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Iron deficiency
SYMPOSIUM: HAEMATOLOGY
Iron deficiency
As the onset is insidious, estimation of the exact prevalence of iron deficiency is difficult. Anaemia is therefore often used as a proxy. The World Health Organization (WHO) estimates that anaemia (the main cause of which is iron deficiency) affects 47% of pre-school age children and 25% of school age children worldwide, with the peak prevalence between 1 and 3 years of age. No region is immune: even in the US, 9% of 1e3 year olds and 16% of adolescent girls are affected (see Tables 1 and 2, and Figure 1).
Katrina Pettit Jennifer Rowley Nick Brown
Abstract Iron deficiency remains one of the world’s greatest public health problems. Globally it is the greatest contributor to anaemia, affecting 47% of pre-school age children and 25% of school age children worldwide, and is a major contributor to both physical and neuro-developmental morbidity. Iron deficiency results from inadequate intake, excess turnover or excessive loss. Whilst inadequate intake is the commonest cause of deficiency in children in the industrialized world, impaired absorption through malabsorption syndromes like inflammatory bowel disease and coeliac disease should also be considered. Blood loss additionally causes iron deficiency, the three most common causes of which are cows’ milk enteropathy, menstruation and hook worm infection. Prevention of iron deficiency, though theoretically simple, is complex at a population level. Treatment requires appropriate management of the underlying cause as well as additional iron replacement. In the western world, the focus has been on preventing iron deficiency through public education and modification of iron availability in children’s diets. It is recommended that children should not receive whole cows’ milk during the first year of life, but should instead be given breast milk or iron fortified formula. Worldwide management strategies again focus on dietary improvements, as well as the control of hook worm and malaria infections to reduce levels of iron deficiency.
Physiology Iron is a ubiquitous cation. In addition to its role in haemoglobin, iron is also required in cytochromes and enzyme reactions. It is distributed both as an active metabolite and in storage pools. In humans it is recycled extremely effectively from ageing red blood cells (RBCs). Iron absorption is therefore the only way of physiologically manipulating stores. Iron is absorbed by the small intestine, although typically only 10% of dietary iron is taken. For optimal nutrition a daily intake of 8e10 mg of iron is required to cover the iron losses from cell desquamation from the skin and intestine and to maintain growth in children. Demands are greatest in infancy and adolescence during periods of high growth. The efficacy of iron absorption is dependent on its form when consumed. It is well absorbed in the haem form (meat) and less well in the non-heam state as this requires both reduction to the ferrous state and release from food binders by gastric juices. In addition, non-heam iron absorption is reduced by other food items (e.g. vegetable fibre phytates in cereals and pulses, calcium and tannins in tea). Vitamin C promotes absorption. Once absorbed iron binds to and is transported by transferrin, a protein synthesized in the liver. Transferrin synthesis is sensitive to iron status and therefore increases in deficiency and decreases in chronic disease. Iron is used in erythropoiesis or stored as either ferritin or haemosiderin. Ferritin is soluble and freely available, and is located in the liver (hepatocytes), bone marrow, spleen (macrophages), RBCs and serum. The circulating ferritin level parallels the size of the total body stores (1 ng/ml ¼ 8 mg iron in storage pool). Some iron is additionally stored as the relatively insoluble haemosiderin in the Kupffer cells of the liver and in macrophages of the bone marrow.
Keywords anaemia; cows’ milk protein enteropathy; dietary modification; hook worm infection; iron deficiency; malabsorption; public health
Introduction Iron deficiency manifests when there are insufficient bioavailable stores. This can result from inadequate intake, excess turnover or excessive loss. It is the most common nutritional disorder in the world, affecting large numbers of children in developing countries but is also highly prevalent in the industrialized world.
Aetiology Katrina Pettit MRCPCH MBBS is a Paediatric SpR in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none.
Dietary inadequacy and low bioavailability Inadequate intake qualitatively or quantitatively is the commonest cause of deficiency in children in the industrialized world. As iron is poorly absorbed, a typical western diet will be barely sufficient in meeting daily requirements. Iron in breast milk is absorbed three times more effectively than that in formula milk and the required intake in breast fed babies is therefore correspondingly smaller. Iron in cows’ milk has a poorer bioavailability. A diet containing a combination of meat, eggs, fruit and vegetables is required for sufficient iron intake.
Jennifer Rowley MBChB BSc(hons) is a Paediatric ST3 in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none. Nick Brown MRCP(Paeds) FRCPCH MSc epidemiology DTM&H is Paediatric consultant in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none.
