Iron is essential for many physiological functions of the body, and it is required for normal growth and development. Iron deficiency (ID) is the most common form of micronutrient malnutrition and is particularly prevalent in infants and young children in developing countries. Iron supplementation is considered the most effective strategy to combat the risk of ID and ID anaemia (IDA) in infants, although iron supplements cause a range of deleterious gut-related problems in malnourished children. The purpose of this review is to assess the available evidence on the effect of iron supplementation on the gut microbiota during childhood ID and to further assess whether prebiotics offer any benefits for iron supplementation. Prebiotics are well known to improve gut-microbial health in children, and recent reports indicate that prebiotics can mitigate the adverse gut-related effects of iron supplementation in children with ID and IDA. Thus, provision of prebiotics alongside iron supplements has the potential for an enhanced strategy for combatting ID and IDA among children in the developing world. However, further understanding is required before the benefit of such combined treatments of ID in nutritionally deprived children across populations can be fully confirmed. Such enhanced understanding is of high relevance in resource-poor countries where ID, poor sanitation and hygiene, alongside inadequate access to good drinking water and poor health systems, are serious public health concerns.

Excess unabsorbed iron in the gastrointestinal tract may select for enteric pathogens and increase the incidence and severity of infectious disease. Aspergillus oryzae (Ao) is a filamentous fungus that has the ability to accumulate and store large amounts of iron, and when used as a supplement or fortificant, has similar absorption to ferrous sulphate (FeSO4) in humans. The objective of this study was to determine the effect of iron-enriched Ao (Ao iron) compared with FeSO4 on iron accumulation, growth and motility of the Gram-negative enteric pathogen, S. Typhimurium. S. Typhimurium was cultured in media containing no added iron or 1 μM elemental iron as either Ao iron or FeSO4. S. Typhimurium cultured with FeSO4 accumulated more iron than those cultured with Ao iron. Genes regulated by the iron-activated transcriptional repressor, Fur, did not differ between control and Ao iron, but decreased in S. Typhimurium cultured with FeSO4 compared with both groups. Growth of S. Typhimurium was greater when cultured with FeSO4 compared with Ao iron and control. S. Typhimurium swam faster, had greater acceleration and travelled further when cultured with FeSO4 compared with Ao iron and control; swim speed, acceleration and distance travelled did not differ between Ao iron and control. These findings provide evidence that Ao iron reduces the virulence of a common enteric pathogen in vitro. Further research is required to determine whether iron-enriched Ao is a suitable iron supplement to improve iron delivery in areas with a high infection burden.

In 2013, the Danish Health Authorities recommended a change in prophylactic iron supplementation to 40–50 mg/d from gestational week 10. Hence, the aims of the present study were (1) to estimate the prevalence of women who follow the Danish recommendation on iron supplementation during the last 3 weeks of the first trimester of pregnancy and (2) to identify potential sociodemographic, reproductive and health-related pre-pregnancy predictors for iron supplementation during the first trimester. We conducted a cross-sectional study with data from the hospital-based Copenhagen Pregnancy Cohort. Characteristics were analysed by descriptive statistics and multivariable logistic regression analysis was performed to examine the associations between predictors and iron supplementation during the last 3 weeks of the first trimester. The study population consisted of 23 533 pregnant women attending antenatal care at Copenhagen University Hospital - Rigshospitalet from October 2013 to May 2019. The prevalence of iron supplementation according to recommendations was 49⋅1 %. The pre-pregnancy factors of ≥40 years of age, the educational level below a higher degree and a vegetarian or vegan diet were identified as predictors for iron supplementation during the first trimester of pregnancy. Approximately half of the women were supplemented with the recommended dose of iron during the first trimester of pregnancy. We identified pre-pregnancy predictors associated with iron supplementation. Interventions that target women of reproductive age are needed. An enhanced focus on iron supplementation during pregnancy should be incorporated in pre-pregnancy and interpregnancy counselling.

Iron deficiency remains the largest nutritional deficiency worldwide and the main cause of anaemia. Severe iron deficiency leads to anaemia known as iron deficiency anaemia (IDA), which affects a total of 1·24 billion people, the majority of whom are children and women from resource-poor countries. In sub-Saharan Africa, iron deficiency is frequently exacerbated by concomitant parasitic and bacterial infections and contributes to over 120 000 maternal deaths a year, while it irreparably limits the cognitive development of children and leads to poor outcomes in pregnancy.

