Expert Review of Hematology

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Anemia in children: prevalence, causes, diagnostic

work-up, and long-term consequences

Slimane Allali, Valentine Brousse, Anne-Sylvia Sacri, Martin Chalumeau &

Mariane de Montalembert

To cite this article: Slimane Allali, Valentine Brousse, Anne-Sylvia Sacri, Martin Chalumeau
& Mariane de Montalembert (2017) Anemia in children: prevalence, causes, diagnostic work-
up, and long-term consequences, Expert Review of Hematology, 10:11, 1023-1028, DOI:
10.1080/17474086.2017.1354696

To link to this article: https://doi.org/10.1080/17474086.2017.1354696

Published online: 12 Oct 2017.

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 EXPERT REVIEW OF HEMATOLOGY, 2017
VOL. 10, NO. 11, 1023–1028
https://doi.org/10.1080/17474086.2017.1354696

REVIEW

Anemia in children: prevalence, causes, diagnostic work-up, and long-term

consequences
Slimane Allali, Valentine Brousse, Anne-Sylvia Sacri, Martin Chalumeau and Mariane de Montalembert
Department of General Pediatrics and Pediatric Infectious Diseases, Hôpital Necker-Enfants malades, Paris, France; Laboratory of Excellence GR-Ex,
Paris, France

ABSTRACT ARTICLE HISTORY

Introduction: Anemia in children is a major public health problem throughout the world. It is often Received 12 March 2017
multifactorial, iron deficiency being the most frequent etiology. Consequences are diverse and largely Accepted 10 July 2017
under evaluated. KEYWORDS
Areas covered: This paper briefly reviews the main causes and focus on the potential consequences of Hematology; hemoglobin;
acute and chronic anemia in children. anemia; iron deficiency;
Downloaded by [RMIT University Library] at 08:30 10 December 2017

Expert commentary: Anemia in children should never be trivialized. Even if iron deficiency is frequently children
involved, other potentially life-threatening causes are possible and should be looked for. The exact
contribution of anemia to child mortality and morbidity is difficult to assess because of overlapping
comorbidities. Chronic anemia may impair growth, cardiac function and cognitive development in
infants but other consequences are rather poorly described and should be explored more thoroughly.

1. Introduction confidence interval [CI] 45.7–49.1) in preschool-age children

In normal conditions, erythrocyte production is in equilibrium
with erythrocyte removal. Imbalanced production and removal
ratio results in anemia, which may be acute and rapidly life
threatening or chronic. Children are especially at risk of ane-
mia: iron deficiency is the most frequent cause at this age
because of the disequilibrium between rapid growth and
insufficient iron intakes [1–3].
The prevalence of anemia varies widely worldwide.
Consequences of chronic anemia may be severe, affecting growth,
cardiac function, and cognitive development. However, some
manifestations may be related to other concomitant pathophysio-
logical mechanisms causing anemia rather than anemia itself.
2. Definition of anemia
Anemia is defined by a hemoglobin (Hb) level below the range
considered normal for age and gender, resulting in decreased
oxygen-carrying capacity. The cutoff values vary widely by age
of children (Tables 1 and 2). Therefore, an Hb level of 10 g/dL
is not considered anemia in a 3-month-old infant, but one of
12 g/dL is considered anemia in a newborn.
and 25.4% (95% CI 19.9–30.9) in school-age children.
Prevalence in preschool children varied widely by country, with
South America, Africa, and India the most exposed [1].
4. Diagnosis of anemia
4.1. Signs and symptoms
When anemia is present insidiously, such as with iron defi-
ciency, the diagnosis is often delayed. Cutaneous pallor is not
helpful because of the wide variability in skin pigmentation
depending on ethnic origin. Conversely, conjunctival pallor,
tongue pallor, and pallor of palms and soles seem to be more
reliable [4,5]. Reduced food intake and fatigue may be fre-
quent [6–8]. The degree of tachycardia is correlated with the
Hb level and reflects the tolerance of anemia [9].
Signs of hemolysis may be present, such as jaundice or dark
urine. Dysmorphic features may help to diagnose a thalassemic
syndrome (frontal bossing, prominent malar eminence, and
depressed bridge of the nose) or Diamond–Blackfan anemia
(hypertelorism, abnormal thumbs, flat nasal bridge, and cleft
palate) [10,11].