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SYMPOSIUM: HAEMATOLOGY
Anaemia prevalence and number of individuals affected in pre-school age children, pregnant women and non-pregnant women in each WHO region WHO region
Africa Americas South-East Asia Europe Eastern Mediterranean Western Pacific Global
Pre-school aged children (0.00e4.99 years)
Pregnant women (no age range defined)
Prevalence (%)
Prevalence (%)
67.6 29.3 65.5 21.7 46.7 23.1 47.4
Affected (millions)
(64.3e71.0) 83.5 (79.4e87.6) (26.8e31.9) 23.1 (21.1e25.1) (61.0e70.0) 115.3 (107.3e123.2) (15.4e28.0) 11.1 (7.9e14.4) (42.2e51.2) 0.8 (0.4e1.1) (21.9e24.4) 27.4 (25.9e28.9) (45.7e49.1) 293.1 (282.8e303.5)
57.1 24.1 48.2 25.1 44.2 30.7 41.8
Non-pregnant women (15.00e49.99 years)
Affected (millions) Prevalence (%)
(52.8e61.3) 17.2 (15.9e18.5) (17.3e30.8) 3.9 (2.8e5.0) (43.9e52.5) 18.1 (16.4e19.7) (18.6e31.6) 2.6 (2.0e3.3) (38.2e50.3) 7.1 (6.1e8.0) (28.8e32.7) 7.6 (7.1e8.1) (39.9e43.8) 56.4 (53.8e59.1)
47.5 17.8 45.7 19.0 32.4 21.5 30.2
Affected (millions)
(43.4e51.6) 69.9 (63.9e75.9) (12.9e22.7) 39.0 (28.3e49.7) (41.9e49.4) 182.0 (166.9e197.1) (14.7e23.3) 40.8 (31.5e50.1) (29.2e35.6) 39.8 (35.8e43.8) (20.8e22.2) 97.0 (94.0e100.0) (28.7e31.6) 468.4 (446.2e490.6)
Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Table 1
Impaired absorption Protein energy malnutrition will impair absorption both at the mucosal and protein synthetic level and exacerbating the deficiency that such children almost invariably have. Other causes, though relatively rare in children, are well recognized and include malabsorption syndromes such as coeliac disease, inflammatory bowel disease, blind loop syndrome and gastric surgery.
Increased losses Blood loss causes iron deficiency. The three most common causes are cows’ milk enteropathy, menstruation and hook worm infection. These will be discussed in further detail. Chronic gastrointestinal losses in older children may also result from inflammatory bowel disease, which may be clinically ‘silent’ until anaemia is advanced due to adaptive compensation in the haemoglobin oxygen dissociation.
Increased demand Children have an increased demand for iron at times of rapid growth during their first year of life. Sufficient iron stores are usually acquired as a foetus to support growth up to the age of 6 months. Infants born prematurely may not have fully established these stores and will have additional iron requirements. From 6 months of age, iron in milk alone is insufficient to support this continued rapid growth. Additional dietary iron is required to prevent deficiency. Iron requirements are again increased during the rapid growth phase of adolescence.
Cows’ milk enteropathy: it is well established that infants fed on cows’ milk or cows’ milk based formula can develop a subclinical or overt colitis. This occult blood loss has a marked impact on the iron stores of younger babies. From the age of 6 months onwards studies have shown a gradual decrease in the amount of occult blood present, until the effect is largely gone at a year. For this reason it is recommended children should not be fed whole cows’ milk until after 1 year. The only acceptable alternatives are iron fortified formula or breast milk. Menstruation: menstruation in adolescent girls has been shown to decrease the iron stores. This is problematic in a population with a tendency to have a low iron diet, although a good dietary iron intake will preclude the adverse effects of this.
Haemoglobin thresholds used to define anaemia Age or gender group
Children (0.50e4.99 years) Children (5.00e11.99 years) Children (12.00e14.99 years) Non-pregnant women (>15.00 years) Pregnant women Men (>15.00 years)
Haemoglobin threshold (g/L)
Hook worm infection: hook worm is caused by Ancylostoma duodenale or Necator americanus and affects an estimated one billion people worldwide. Eggs passed in the stool hatch into larvae which can survive for 3 weeks until they penetrate human skin when people walk barefoot on infested soil. The larvae reach the lungs via blood vessels, penetrate into pulmonary alveoli, ascend the bronchial tree to the epiglottis, and are swallowed. The larvae develop into adults in the small bowel where they attach to the wall and feed on the hosts’ blood. Adult worms may live for around 2 years. This chronic blood loss causes iron deficiency. The prevalence of hook worm infection increases with age reaching a plateau in late adolescence. A study of children in
110 115 120 120 110 130
Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Table 2
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SYMPOSIUM: HAEMATOLOGY
Category of public health significance (anaemia prevalence) Normal (<5.0%) Mild (5.0–19.9%)
Moderate (20.0–29.9%) Severe (≥40.0%)
No data
Figure 1 Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Zanzibar showed that 62% were anaemic, with 82% of this being attributable to iron deficiency, of which the strongest predictor was hook worm infection. Another study of an Australian aboriginal community showed hook worm infection was endemic, being present in 93% of children. The hook worm infection was significantly associated with iron deficiency and anaemia in people over 14 years.