Currently available iron compounds are cheap and readily available, but constitute a non-physiological approach to providing iron that leads to significant side effects. Consequently, iron deficiency and IDA remain without an effective treatment, particularly in populations with high burden of infectious diseases. So far, despite considerable investment in the past 25 years in nutrition interventions with iron supplementation and fortification, we have been unable to significantly decrease the burden of this disease in resource-poor countries.

If we are to eliminate this condition in the future, it is imperative to look beyond the strategies used until now and we should make an effort to combine community engagement and social science approaches to optimise supplementation and fortification programmes.

Growth faltering and anaemia remain unacceptably high among infants and young children in Ethiopia. In this study, we investigated the relationships among Fe supplement use (ISU), Hb concentration and linear growth, hypothesising positive relationships between ISU and Hb, ISU and linear growth and Hb and linear growth. We used a nationally representative data of 2400 children aged 6–24 months from the Ethiopian Demographic and Health Survey (EDHS) 2011, conducted following a stratified, two-stage cluster sampling. We examined the links by Pearson’s correlation, bivariate and multivariate linear regression analyses and reported adjusted estimates. We found that ISU was not significantly associated with either Hb (β=1·09; 95 % CI −2·73, 5·01, P=0·567) or linear growth (β=0·07; 95 % CI −0·06, 0·21, P=0·217). We found a positive, however, weak, correlation between Hb and linear growth (r 0·09; 95 % CI 0·06, 0·11, P<0·001). Hb predicted linear growth independent of a variety dietary and non-dietary factors (β=0·08; 95 % CI 0·04, 0·11, P<0·001). Although not the primary focus of the study, our analysis showed that age and breast-feeding duration were independently associated with Hb; age, birth type, size at birth, sex, breast-feeding duration, dietary diversity and deworming were independently associated with linear growth, indicating that Hb and linear growth are multifactorial with both nutritional and non-nutritional factors implicated. Further studies, with better design and exposure assessment, are warranted on the relation of ISU with Hb or linear growth.

Fe supplementation is a common strategy to correct Fe-deficiency anaemia in children; however, it may modify the gut microbiota and increase the risk for enteropathogenic infection. In the present study, we studied the impact of Fe supplementation on the abundance of dominant bacterial groups in the gut, faecal SCFA concentration and gut inflammation in children living in rural South Africa. In a randomised, placebo-controlled intervention trial of 38 weeks, 6- to 11-year-old children with Fe deficiency received orally either tablets containing 50 mg Fe as FeSO4 (n 22) for 4 d/week or identical placebo (n 27). In addition, Fe-sufficient children (n 24) were included as a non-treated reference group. Faecal samples were analysed at baseline and at 2, 12 and 38 weeks to determine the effects of Fe supplementation on ten bacterial groups in the gut (quantitative PCR), faecal SCFA concentration (HPLC) and gut inflammation (faecal calprotectin concentration). At baseline, concentrations of bacterial groups in the gut, faecal SCFA and faecal calprotectin did not differ between Fe-deficient and Fe-sufficient children. Fe supplementation significantly improved Fe status in Fe-deficient children and did not significantly increase faecal calprotectin concentration. Moreover, no significant effect of Fe treatment or time × treatment interaction on the concentrations of bacterial groups in the gut or faecal SCFA was observed compared with the placebo treatment. Also, there were no significant differences observed in the concentrations of any of the bacterial target groups or faecal SCFA at 2, 12 or 38 weeks between the three groups of children when correcting for baseline values. The present study suggests that in African children with a low enteropathogen burden, Fe status and dietary Fe supplementation did not significantly affect the dominant bacterial groups in the gut, faecal SCFA concentration or gut inflammation.

Fe deficiency is still common in infancy, even in affluent societies, and has prompted Fe fortification of food products and use of Fe supplements in many populations. In the present study, we tested the hypothesis that Fe status among 9-month-old infants following the Danish Fe supplementation recommendation (>400 ml Fe-fortified formula or 8 mg Fe/d) is associated with more favourable levels of Fe status indicators compared to those not following the recommendation. A random sample of 9-month-old infants living in Copenhagen was established and 312 healthy term infants were examined at 9·1 (sd 0·3) months of age. Blood samples were available from 278 infants. Overall, twenty infants (7·8 %) had Fe deficiency (serum ferritin < 12 μg/l) and < 1 % had Fe deficiency anaemia (serum ferritin < 12 μg/l and Hb < 100 g/l). Serum ferritin was positively associated with birth weight (P < 0·001), intake of fortified formula and follow-on formula (P = 0·001), and female sex (P < 0·001). Cow's milk intake and length of exclusive breast-feeding were negatively associated with Hb levels (P = 0·013 and P < 0·001). Serum ferritin levels were significantly higher (P < 0·0001) and transferrin receptor (TfR) was significantly lower (P = 0·003) among infants (n 188) meeting the Fe supplementation recommendation compared to those (n 67) not meeting the recommendation. No significant difference between these two groups was found for Hb. In conclusion, this study confirmed that Fe status of infants following the Danish Fe supplementation recommendation was significantly associated with increased serum ferritin and decreased levels of TfR indicating more favourable Fe status, compared to infants not following the recommendation.