3. Prevalence of anemia 4.2. Biological work-up

In 2008, the World Health Organization (WHO) published survey
data from the WHO’s 192 member states with the Hb thresholds
of 11, 11.5, and 12 g/dL in children 0.5–4.99 (preschool age), 5–
11.99, and 12–14.99 years old (the last two considered school
age), respectively. Global anemia prevalence was 47.4% (95%
Anemia in children is often multifactorial [2]. Understanding its
cause requires assessing reticulocyte count (increased with
hemolytic anemia, except in neonates who may not produce
enough reticulocytes because of impaired erythropoietin
[EPO] production until approximately 6 months of age),

CONTACT Mariane de Montalembert mariane.demontal@aphp.fr Laboratory of Excellence GR-Ex, Paris, France; Department of General Pediatrics and
Pediatric Infectious Diseases, Hôpital Necker-Enfants malades, 149 rue de Sèvres, Paris 75015, France
© 2017 Informa UK Limited, trading as Taylor & Francis Group
 1024 S. ALLALI ET AL.

Table 1. Normal red blood cell count values (hemoglobin [Hb] level and mean Table 4. Most frequent causes of anemia in children after the neonatal period.
corpuscular volume [MCV]) in children by age (Oxford Handbook of Clinical Reticulocyte count
Hematology edited by Provan, Singer, Baglin, and Dokal (2009), Tab. 21.4, p.
810, by permission of Oxford University Press). ≥120 K/µL <120 K/µL
Age Hb (g/L) MCV (fl) (1) Hereditary hemolytic anemia – Iron deficiency: the most frequent
– Red cell membrane disorders (her- cause
Birth 149–237 100–125 editary spherocytosis, hereditary – Bone marrow involvement (leuke-
2 weeks 134–198 88–110 elliptocytosis, etc.) mia, neuroblastoma, lymphoma,
2 months 94–130 84–98 – G6PD or PK deficiency etc.). If anemia is associated with
6 months 100–130 73–84 – Abnormal hemoglobin (thalassemia leukopenia or thrombocytopenia,
1 year 101–130 70–82 and sickle cell disease) always consider bone marrow
2–6 years 115–138 72–87 (2) Acquired immune anemia examination.
6–12 years 111–147 76–90 Autoimmune hemolytic anemia – Renal, endocrine disease
Adult (male) 121–166 77–92 (warm or cold) – Inflammatory anemia
Adult (female) 121–151 77–94 – Megaloblastic anemia: vitamin B12
(3) Acquired nonimmune anemia and folate deficiencies, inborn errors
– Hemolytic uremic syndrome of metabolism, congenital dysery-
Table 2. Hemoglobin thresholds used by the World Health Organization (WHO) – Hypersplenism thropoietic anemia
to define anemia (Reprinted from Vitamin and Mineral Nutrition Information – Prosthetic heart valve – Thalassemia
System. Haemoglobin concentrations for the diagnosis of anemia and assess- – Paroxysmal nocturnal – Aplastic anemia
ment of severity. World Health Organization; Copyright (2011)). hemoglobinuria – Fanconi syndrome, Diamond–
– Malaria Blackfan anemia, transient
Mild Severe
erythroblastopenia
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Hemoglobin anemia Moderate anemia