deficiency is also associated with low birth weight and poor obstetric outcome. Development Iron deficiency anaemia in early life is related to altered behavioural and neural development. Iron is essential for the proper neurogenesis and differentiation of certain brain cells. Studies show that iron deficient pregnant mothers who remain so in the early weeks of breast feeding are more likely to have babies who display long-term developmental problems as this time period is critical for the baby’s developing brain. Further studies have shown that iron deficiency in infancy (up to 2 years of age) is related to poorer cognitive, motor and socio-emotional function, as well as persisting neurophysiologic differences from pre-school children right up to adolescents. In older pre-school children, development is also affected by iron deficiency, causing poorer motor, cognitive and language development as well as a poorer learning performance and behaviour. Severe iron deficiency has additionally been associated with thrombotic stroke in this age group.
Manifestations Anaemia The most common manifestation of iron deficiency is anaemia. Anaemia occurs when iron stores have been exhausted and there is insufficient iron for the synthesis of haemoglobin. A haemoglobin level of 110 g/litre is the cut off below which anaemia is said to be present (see Table 2). As this progresses microcytosis and then hypochromia develop and the reticulocyte count falls. The anaemia then causes symptoms of fatigue, loss of stamina, shortness of breath, weakness, dizziness, loss of appetite and pallor. If severe and untreated cardiac failure can ensue. Pregnancy and birth weight Pregnant women are particularly vulnerable to iron deficiency and iron deficiency anaemia. The WHO estimates that the prevalence of anaemia in pregnant women is 41.8% worldwide. The increased incidence of iron deficiency and anaemia in women pre-pregnancy is a major contributing factor. However, even women who enter pregnancy with good iron stores are at risk of iron deficiency due to the extra demands of supporting a growing foetus. Evidence shows that anaemia in pregnancy is a risk factor for preterm delivery and subsequent low birth weight, and iron
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Immunological The role of iron in immune function is controversial. There may be subtle measurable humoural immune differences in iron deficient children relative to their iron replete counterparts, the clinical significance appears minimal. It is likely that at least part of the explanation lies in the fact that many infective organisms (including the plasmodia causing malaria) require iron as a metabolic co-factor and that deficiency protects the host. This could certainly explain the consistent
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observation that malnourished children have a lower incidence of complicated malaria than their well nourished counterparts.
is the best long-term solution to both prevent and treat this deficiency. The WHO recommends that each region is assessed according to its’ needs and that a practical approach is taken to assess groups most at risk. They suggest reviewing eating patterns, the content and bioavailability of iron and absorption inhibitors and enhancers, to determine where practical implementations can be made. The iron status before and after changes are implemented should be assessed. In addition worldwide food fortification is recommended but this should be individualized to the region, to allow maximal benefit to the population being served.
Treatment Underlying cause The treatment of iron deficiency includes appropriate management of the underlying cause and additional iron replacement. Iron supplements are taken orally and continued for 6 months after the haemoglobin has normalized (if this was also reduced) to allow the iron stores to be replenished. The different ferrous salts are very similar in terms of efficacy of absorption of iron (those available include fumarate, gluconate and sulphate). Therefore choice of preparation is decided by palatability, incidence of side effects and cost. The oral dose of elemental iron is 3e6 mg/kg (maximum 200 mg) in two to three divided doses. The haemoglobin concentration should rise by 1e2 g/litre per day or 20 g/litre over 3e4 weeks. Poor compliance is the commonest reason for lack of response. Once replenished, iron supplements should be stopped to prevent the toxicity that occurs with chronic overload including pancreatic, pituitary, hepatic and cardiac deposition. Blood transfusions in children are only required if the child is compromised and/or at risk of high output cardiac failure.