Excess calcium is well known to induce iron deficiency. Furthermore, excess calcium increases hepatic copper concentration and decreases renal copper concentration. We investigated the effect of iron supplementation on the tissue distribution of copper in rats given a high-calcium diet. Male rats (5 weeks old) were divided into four groups; a control group, and three groups given a diet containing 5-fold higher calcium than its requirement and an intraperitoneal iron supplementation of 0, 1 or 2 mg/week as iron dextran. The animals were fed their respective experimental diets with or without iron supplementation for 4 weeks. Although the high-calcium diet had no effect on calcium concentrations in the liver, kidney, testis, spleen and plasma, it reduced haematocrit and iron concentrations in the liver, kidney and testis and the rats had a moderate iron deficiency. The iron supplementation restored to normal these signs of iron deficiency. The high-calcium diet increased hepatic copper concentration but decreased plasma copper concentration and ceruloplasmin activity, which was restored by the iron supplementation. The copper concentration in bile was neither affected by the high-calcium diet nor the iron supplementation. The high-calcium diet decreased the copper concentration in the kidney, which was not restored by the iron supplementation. These results suggest that secondary iron deficiency stimulates hepatic accumulation of copper in rats given excess calcium by suppressing copper efflux into the circulation. The reduced renal copper concentration by excess calcium is independent of the iron deficiency.

Although routine Fe supplementation in pregnancy is a common practice, its clinical benefits or risks are uncertain. Children born to mothers in the Fe group in a trial of Fe supplementation in pregnancy have been found to have a significantly higher risk of abnormal behaviour at 4 years of age than those born to mothers in the placebo group. The objective of the present study therefore was to determine whether Fe supplementation in pregnancy influences child behaviour at early school age. The study was a follow-up of children at 6–8 years of age after women (n 430) were randomly allocated to receive a daily Fe supplement (20 mg) or placebo from 20 weeks gestation until delivery. The supplement reduced the incidence of Fe-deficiency anaemia at delivery from 9 % to 1 %. Child behaviour and temperament were assessed using the Strengths and Difficulties Questionnaire and the Short Temperament Scale for Children. Of the children, 264 (61 %) participated in the follow-up. Mean behaviour and temperament scores and the proportion of parent-rated and teacher-rated abnormal total difficulties scores did not differ between the Fe and placebo groups. However, the incidence of children with an abnormal teacher-rated peer problems subscale score was higher in the Fe group (eleven of 112 subjects; 8 %) than in the placebo group (three of 113 subjects; 2 %); the relative risk was 3·70 (95 % CI 1·06, 12·91; P = 0·026). We conclude that prenatal Fe supplementation had no consistent effect on child behaviour at early school age in this study population. Further investigation regarding the long-term effects of this common practice is warranted.

We aimed to study the response of serum transferrin receptors (sTfR) to Fe supplementation in women of childbearing age with Fe-deficiency erythropoiesis (IDE) and Fe-deficiency anaemia (IDA). Primary screening was performed in 942 women ranging in age from 18 to 45 years. After Fe-related biochemical indices such as serum ferritin, Zn protoporphyrin and Hb were determined, the subjects were divided into four groups: normal, Fe store depletion, IDE and IDA. A total of 131 women were randomly selected from the normal, IDE and IDA groups. Subsequently, seventy-six women with IDE and IDA were given various doses of Fe (14 mg/d for IDE; 28 mg/d for IDA) with ferrous l-threonate capsules for twelve consecutive weeks. After receiving Fe supplements, the levels of Fe and sTfR were determined at weeks 0, 3, 6, 9 and 12.The levels of sTfR in women of childbearing age with IDE and IDA were significantly higher than those in the normal group. After receiving Fe supplements, the levels of sTfR were significantly decreased in women of childbearing age with IDE and IDA, while the levels of serum ferritin were significantly increased. In conclusion, STfR can be used as a reliable indicator for assessing the efficacy of Fe supplements.

