Screening of iron deficiency anaemia in early childhood

The World Health Organization (WHO) European Region is developing a new pocket book for primary health care for children and adolescents in Europe. This article is part of a series of reviews, which aim to summarize the existing recommendations and the most recent evidence on preventive interventions applied to children under five years of age to inform the WHO editorial group to make recommendations for health promotion in primary health care. In this article, we looked at the efficacy of universal screening of IDA in children under five years of age for improving growth, cognitive function, and psychomotor development.

Iron is necessary for the production of haemoglobin. When iron stores are too low, usually due to dietary iron deficiency, the haemoglobin synthesis is impaired and results in iron deficiency anaemia (IDA). IDA is defined as haemoglobin level under two standard deviations for age and sex (< 11 g/dL for children between six months and five years), with serum ferritin under 10 to 12 μg/L [1, 2]. Children under five years of age are especially at risk, and the major concern is that IDA may affect cognitive and psychomotor development.

WHO estimated the worldwide prevalence of anaemia at 42.6% in children between 6 and 59 months of age in 2011 [3]. Focusing on the European region, it was estimated that 22.9% of children between 6 and 59 months had anaemia, translating to 12.7 millions of children with anaemia. Iron deficiency (ID) is the most prevalent nutritional deficiency in children and the major cause of anaemia. WHO estimated that between 44 and 65% of children with anaemia in the European region were amendable to iron supplementation [3]. Prevalence of IDA in children under five years of age was recently estimated at between 1 and 4% in the UK, the US, and other developed countries [2, 4].

Although IDA most commonly presents without symptoms, ID and IDA have been associated with cognitive impairment and neurodevelopmental delay at short and long term. However, this was based in observational studies with methodological flaws such as confounding with nutritional and socioeconomic factors, which make the cause-effect of the relationship difficult to establish.

The aim of screening IDA in children is the prompt identification and therefore early treatment of anaemia, which may improve health outcomes including growth, cognitive, psychomotor, and neurodevelopmental outcomes, mortality, and quality of life. Most infants with no risk factors such as prematurity or low birth weight are at low risk of iron deficiency during the first six months of life, due to iron stores from the perinatal period. This explains why screening programme usually focus on children from six months of age [3].

Criteria for a good screening programme that were adopted by the WHO are summarized in the core document [5].

We found no studies that evaluated the effectiveness of IDA screening in asymptomatic children between six and 24 months of age [8].

There is no single gold standard test to use as a screening tool for detection of IDA. Serum haemoglobin or haematocrit is usually the first test used to detect anaemia. However, this does not allow to distinguish between IDA and other causes of anaemia. Additional tests such as serum ferritin, transferrin saturation, erythrocyte protoporphyrin, and C-reactive protein (CRP) are required to detect iron deficiency.

Haemoglobin or haematocrit has a sensitivity estimated at 73% for detecting IDA, with a lower specificity estimated at 25%, as around half of cases with anaemia result from other causes than iron deficiency [1, 7]. The positive predictive value (PPV) of low haemoglobin for iron deficiency was estimated from 10 to 40% in children of 12 months of age [7]. PPV was found to be low if anaemia prevalence is under 10%, but increases in areas where anaemia prevalence is higher than 10% [1].

According to USPSTF review, there is a lack of data evaluating the sensitivity and specificity of other single tests for the detection of iron deficiency, such as serum ferritin, transferrin saturation, erythrocyte protoporphyrin, and CRP. Serum ferritin and CRP are acute phase reactants, and should therefore be measured in absence of infection or inflammation to avoid false positive results [7]. Serum ferritin is however considered as a ‘useful laboratory measure of iron status, with a low value being diagnostic of iron deficiency’ [9]. In 2007, the WHO and the CDC published a report on the assessment of the iron status in populations. This document was the result of a consultation that aimed to review and select the best indicators available to assess the iron status of populations and to evaluate the impact of interventions to control ID [6]. The authors reviewed the literature on indicators of iron status, ‘including red blood cell parameters, ferritin, free erythrocyte protoporphyrin, serum and plasma iron, total iron binding capacity, transferrin saturation and serum transferrin receptor’ and on the interpretation of indicators of iron status during an acute phase response. The authors reached the conclusions for recommendations that ‘measurements of serum ferritin and transferrin receptor provide the best approach to measuring the iron status of populations’, although ‘in places where infectious diseases are common, serum ferritin is not a useful indicator because inflammation leads to a rise in the concentration of serum ferritin as a result of the acute phase response to disease.’ Also, ‘serum ferritin is the best indicator of a response to an intervention to control iron deficiency and should be measured with the haemoglobin concentration in all programme evaluations’ [6]. Although this review and recommendations were focused to assess the iron status in populations, findings might be considered for application to IDA screening.

As an invasive blood test for population-based screening in children is unlikely to be accepted, the UK NSC review aimed to identify studies that would assess the diagnostic accuracy of non-invasive or minimally invasive screening test (such as urinary hepcidin) against a valid reference standard for identification of IDA (such as serum haemoglobin, haematocrit, serum ferritin or transferrin saturation levels) [4]. Review authors aimed to include studies that assessed screen test in a non-selected sample representative of the general UK population. However, no studies were identified that fulfilled their inclusion criteria.

A public consultation on IDA was conducted during the three months following the UK NSC publication of their updated recommendations in 2017 [12]. A German university replied to inform about a new non-invasive technique developed for the detection of erythrocyte zinc protoporphyrin by an optical measurement on the lower lip. According to this source, applying this technique to children under five years of age is feasible, and has a sensitivity of 83% and specificity of 93% against soluble transferrin receptor (for a threshold at 50 μmol / mol heme) [12].

Potential harms of screening include false positive results, leading to parents anxiety, and cost [7].

The 2015 USPSTF review found no studies that evaluated the direct harms derived from routine IDA screening on child health outcomes, and inadequate evidence on the harms of treatment of IDA in children between 6 and 24 months of age [8].

Reported adverse effects of oral iron include ‘limited gastrointestinal symptoms, darkening colour of stool, staining of teeth and gums, and drugs interactions with other medications’ [7]. The Cochrane authors did not include adverse effects from iron treatment as an outcome in their review [14]. The 2015 USPSTF review reported findings from one randomized controlled trial published in 1991. From 334 children, no differences were found between the iron and placebo groups in overall incidence or incidence of specific adverse events, including gastrointestinal events [8].