Age or gender group threshold (g/L) (g/L) anemia (g/L) (g/L)
G6PD: glucose-6-phosphate dehydrogenase; PK: pyruvate kinase.
0.50–4.99 years 110 100–109 70–99 <70
5.00–11.99 years 115 110–114 80–109 <80
12.00–14.99 years 120 110–119 80–109 <80
Nonpregnant 120 110–119 80–109 <80
women nosis. Premature babies are often anemic because of insufficient
(≥15.00 years)
Pregnant women 110 100–109 70–99 <70 EPO production, shortened iron supplies from their mothers, and
Men (≥15.00 years) 130 110–129 80–109 <80 frequent blood sampling. Iron deficiency is commonly assumed
to be responsible for 50% of the cases of anemia and to be the
primary cause in children [1]. However, the proportion of anemia
mean corpuscular volume (MCV), and leukocyte and platelet attributable to iron deficiency varies considerably across coun-
counts. Blood smear analysis may be helpful and is readily tries, notably in malaria-endemic areas where malaria strongly
available in many settings. In the neonatal period, the term of contributes to the high prevalence of anemia in children [14–16].
pregnancy (weeks of amenorrhea), circumstances of delivery, Reduced iron stores impair Hb synthesis and induce microcytic
including timing of clamping of the umbilical cord, and mater- hypochromic anemia, with decreased MCV and mean Hb con-
nal and baby’s blood groups must be recorded [12]. tent and increased red cell distribution width [17]. Iron deficiency
If absolute reticulocyte count is low (<120 K/µL), iron status particularly affects preschool-age children (0–5 years) because of
(serum ferritin level), as well as C-reactive protein (CRP) level, the disequilibrium at this age between rapid growth and insuffi-
should be determined. In case of jaundice and/or increased cient iron intakes [18]. A recent review reanalyzed data from 1330
reticulocyte count, control of direct Coombs test with elution, children aged 6–23 months with iron-deficient anemia and used
glucose-6-phosphate dehydrogenase (G6PD) and pyruvate to diagnose anemia and iron deficiency the WHO criteria and a
kinase activities, and Hb electrophoresis is mandatory. Study serum ferritin level <12 ng/mL, respectively [19]. Low birth
of red blood cell membrane (ektacytometry or eosin-5ʹ-malei- weight and prolonged breastfeeding without iron fortification
mide cytometry assay) is needed to diagnose red cell mem- were identified as main risk factors of severe iron-deficiency
brane disorders such as hereditary spherocytosis [13]. anemia (odds ratio [OR] 5.7 [95% CI 2.7–12.2] and OR 6.5 [95%
CI 3.3–12.6], respectively) [20].
Diagnosing iron deficiency may be difficult because any con-
5. Most frequent causes of anemia in children comitant inflammation increases the level of serum ferritin, and
The causes of anemia by age are listed in Tables 3 and 4, exclud- thus, measurement of serum ferritin should be systematically
ing obstetrical causes, for which anamnesis usually allows diag- combined with CRP measurement [21]. The usual threshold to
define iron deficiency is serum ferritin level <12 ng/mL [22]. One
method to account for the increase in serum ferritin values caused
Table 3. Most frequent causes of anemia in term neonates (obstetrical causes
excluded). by inflammation is to raise the cutoff that defines deficiency to
Reticulocyte count 30 ng/mL, while other more complex approaches consist in apply-
>120 K/µL <120 K/µL ing arithmetic correction factors or using linear regression correc-
– Fetomaternal red cell antigen – Hemolytic anemia not excluded tions [23]. Transferrin receptor assay is useful because it is less
incompatibility – Infection (parvovirus B19) modified by inflammation, but it is not universally available
– α-Thalassemiaa – Fanconi syndrome, Diamond- [24,25]. The contribution of other markers, such as hepcidin level,
– G6PD or PK deficiency Blackfan anemia
– Hereditary spherocytosis
zinc protoporphyrin, or reticulocyte Hb concentration, remains
under investigation.
a
Disorders of β-chains (β-thalassemia, sickle cell disease) are not responsible for
neonatal anemia because γ chains, and not β chains, are active in this period. Moderate levels of evidence of the value of the different
G6PD: glucose-6-phosphate dehydrogenase; PK: pyruvate kinase. iron status markers and their cutoffs explain the variability of