Infection control: in large parts of the world helminth infection is an important cause of iron deficiency. Treatment is with anti helminth medications such as mebendazole, usually for 3 days. However re-infection is a real problem as a previous infection does not incur immunity. Effective prevention is by not walking barefoot and through the sanitary disposal of faeces.
Scenarios Scenario 1 Jessica is the 14-month-old baby of a young first time single mother, who lives with her maternal grandparents. She is referred for assessment by her Health Visitor who has noticed a striking pallor when seen for her MMR vaccination. She is markedly anaemic but otherwise well. There is no hepatosplenomegaly or lymphadenopathy. Her Hb is 3 and MCV 56. On questioning about her diet, the mother informs you she was instructed by her own mother that babies should be fed only cows’ milk from the age of 1 month until they are walking. As she is well she is treated with dietary advice and iron supplementation and 3 months later her Hb is normal. Comment: This is a common misconception in older generations. Cows’ milk is unsuitable for babies until a year of age as the iron is poorly bioavailable. It can cause gastrointestinal blood loss through a mild colitis and fills babies’ stomachs so they have no appetite for solids.
Public health In order to tackle the problem globally the WHO has made specific recommendations including: Reducing poverty Improving access to diversified diets Improve health services and sanitation Promote better care and feeding practices These recommendations are in keeping with the Millennium Development Goals (MDGs) 1e4. UK: in the UK, as in much of the western world, the focus has been on preventing iron deficiency through public education and measures to increase iron availability in children’s diets. In pregnancy women are screened for iron deficiency anaemia and treated if necessary. However, iron is not given routinely to prevent deficiency during pregnancy. In the first year of life it is recommended that children should not receive whole cows’ milk but should instead be given breast milk or iron fortified formula. In addition many cereals for infants and the rest of the population are fortified with iron. Current recommendations for weaning babies advise introducing a varied and iron rich diet from 6 months of age, from which the iron sources should be available in both haem (meat) and nonhaem forms. When cows’ milk is introduced it should not be in excess. For older children and teenagers the recommendations are still largely around having a varied diet, and additionally state that tea should not be drunk at mealtimes, but orange juice can be.
Scenario 2 Ed, a 15-year-old boy, is referred for delayed puberty. He feels constantly tired and has intermittent abdominal pain both put down to exam stress. Other than mild pallor and scattered oral ulceration examination is normal. His Hb is 67 g/litre, MCV 70 and CRP 78 mg/dl. The clinical impression of Crohn’s is confirmed by upper GI endoscopy and biopsy, and he responds well to induction with elemental diet. Comment: The older the child, the more likely the pathology is non-dietary. Scenario 3 Ellie, a 12-year-old girl, is referred for assessment of her chronic fatigue. Examination is unremarkable but her Hb is 7 and MCV 67. On closer questioning she reveals that, like her mother, her periods started at the age of 11 and have always been very heavy. She responds well to iron replacement and the oral contraceptive pill. Comment: Easily missed at this age but easily treated. A
Worldwide: around the world the cause of iron deficiency is much more likely to be secondary to malnutrition and chronic infection. However, it remains the case that improvement in diet
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FURTHER READING American Academy of Pediatrics Committee on Nutrition. The use of whole cows’ milk in infancy e committee on nutriton. Pediatrics 1992; 89: 1105e9. Booth IW, Aukett MA. Iron deficiency anaemia in infancy and early childhood. Arch Dis Child 1997; 76: 549e53. Huang SC, Yang YJ, Cheng CN, et al. The etiology and treatment outcome of iron deficiency and iron deficiency anemia in children. J Pediatr Hematol Oncol 2010; 32: 282e5. McClean E, Egli I, Cogswell M. In: de Benoist B, ed. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. WHO Publications, 2008. Stoltzfus RJ, Dreyfuss ML, Chwaya H, Albonico M. Hookworm control as a strategy to prevent iron deficiency. Nutr Rev 1997; 55: 223e32. United Nations millennium development goals, www.un.org/ millenniumgoals; 2000. WHO, UNICEF, UNU. Iron deficiency anaemia: assessment, prevention, and control. WHO/NHD/01.3. Geneva, Switzerland: World Health Organization, 2001.
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Practice points C
C
C C
C
Untreated iron deficiency in young children can cause neurodevelopmental delay which may be irreversible. Iron deficiency can occur independently of iron deficiency anaemia and any child with chronic ill health should be investigated for it. The commonest cause of iron deficiency is diet related. In older children with iron deficiency blood loss should be considered. In global terms hook worm eradication and malaria control would reduce levels of iron deficiency greatly.
Acknowledgement Thanks to Rebecca Moon for her helpful comments.