We evaluated the adverse effect of asymptomatic Helicobacter pylori infection in children on the response to Fe supplementation. One hundred and sixty-nine children aged 1–10 years from the urban poor community underwent a [13C]urea breath test for H. pylori and haematological tests at admission and after 8 weeks. Both H. pylori-positive and -negative children were randomly assigned to receive ferrous fumarate syrup (20 mg elemental Fe twice daily) or placebo for 8 weeks and a single dose of vitamin A (33,000μg). Admission findings were compared between H. pylori-positive and -negative children. Response to Fe was compared between Fe-supplemented H. pylori-positive and -negative children. Seventy-nine per cent of the children were aged 1–5 years and half of them were boys. In eighty-five H. pylori-positive and eighty-four H. pylori-negative children, the differences in mean Hb (112 (sd 12·6) v. 113 (sd 12·0) g/l), haematocrit (34 (sd 3·5) v. 35 (sd 3·2) %) and ferritin (23·8 v. 21·0 μg/l) were similar. After 8 weeks of Fe supplementation, mean Hb was 5·3 g/l more (95 % CI 1·59, 9·0) and haematocrit was 1·4 % more (95 % CI 0·2, 2·6) in H. pylori-negative (n 44) compared with H. pylori-positive (n 42) children. Mean ferritin was similar at admission and improved in both H. pylori-positive and -negative children. Asymptomatic H. pylori infection was not associated with higher rates of anaemia or Fe deficiency in children, but had a significant adverse effect on response to Fe therapy. However, this result is based on exploratory analysis and needs confirmation.

Strategies such as dietary diversification and food fortification have yielded significant results in controlling iron deficiency anaemia in developed countries. Reducing the prevalence of iron deficiency anaemia in developing countries is still a matter of importance. The major factors responsible for iron deficiency anaemia in the vulnerable segments of developing countries are reduced intake and poor bioavailability of dietary iron. Dietary diversification and food-based approaches pose considerable challenges before they can be implemented on a wide scale. Anaemia control programmes based on the administration of prophylactic doses of iron and folic acid tablets have been widely implemented. As the programmes were not effective in countries such as India, the dosage of iron was increased. The role of excess iron in causing intestinal oxidative stress has drawn attention to other approaches of iron supplementation. Prophylactic administration of iron along with antioxidants like vitamins E and C or foods rich in these vitamins is one such strategy. To reduce the intestinal oxidative stress, intermittent supplementation of iron is being considered. The potential benefits and shortcomings of these approaches are reviewed.

Patients expected to need at least three units of blood for their elective cardiovascular or orthopaedic surgery, were allocated randomly to receive intravenous (i.v.) Epoetin alfa 600 IU kg−1 (n = 27), 300 IU kg−1 (n = 30) or placebo (n = 23), on days 1, 4 and 7. Provided haemoglobin ≥ 11 g dL−1, one unit of blood was collected on days 1, 4, 7, 11 and 14. Iron supplementation was given throughout the study. Surgery was scheduled between days 18 and 21. Significantly more patients treated with Epoetin alfa (100% for 600 IU kg −1 ; 97% for 300 IU kg−1) were able to donate ≥ 4 units of blood compared with placebo (78%) (P = 0.011 and P = 0.032). No significant differences were seen in total patient exposure to homologous blood (7.4%, 3.3% and 17.4%, respectively). Mean red cell volume donated (P = 0.005 for 600 IU kg−1 ; P = 0.158 for 300 IU kg−1 both vs. placebo) and production (P < 0.001 and P = 0.012, respectively) were dose related. Twenty-four patients became iron deficient. No differences in the incidence of adverse events were seen between the groups.

A double-blind clinical trial was conducted among 9- to 11-year-old children in sixteen schools in the Chon Buri province of Thailand to assess the effects of an iron supplement combined with an anthelminthic agent (i.e. albendazole). In addition to the albendazole, Fe or placebo tablets were distributed to 2268 children enrolled in grades three to five without knowledge of the Fe status of the children. Criteria for case inclusion were: (a) absence of A E Bart's or haemoglobin (Hb) H disease, (b) absence of abnormal Hb EE, and (c) age, 108–144 months. The results showed a significant improvement in the Fe status of the children after 16 weeks of treatment. The increments were: Hb from 124 to 128 g/l, serum ferritin from 34.54 to 104.72 μg/l, transferrin saturation from 24.09 to 35.05%; free erythrocyte protoporphyrin decreased from 444.7 to 281.4 μg/l erythrocytes. These changes were significantly greater than in the control group that received only the anthelminthic agent. However, the administration of albendazole only also resulted in significant changes in the same Fe indicators.