Table 5. Causes of microcytic anemia.
Inadequate intake Malabsorption Inflammation
– Celiac disease
– Breastfeeding with inadequate com- – Helicobacter pylori gastritis
plementary food – Autoimmune atrophic gas-
– Preterm, small for gestational age tritis
– Growth spurt -Iron-refractory, iron-defi-
– Inadequate calorie intake cient anemia
– Vegetarian diet
DMT1: divalent metal transporter 1.
the current recommendations for screening iron deficiency
and iron-deficiency anemia in infants and young children
[26,27].
Microcytic anemia can also be related to other causes, far
less frequent (Table 5) [28–31].
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6. Consequences of acute anemia in children
Hb is responsible for oxygen delivery to tissues. The oxygen
content of arterial blood is the sum of the oxygen bound to
Hb and the oxygen dissolved in plasma. The total arterial
oxygen content is proportional to the oxygen-carrying capa-
city of Hb (which, for instance, is reduced for carboxy- and
met-Hb), the amount of Hb, arterial Hb saturation, and partial
pressure of oxygen in arterial blood. Oxygen delivery to tissue
is the result of cardiac output, arterial oxygen content, and
capillary resistance [32]. The tolerance of anemia depends in
part on the kinetics of Hb level decrease. Indeed, when Hb
level decreases, adaptive mechanisms occur to preserve oxy-
gen delivery to tissues, such as increase in heart rate and
cardiac output and decrease in the hemoglobin–oxygen bind-
ing affinity through increased 2,3-diphosphoglycerate produc-
tion [32,33]. Iron-deficiency anemia may be clinically well
tolerated (moderate fatigue) even at very low Hb level
because of the slow onset of anemia. In contrast, acute severe
anemia will induce fatigue, tachycardia, and breathlessness. In
the absence of correction of anemia, hypotension, mental
confusion, and finally heart failure may occur. In critically
anemic patients, redistribution of blood to the brain and
heart shunts oxygen distribution away from less vital organs
and may provoke gut ischemia with secondary bacterial trans-
location and lead to multiple-organ failure [33]. Cardiac toler-
ance is better in children than in adults because the former
usually have normal preexisting cardiac function.
At the molecular level, severe anemia-related tissue hypoxia
activates hypoxia-inducible factor (HIF), which in turn promotes
EPO production. In a mouse model, plasma EPO production
increased at an Hb threshold close to 10 g/dL; different levels
of expression of HIF subunits in anemic conditions were found
in the brain, kidney, and liver, which suggest heterogeneous
organ-specific hypoxic tissue response [34].
7. Consequences of chronic anemia in children
Consequences of chronic anemia are extremely difficult to
decipher because complications may be related as well to
EXPERT REVIEW OF HEMATOLOGY 1025
Defect in heme synthesis or iron
acquisition Blood loss
Inflammatory – Thalassemia – Immediate cord clamping at
syndromes – Sideroblastic anemia birth
– Erythropoietic porphyria – Polymenorrhea
– DMT1 mutations – Parasitic infestations (hookworms,
– Ferroportin disease whipworms)
– Hereditary atransferrinemia – Peptic ulcer
– Hereditary – H. pylori gastritis
aceruloplasminemia – Meckel diverticulum
low Hb level as to the cause of anemia itself. For instance,
aregenerative anemia may be caused by nutritional deficien-
cies (mostly iron in children and rarely vitamin B12 and folate),
which by themselves can induce damage. Complications may
also be part of complex syndromes (Fanconi or Diamond–
Blackfan syndromes for instance).
Hemolytic anemia associates low level of Hb and high
plasma heme level, which induces endothelial activation,
inflammation, and oxidative damage [35]. Sickle cell disease
(SCD) combines anemia and vaso-occlusion, which induces
hypoperfusion-related organ failure [36]. Consequently, aim-
ing to assess the impact of anemia in children requires search-
ing for the common denominators of different anemic
diseases and to consider the symptoms that worsen with
decreased Hb level. Several items will be drawn from the
experience with children with thalassemic syndromes, which
initially affect exclusively red cells.
7.1. Bone disease
Severe anemia in children results in fragility and distortion of
bones [10]. Bone modifications are related to both severe
anemia and sometimes expansion of bone marrow aiming to
compensate for the anemia. The role of low levels of osteo-
calcin in bone health impairment has been questioned [37].
The following signs are characteristics of thalassemia major
but may be found with other causes of severe chronic anemia
and enhanced erythropoietic drive (such as SCD or even,
rarely, hereditary spherocytosis). The skull is elongated
(tower skull), with frontal and posterior bossing, and possibly
hypertrophia of the maxilla, retraction of the upper lip, and
prominent molar eminences. The bridge of the nose is