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Iron deficiency
As the onset is insidious, estimation of the exact prevalence of iron deficiency is difficult. Anaemia is therefore often used as a proxy. The World Health Organization (WHO) estimates that anaemia (the main cause of which is iron deficiency) affects 47% of pre-school age children and 25% of school age children worldwide, with the peak prevalence between 1 and 3 years of age. No region is immune: even in the US, 9% of 1e3 year olds and 16% of adolescent girls are affected (see Tables 1 and 2, and Figure 1).
Katrina Pettit Jennifer Rowley Nick Brown
Abstract Iron deficiency remains one of the world’s greatest public health problems. Globally it is the greatest contributor to anaemia, affecting 47% of pre-school age children and 25% of school age children worldwide, and is a major contributor to both physical and neuro-developmental morbidity. Iron deficiency results from inadequate intake, excess turnover or excessive loss. Whilst inadequate intake is the commonest cause of deficiency in children in the industrialized world, impaired absorption through malabsorption syndromes like inflammatory bowel disease and coeliac disease should also be considered. Blood loss additionally causes iron deficiency, the three most common causes of which are cows’ milk enteropathy, menstruation and hook worm infection. Prevention of iron deficiency, though theoretically simple, is complex at a population level. Treatment requires appropriate management of the underlying cause as well as additional iron replacement. In the western world, the focus has been on preventing iron deficiency through public education and modification of iron availability in children’s diets. It is recommended that children should not receive whole cows’ milk during the first year of life, but should instead be given breast milk or iron fortified formula. Worldwide management strategies again focus on dietary improvements, as well as the control of hook worm and malaria infections to reduce levels of iron deficiency.
Physiology Iron is a ubiquitous cation. In addition to its role in haemoglobin, iron is also required in cytochromes and enzyme reactions. It is distributed both as an active metabolite and in storage pools. In humans it is recycled extremely effectively from ageing red blood cells (RBCs). Iron absorption is therefore the only way of physiologically manipulating stores. Iron is absorbed by the small intestine, although typically only 10% of dietary iron is taken. For optimal nutrition a daily intake of 8e10 mg of iron is required to cover the iron losses from cell desquamation from the skin and intestine and to maintain growth in children. Demands are greatest in infancy and adolescence during periods of high growth. The efficacy of iron absorption is dependent on its form when consumed. It is well absorbed in the haem form (meat) and less well in the non-heam state as this requires both reduction to the ferrous state and release from food binders by gastric juices. In addition, non-heam iron absorption is reduced by other food items (e.g. vegetable fibre phytates in cereals and pulses, calcium and tannins in tea). Vitamin C promotes absorption. Once absorbed iron binds to and is transported by transferrin, a protein synthesized in the liver. Transferrin synthesis is sensitive to iron status and therefore increases in deficiency and decreases in chronic disease. Iron is used in erythropoiesis or stored as either ferritin or haemosiderin. Ferritin is soluble and freely available, and is located in the liver (hepatocytes), bone marrow, spleen (macrophages), RBCs and serum. The circulating ferritin level parallels the size of the total body stores (1 ng/ml ¼ 8 mg iron in storage pool). Some iron is additionally stored as the relatively insoluble haemosiderin in the Kupffer cells of the liver and in macrophages of the bone marrow.
Keywords anaemia; cows’ milk protein enteropathy; dietary modification; hook worm infection; iron deficiency; malabsorption; public health
Introduction Iron deficiency manifests when there are insufficient bioavailable stores. This can result from inadequate intake, excess turnover or excessive loss. It is the most common nutritional disorder in the world, affecting large numbers of children in developing countries but is also highly prevalent in the industrialized world.
Aetiology Katrina Pettit MRCPCH MBBS is a Paediatric SpR in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none.
Dietary inadequacy and low bioavailability Inadequate intake qualitatively or quantitatively is the commonest cause of deficiency in children in the industrialized world. As iron is poorly absorbed, a typical western diet will be barely sufficient in meeting daily requirements. Iron in breast milk is absorbed three times more effectively than that in formula milk and the required intake in breast fed babies is therefore correspondingly smaller. Iron in cows’ milk has a poorer bioavailability. A diet containing a combination of meat, eggs, fruit and vegetables is required for sufficient iron intake.
Jennifer Rowley MBChB BSc(hons) is a Paediatric ST3 in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none. Nick Brown MRCP(Paeds) FRCPCH MSc epidemiology DTM&H is Paediatric consultant in the Paediatric Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK. Conflict of interests: none.
