia (all causes) in children aged under 5 years in the UK is almost 12%.
Limited dietary sources and bioavailability of Iron
Poor socio-economic circumstances
Cost of iron supplemented milk formula
Lack of awareness of importance of dietary iron
Ethnicity
Diet (influenced by cultural beliefs) is the main causative factor that predisposes Asian infants to a low iron status
Asian mothers tend to introduce solid foods later, start cows milk earlier and use it for longer – as much as 60% of energy may be from cows milk at 18 months

Question 18

Evidence of a role for iron deficiency in Neurodevelopment (summarised from Prado & Dewy, 2014)

Answer 18

Iron is required for the synthesis of enzymes that regulates central nervous system cell division
Evidence from Animal models (summarised from Prado & Dewy, 2014):

While gestational and neonatal iron deficiency in rodents does not affect overall brain size, a decrease in the size of the hippocampus (a structure that underlies learning and memory) has been shown

Gestational and neonatal iron deficiency in rodents results in truncated dendritic branching in the hippocampus, which persists into adulthood despite iron repletion.

Gestational and early postnatal iron deficiency in rodents results in decreased synaptic maturity and efficacy in the hippocampus, which persists despite iron repletion.

Iron plays a role in myelin synthesis. Iron deficiency during prenatal and early postnatal development decreases myelin synthesis and alters myelin composition
subsequently not corrected with iron repletion

Question 19

Impact of iron deficiency in utero

Answer 19

Placental transfer begins during the 1st trimester, but it is only during the 3rd trimester that significant accretion occurs (Single et al., 1985).

Two thirds of total body iron present in the term infant is accreted during the 3rd trimester, with storage organ iron contents progressively increasing during this period (Single et al., 1985).

Question 20

Short-term effects of iron deficiency in utero – observational evidence

Answer 20

IDA in pregnant women in Vietnam increased the risk of lower infant cognitive development in offspring at six-months (Tran et al., 2013).
Infants of mothers who had persistent antenatal IDA had lower BSID scores than other infants.

Question 21

Long-term effects of iron deficiency in utero – Observational evidence

Answer 21

Tamura et al., (2002) evaluated the association between foetal iron status (cord serum ferritin levels) with test scores of mental and psychomotor development at 5 years:
Children in lowest quartile scored lower on tests of cognition
Also, had significantly worse language ability and fine motor skills than infants in highest two quartiles.

In contrast, maternal iron status during early pregnancy was not associated with brain development and IQ in the offspring at 8 years (Lewis et al., 2013).
What might a critique be here considering what we know about accretion of iron in the foetus?

Question 22

Summary of the effects of iron deficiency in utero…

Answer 22

Plenty of data from animal models and also observational data in humans to indicate that antenatal ID and IDA has adverse short-term neurocognitive outcomes for offspring

However, results from RCTs that have evaluated the longer-term effects of iron supplementation in pregnant mothers on the cognitive development of offspring are inconsistent to date:

“Collectively, the clinical evidence does not appear to show that iron supplementation in pregnancy causes improvements in long-term child mental development”.
(Larson et al., 2017)

“If iron deficiency occurs in very early life then the damage may be irreversible, and it may not be possible to reverse this damage with iron treatment”
(Beard, 2008).

Question 23

Summary of literature

Answer 23

There is plenty of observational evidence to show that there does appear to be short term (and possibly long term) associations with ID/IDA in pregnancy and cognitive development in infants

Conflicting data exist regarding the possibility of improved cognitive development in infants with iron administration during pregnancy

There is plenty of observational evidence to demonstrate an association between iron deficiency during early infancy and cognitive development outcomes.

However, there is a lack of evidence to suggest that any neurocognitive benefits of iron supplementation in infants (less than 2-3 years of age) persists in the short or long term (Larson et al, 2017)

If iron deficiency occurs in utero or very early life then the damage may be irreversible, and it may not be possible to reverse this damage with iron treatment (Beard, 2008)

There does appear to be some evidence for benefits of iron supplementation on cognitive development primary school children who are anaemic at baseline

Overall, there is a lack of evidence from well designed intervention trials demonstrating the cognitive impact of maternal iron supplementation and iron supplementation in pre-school and school aged children

Question 24

So what does this mean…. (Larson et al., 2017)

Answer 24

Failure to convincingly identify a benefit from iron supplementation in pregnancy or early infancy on cognition may be because:
1. Such a benefit does not exist!
Perhaps because iron at these doses and via this route does not impact on brain development
This would to some degree be in conflict with animal models and most observational data in humans
2. The effects from ID on early brain development are irreversible.
3. Methodological issues with RCTs
e.g. Undertaken in heterogeneous populations or populations where effects from iron may be unlikely to produce benefit?

Question 25

Addressing the problem…

Answer 25

Dietary education and feeding practices
dark-green leafy vegetables, such aswatercress and kale
iron-fortified cereals or bread
brown rice
pulses and beans
nuts and seeds
white and red meat
fish
eggs
Addition of iron-rich complimentary foods to children and infants
Supplementary Iron
Fortification – Flour in UK, Sweden and U.S

Question 26

Preventing Iron-deficiency in pre-term infants

Answer 26

Pre-term infants are at increased risk of developing iron deficiency.
Delayed clamping of the umbilical cord at birth allows additional transfer of ~100ml of placental blood to infant (Pasricha et al., 2013).
Supplementation is necessary to prevent iron deficiency in preterm infants.
Early iron supplementation at 2 weeks postnatal age improves serum ferritin and haemoglobin levels in preterm very low birth weight infants vs. late supplementation (6 weeks postnatal age) (Joy et al., 2013).