depressed, and eyes may show a mongoloid slant. There
may be a shortening of upper arms. Scoliosis, kyphosis, and
vertebral collapse are possible. The most frequent radiological
observation is osteopenia. The skull shows a widening of the
diploic space, thinning of the outer table, new bone formation
to the inner table (‘hair-on-end’ appearance), absence of para-
nasal sinuses, and pneumatization with possible osteolytic
areas of the skull (Figure 1). Thinning of long bones is respon-
sible for pathological fractures. Osteoporosis represents an
important cause of morbidity in patients with thalassemia
major [38]. A decrease in bone mineral density has also been
described in children with SCD, which was unrelated to dis-
ease severity or vitamin D deficiency and suggests a possible
role of anemia itself [39].
 1026 S. ALLALI ET AL.
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Figure 1. Skull of a child with thalassemia. Note the frontal bossing and hair-on-
end appearance (courtesy of Professor M. Bradai, Blida, Algeria).
7.2. Liver and spleen enlargement
Liver and spleen enlargement are frequently present in ane-
mic children and are possibly due to extramedullary hemato-
poiesis (Figure 2) [40]. However, liver enlargement may also
reflect hepatic iron overload, related to chronic transfusion or
to increased intestinal iron absorption in patients with ineffec-
tive erythropoiesis. Spleen enlargement is often observed sec-
ondary to the increased destruction of red blood cells by the
reticuloendothelial system in chronic hemolytic anemia.
7.3. Growth impairment and pubertal delay
Chronic anemia is known to have a negative effect on growth
and puberty [41]. However, these features are multifactorial,
Figure 2. Spleen myeloid metaplasia: note numerous clusters of erythroblasts
within the splenic red pulp (courtesy of Professor T. Molina, Hôpital Necker-
Enfants malades, Paris, France). Full color available online.
and distinguishing between the consequences of low Hb level
and the complications of underlying pathologies causing ane-
mia is difficult. Besides the genetic syndromes associating
anemia and congenital short stature (such as Diamond–
Blackfan disease), stunted growth is most severe in thalasse-
mia major syndromes and chronic renal diseases, for presum-
ably multiple-associated endocrine and metabolic causes [42].
Permanently increasing Hb level to >9–10 g/dL restores
growth spurts in most children with thalassemia major [43].
Pubertal delay and growth retardation are frequent in SCD.
However, adult patients are often underweight but have a
normal height [44,45].
7.4. Brain consequences
Data are again equivocal because of many confounding fac-
tors. Nevertheless, iron-deficient anemic school children can
show decreased motor activity, social inattention, and
decreased school performance [46,47]. Six-month-old children
with iron-deficient anemia show delayed maturation of audi-
tory brainstem response as compared with non-anemic con-
trol infants [48]. In the same line, daily iron supplementation in
2- to 5-year-old children has been reported to produce a small
improvement in cognitive development, but this result might
be due to the effects of iron itself [49]. The severity of anemia
has been found associated with cognitive delay in infants
with SCD [50]. A study of SCD infants aged 3, 9, and 12 months
showed significantly lower scores on the Bayley Infant
Neurodevelopmental Screener (BINS) for patients than con-
trols. BINS scores were positively correlated with Hb level at
9 months of age [51].
Increased risk of stroke has been reported in different chronic
diseases responsible for anemia. The most documented associa-
tion has been found in children with SCD, but low Hb level is not
the main determinant of cerebral vasculopathy in this population
[50]. Hypercoagulability seems more responsible than anemia for
increased stroke risk in patients with thalassemia [52]. In the
general population, anemia is present in 15–29% of adults with
acute stroke [53]. However, except for SCD children, anemia is
not a risk factor for pediatric stroke [54].
7.5. Cardiac consequences
To preserve oxygen delivery to tissues in cases of anemia,
cardiac output increases via increased stroke volume and
heart rate [33]. Consequences are tachycardia, heart murmur,
cardiomegaly, and electrocardiographic abnormalities.
Increased left ventricular end-diastolic diameter, left ventricu-
lar posterior wall thickness, and right ventricular dilatation
have been found correlated with the severity of anemia in
SCD children [55,56]. In the long term, cardiac function is
altered, with symptoms of left heart failure.
7.6. Overall mortality
Anemia is a known risk factor for death even when mild or
moderate [57]. In a meta-analysis of 12,000 children from six
African countries, risk of death was decreased by 24% for each
1 g/dL increase in Hb level [58]. However, given the multiple