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SYMPOSIUM: HAEMATOLOGY
Anaemia prevalence and number of individuals affected in pre-school age children, pregnant women and non-pregnant women in each WHO region WHO region
Africa Americas South-East Asia Europe Eastern Mediterranean Western Pacific Global
Pre-school aged children (0.00e4.99 years)
Pregnant women (no age range defined)
Prevalence (%)
Prevalence (%)
67.6 29.3 65.5 21.7 46.7 23.1 47.4
Affected (millions)
(64.3e71.0) 83.5 (79.4e87.6) (26.8e31.9) 23.1 (21.1e25.1) (61.0e70.0) 115.3 (107.3e123.2) (15.4e28.0) 11.1 (7.9e14.4) (42.2e51.2) 0.8 (0.4e1.1) (21.9e24.4) 27.4 (25.9e28.9) (45.7e49.1) 293.1 (282.8e303.5)
57.1 24.1 48.2 25.1 44.2 30.7 41.8
Non-pregnant women (15.00e49.99 years)
Affected (millions) Prevalence (%)
(52.8e61.3) 17.2 (15.9e18.5) (17.3e30.8) 3.9 (2.8e5.0) (43.9e52.5) 18.1 (16.4e19.7) (18.6e31.6) 2.6 (2.0e3.3) (38.2e50.3) 7.1 (6.1e8.0) (28.8e32.7) 7.6 (7.1e8.1) (39.9e43.8) 56.4 (53.8e59.1)
47.5 17.8 45.7 19.0 32.4 21.5 30.2
Affected (millions)
(43.4e51.6) 69.9 (63.9e75.9) (12.9e22.7) 39.0 (28.3e49.7) (41.9e49.4) 182.0 (166.9e197.1) (14.7e23.3) 40.8 (31.5e50.1) (29.2e35.6) 39.8 (35.8e43.8) (20.8e22.2) 97.0 (94.0e100.0) (28.7e31.6) 468.4 (446.2e490.6)
Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Table 1
Impaired absorption Protein energy malnutrition will impair absorption both at the mucosal and protein synthetic level and exacerbating the deficiency that such children almost invariably have. Other causes, though relatively rare in children, are well recognized and include malabsorption syndromes such as coeliac disease, inflammatory bowel disease, blind loop syndrome and gastric surgery.
Increased losses Blood loss causes iron deficiency. The three most common causes are cows’ milk enteropathy, menstruation and hook worm infection. These will be discussed in further detail. Chronic gastrointestinal losses in older children may also result from inflammatory bowel disease, which may be clinically ‘silent’ until anaemia is advanced due to adaptive compensation in the haemoglobin oxygen dissociation.
Increased demand Children have an increased demand for iron at times of rapid growth during their first year of life. Sufficient iron stores are usually acquired as a foetus to support growth up to the age of 6 months. Infants born prematurely may not have fully established these stores and will have additional iron requirements. From 6 months of age, iron in milk alone is insufficient to support this continued rapid growth. Additional dietary iron is required to prevent deficiency. Iron requirements are again increased during the rapid growth phase of adolescence.
Cows’ milk enteropathy: it is well established that infants fed on cows’ milk or cows’ milk based formula can develop a subclinical or overt colitis. This occult blood loss has a marked impact on the iron stores of younger babies. From the age of 6 months onwards studies have shown a gradual decrease in the amount of occult blood present, until the effect is largely gone at a year. For this reason it is recommended children should not be fed whole cows’ milk until after 1 year. The only acceptable alternatives are iron fortified formula or breast milk. Menstruation: menstruation in adolescent girls has been shown to decrease the iron stores. This is problematic in a population with a tendency to have a low iron diet, although a good dietary iron intake will preclude the adverse effects of this.
Haemoglobin thresholds used to define anaemia Age or gender group
Children (0.50e4.99 years) Children (5.00e11.99 years) Children (12.00e14.99 years) Non-pregnant women (>15.00 years) Pregnant women Men (>15.00 years)
Haemoglobin threshold (g/L)
Hook worm infection: hook worm is caused by Ancylostoma duodenale or Necator americanus and affects an estimated one billion people worldwide. Eggs passed in the stool hatch into larvae which can survive for 3 weeks until they penetrate human skin when people walk barefoot on infested soil. The larvae reach the lungs via blood vessels, penetrate into pulmonary alveoli, ascend the bronchial tree to the epiglottis, and are swallowed. The larvae develop into adults in the small bowel where they attach to the wall and feed on the hosts’ blood. Adult worms may live for around 2 years. This chronic blood loss causes iron deficiency. The prevalence of hook worm infection increases with age reaching a plateau in late adolescence. A study of children in
110 115 120 120 110 130
Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Table 2
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SYMPOSIUM: HAEMATOLOGY
Category of public health significance (anaemia prevalence) Normal (<5.0%) Mild (5.0–19.9%)
Moderate (20.0–29.9%) Severe (≥40.0%)
No data
Figure 1 Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications, 2008.
