Two systematic reviews were recently commissioned by the USPSTF and the UK NSC to update their 2006 and 2012 recommendations respectively, based on the latest evidence available.
The USPSTF review included trials and control observational studies assessing screening in children between six and 24 months of age conducted in developed countries, as well as the effectiveness and harms of routine iron supplementation, and the association between a change in iron status and improvement in child health outcomes . Studies conducted in resource-poor populations were excluded. Of note, the focus was on ‘studies that involved iron supplementation and treatment regimens commonly used in clinical practice in the US.’ The literature search was conducted up to August 2014 with the aim to identify new studies to update the previous USPSTF systematic reviews [15, 16]. Review authors identified ten new studies addressing routine iron supplementation (which is beyond the scope of this summary), and no new study addressing any of the key questions established on screening for IDA. An update of the search was conducted in June 2018 and identified one study, but this study did not address the key questions on IDA screening . For each of the key question below, we therefore summarized the available evidence from studies that were identified from the previous USPSTF systematic reviews.
The UK NSC structured the review in four key questions to look at the evidence supporting IDA screening in children under five years of age . The review authors included different types of studies for each key question, but only included studies with children from the UK or other similar population. The literature search was conducted up to March 2017.
Effectiveness of population-based IDA screening in children under five years of age
We found no studies that evaluated the effectiveness of IDA screening in asymptomatic children between six and 24 months of age .
Accuracy of IDA screening in asymptomatic children under five years of age
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 . PPV was found to be low if anaemia prevalence is under 10%, but increases in areas where anaemia prevalence is higher than 10% .
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 . Serum ferritin is however considered as a ‘useful laboratory measure of iron status, with a low value being diagnostic of iron deficiency’ . 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 . 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’ . 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) . 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 . 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) .
Potential harms of screening children under five years of age for IDA
Potential harms of screening include false positive results, leading to parents anxiety, and cost .
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 .
Effectiveness of IDA treatment for improving health outcomes
Association between IDA and health outcomes
ID and IDA have been associated with cognitive and developmental delays, and some data showed that outcomes improve when children are identified and treated early. But this was from observational studies with methodological flaws and without an untreated control group .
None of the included systematic reviews identified any prospective study that would assess the effect of ID or IDA in children on developmental or other adverse health outcomes. No case control studies assessing clear historic data on ID or IDA status in children with adverse health outcomes were identified either [4, 8].
The UK NSC review concluded that ‘although iron treatment improves iron status in young children, there is conflicting evidence whether it has any effect of longer term health or developmental outcomes such as cognition’ .
Effectiveness of IDA treatment
Oral iron in different forms is usually used for treating IDA in children, but iron can also be administered parenterally.
A Cochrane review was conducted with the aim to determine the effects of iron therapy on psychomotor development and cognitive function among children under three years of age with IDA . The review authors conducted the literature search up to April 2013 and included eight trials. The pooled difference in pre- to post-treatment change in Bayley Scale Psychomotor Development Index between iron and placebo groups was − 1.25 (95% CI − 4.56 to 2.06; 5 trials) and in Bayley Scale Mental Development Index was 1.04 (95% CI − 1.30 to 3.39; 5 trials), with a low quality of the evidence for both outcomes. The review authors concluded that there was ‘no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development or cognitive function within 30 days after commencement of therapy’ and that ‘the effect of longer-term treatment remains unclear.’
The 2015 USPSTF review found no new study that looked at efficacy of oral iron for treating IDA in children between six and 24 months . Their previous systematic review included only one study published in 1986, which is included in the Cochrane review (described above). This study showed improved growth velocity as well as haemoglobin and ferritin levels, but no differences in psychomotor development. Authors of the USPSTF review judged this study as poor quality ‘due to baseline differences in age and unclear reporting of methods.’
The UK NSC review identified two systematic reviews . The Cochrane review already described above, and one review published in 2013, that evaluated the effect of iron therapy on developmental outcomes in pre-school children with non-anaemic iron deficiency, which does not reply to the question of the effect of iron in treating IDA . No further trials addressing this question were found.
Potential harms of treating IDA in children under five years of age
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’ . The Cochrane authors did not include adverse effects from iron treatment as an outcome in their review . 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 .