overlapping comorbidities in children who die in developing
countries, infections and especially malaria being the main
examples, there are likely several contributors to death, and
determining the specific contribution of anemia to child mor-
tality is extremely difficult.
8. Expert commentary
Anemia is frequent in children worldwide and is assumed to
be mostly due to iron deficiency. Despite this high frequency,
there are little validated data on the best screening methods,
and some recommended tools, such as coupling serum ferritin
and CRP levels, are too expensive to be widely used in low-
income countries, where anemia is the most prevalent.
Anemia in children should never be trivialized, since other
causes than iron deficiency are possible and may be poten-
tially life threatening. Full-term neonates with Hb level
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<13.5 g/dL require a diagnostic work-up, iron deprivation
being exceptional and iron supplementation in most cases
not justified in anemic neonates. Likewise, giving folic acid
must be coupled with a checkup to search for the main causes
of neonatal anemia. In case of iron deficiency, normalization of
iron stores should be systematically controlled at the end of
iron treatment in order to exclude malabsorption or chronic
occult bleeding.
Assessing the effects of anemia on its own is difficult
because comorbidities may interfere with the genesis of com-
plications. Chronic anemia may impair growth, cardiac func-
tion, and cognitive development in infants, but other
consequences are rather poorly evaluated and should be stu-
died more thoroughly.
9. Five-year view
Improved knowledge of the definition and causes for pediatric
anemia should be favored among first-line physicians, with sim-
ple directional trees to help them diagnose the cause of anemia.
Strategies to prevent and screen for iron-deficient anemia
should be improved, especially in low-income countries.
Hopefully, current studies such as the BRINDA project will
help better defining how to adjust ferritin for inflammation
in the assessment of iron deficiency [23].
Targeted next-generation sequencing and whole-genome
sequencing could be useful approaches in the near future to
help identifying new mutations causing anemias for which
conventional techniques failed providing accurate diagnosis.
Experimental programs have to evaluate the best benefit–cost
ratio of their respective implementation.
Key issues
● A full-term neonate with Hb level <13.5 g/dL has anemia
and should have a diagnostic work-up.
● Iron deprivation in a full-term neonate is exceptional. Iron
supplementation in an anemic neonate is in most cases not
justified.
● The most frequent causes of hemolytic anemia in neo-
nates are G6PD deficiency, hereditary spherocytosis, and
EXPERT REVIEW OF HEMATOLOGY 1027
fetomaternal red cell antigen incompatibility. SCD is not a
cause of neonatal anemia.
● Iron deficiency can be assessed by measuring serum ferritin
and CRP levels. Inflammation increases serum ferritin level.
● Chronic anemia may be relatively well tolerated but may
impair growth, cardiac function and cognitive development
in infants. Other consequences are rather poorly established.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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