Zanzibar showed that 62% were anaemic, with 82% of this being attributable to iron deficiency, of which the strongest predictor was hook worm infection. Another study of an Australian aboriginal community showed hook worm infection was endemic, being present in 93% of children. The hook worm infection was significantly associated with iron deficiency and anaemia in people over 14 years.
deficiency is also associated with low birth weight and poor obstetric outcome. Development Iron deficiency anaemia in early life is related to altered behavioural and neural development. Iron is essential for the proper neurogenesis and differentiation of certain brain cells. Studies show that iron deficient pregnant mothers who remain so in the early weeks of breast feeding are more likely to have babies who display long-term developmental problems as this time period is critical for the baby’s developing brain. Further studies have shown that iron deficiency in infancy (up to 2 years of age) is related to poorer cognitive, motor and socio-emotional function, as well as persisting neurophysiologic differences from pre-school children right up to adolescents. In older pre-school children, development is also affected by iron deficiency, causing poorer motor, cognitive and language development as well as a poorer learning performance and behaviour. Severe iron deficiency has additionally been associated with thrombotic stroke in this age group.
Manifestations Anaemia The most common manifestation of iron deficiency is anaemia. Anaemia occurs when iron stores have been exhausted and there is insufficient iron for the synthesis of haemoglobin. A haemoglobin level of 110 g/litre is the cut off below which anaemia is said to be present (see Table 2). As this progresses microcytosis and then hypochromia develop and the reticulocyte count falls. The anaemia then causes symptoms of fatigue, loss of stamina, shortness of breath, weakness, dizziness, loss of appetite and pallor. If severe and untreated cardiac failure can ensue. Pregnancy and birth weight Pregnant women are particularly vulnerable to iron deficiency and iron deficiency anaemia. The WHO estimates that the prevalence of anaemia in pregnant women is 41.8% worldwide. The increased incidence of iron deficiency and anaemia in women pre-pregnancy is a major contributing factor. However, even women who enter pregnancy with good iron stores are at risk of iron deficiency due to the extra demands of supporting a growing foetus. Evidence shows that anaemia in pregnancy is a risk factor for preterm delivery and subsequent low birth weight, and iron
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Immunological The role of iron in immune function is controversial. There may be subtle measurable humoural immune differences in iron deficient children relative to their iron replete counterparts, the clinical significance appears minimal. It is likely that at least part of the explanation lies in the fact that many infective organisms (including the plasmodia causing malaria) require iron as a metabolic co-factor and that deficiency protects the host. This could certainly explain the consistent
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observation that malnourished children have a lower incidence of complicated malaria than their well nourished counterparts.
is the best long-term solution to both prevent and treat this deficiency. The WHO recommends that each region is assessed according to its’ needs and that a practical approach is taken to assess groups most at risk. They suggest reviewing eating patterns, the content and bioavailability of iron and absorption inhibitors and enhancers, to determine where practical implementations can be made. The iron status before and after changes are implemented should be assessed. In addition worldwide food fortification is recommended but this should be individualized to the region, to allow maximal benefit to the population being served.
Treatment Underlying cause The treatment of iron deficiency includes appropriate management of the underlying cause and additional iron replacement. Iron supplements are taken orally and continued for 6 months after the haemoglobin has normalized (if this was also reduced) to allow the iron stores to be replenished. The different ferrous salts are very similar in terms of efficacy of absorption of iron (those available include fumarate, gluconate and sulphate). Therefore choice of preparation is decided by palatability, incidence of side effects and cost. The oral dose of elemental iron is 3e6 mg/kg (maximum 200 mg) in two to three divided doses. The haemoglobin concentration should rise by 1e2 g/litre per day or 20 g/litre over 3e4 weeks. Poor compliance is the commonest reason for lack of response. Once replenished, iron supplements should be stopped to prevent the toxicity that occurs with chronic overload including pancreatic, pituitary, hepatic and cardiac deposition. Blood transfusions in children are only required if the child is compromised and/or at risk of high output cardiac failure.
Infection control: in large parts of the world helminth infection is an important cause of iron deficiency. Treatment is with anti helminth medications such as mebendazole, usually for 3 days. However re-infection is a real problem as a previous infection does not incur immunity. Effective prevention is by not walking barefoot and through the sanitary disposal of faeces.
Scenarios Scenario 1 Jessica is the 14-month-old baby of a young first time single mother, who lives with her maternal grandparents. She is referred for assessment by her Health Visitor who has noticed a striking pallor when seen for her MMR vaccination. She is markedly anaemic but otherwise well. There is no hepatosplenomegaly or lymphadenopathy. Her Hb is 3 and MCV 56. On questioning about her diet, the mother informs you she was instructed by her own mother that babies should be fed only cows’ milk from the age of 1 month until they are walking. As she is well she is treated with dietary advice and iron supplementation and 3 months later her Hb is normal. Comment: This is a common misconception in older generations. Cows’ milk is unsuitable for babies until a year of age as the iron is poorly bioavailable. It can cause gastrointestinal blood loss through a mild colitis and fills babies’ stomachs so they have no appetite for solids.
Public health In order to tackle the problem globally the WHO has made specific recommendations including: Reducing poverty Improving access to diversified diets Improve health services and sanitation Promote better care and feeding practices These recommendations are in keeping with the Millennium Development Goals (MDGs) 1e4. UK: in the UK, as in much of the western world, the focus has been on preventing iron deficiency through public education and measures to increase iron availability in children’s diets. In pregnancy women are screened for iron deficiency anaemia and treated if necessary. However, iron is not given routinely to prevent deficiency during pregnancy. In the first year of life it is recommended that children should not receive whole cows’ milk but should instead be given breast milk or iron fortified formula. In addition many cereals for infants and the rest of the population are fortified with iron. Current recommendations for weaning babies advise introducing a varied and iron rich diet from 6 months of age, from which the iron sources should be available in both haem (meat) and nonhaem forms. When cows’ milk is introduced it should not be in excess. For older children and teenagers the recommendations are still largely around having a varied diet, and additionally state that tea should not be drunk at mealtimes, but orange juice can be.
Scenario 2 Ed, a 15-year-old boy, is referred for delayed puberty. He feels constantly tired and has intermittent abdominal pain both put down to exam stress. Other than mild pallor and scattered oral ulceration examination is normal. His Hb is 67 g/litre, MCV 70 and CRP 78 mg/dl. The clinical impression of Crohn’s is confirmed by upper GI endoscopy and biopsy, and he responds well to induction with elemental diet. Comment: The older the child, the more likely the pathology is non-dietary. Scenario 3 Ellie, a 12-year-old girl, is referred for assessment of her chronic fatigue. Examination is unremarkable but her Hb is 7 and MCV 67. On closer questioning she reveals that, like her mother, her periods started at the age of 11 and have always been very heavy. She responds well to iron replacement and the oral contraceptive pill. Comment: Easily missed at this age but easily treated. A
Worldwide: around the world the cause of iron deficiency is much more likely to be secondary to malnutrition and chronic infection. However, it remains the case that improvement in diet
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FURTHER READING American Academy of Pediatrics Committee on Nutrition. The use of whole cows’ milk in infancy e committee on nutriton. Pediatrics 1992; 89: 1105e9. Booth IW, Aukett MA. Iron deficiency anaemia in infancy and early childhood. Arch Dis Child 1997; 76: 549e53. Huang SC, Yang YJ, Cheng CN, et al. The etiology and treatment outcome of iron deficiency and iron deficiency anemia in children. J Pediatr Hematol Oncol 2010; 32: 282e5. McClean E, Egli I, Cogswell M. In: de Benoist B, ed. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. WHO Publications, 2008. Stoltzfus RJ, Dreyfuss ML, Chwaya H, Albonico M. Hookworm control as a strategy to prevent iron deficiency. Nutr Rev 1997; 55: 223e32. United Nations millennium development goals, www.un.org/ millenniumgoals; 2000. WHO, UNICEF, UNU. Iron deficiency anaemia: assessment, prevention, and control. WHO/NHD/01.3. Geneva, Switzerland: World Health Organization, 2001.
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Practice points C
C
C C
C
Untreated iron deficiency in young children can cause neurodevelopmental delay which may be irreversible. Iron deficiency can occur independently of iron deficiency anaemia and any child with chronic ill health should be investigated for it. The commonest cause of iron deficiency is diet related. In older children with iron deficiency blood loss should be considered. In global terms hook worm eradication and malaria control would reduce levels of iron deficiency greatly.
Acknowledgement Thanks to Rebecca Moon for her helpful comments.
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