The Effect of Intermittent Antenatal Iron Supplementation on Infant Outcomes in Rural Vietnam: A Cluster Randomized Trial.

Objectives: Intermittent antenatal iron supplementation is an attractive alternative to daily dosing during pregnancy, however the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Vietnam. Methods: This cluster randomised trial was conducted in Ha Nam province, Vietnam. 1,258 pregnant women in 104 communes were assigned to daily iron-folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Results: There was no difference in birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI -22 to 78), or twice weekly MMN compared to daily IFA (MD -36.8 g; 95% CI -82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly compared to daily IFA (geometric mean ratio (GMR) 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (GMR 0.62; 95% CI 0.57 to 0.68), with no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56). Conclusions: Twice-weekly antenatal IFA supplementation achieved similar mean birthweight, and improved cognitive scores in infants at 6 months of age, compared to daily IFA supplementation, and should be considered for use in settings with low anemia prevalence.

Hepcidin Screening to Guide Iron Supplementation in African Children.

Objectives: Hematologic and non-hematologic benefits from iron supplementation are chiefly seen in iron deficient individuals; concerns that iron might promote infection especially in non-iron deficient individuals have complicated global anemia control policies, particularly in malaria-endemic settings. Iron homeostasis, including intestinal absorption, is controlled by hepcidin. Hepcidin is regulated by iron, erythropoietic drive, and inflammation, suggesting its potential utility to appraise iron status and thus guide iron supplementation. Methods: In 1338 African pre-school children we evaluated the Area Under the ROC Curve (AUCROC) for plasma hepcidin concentration as a diagnostic test of iron status, anemia type and erythrocyte incorporation of oral iron, determining and modeling the effects of cutoffs. Results: Hepcidin detected iron deficiency with an AUCROC = 0.85 (optimal sensitivity/ specificity at a cutoff of 5.5 ng/ml); this was not significantly affected by gender, wasting, malaria or carriage of inherited red cell disorders. In anemic children, hepcidin distinguished iron deficiency anemia from anemia of inflammation (AUCROC=0.89, optimal sensitivity/specificity cutoff 5.4 ng/ml). Hepcidin was the best predictor for >20% incorporation into erythrocytes of orally-administered 57Fe (AUCROC=0.90, optimal sensitivity/ specificity cutoff <6.9 ng/ml). If a hepcidin cutoff of 5.5 ng/ml had been used to guide iron supplementation in this population, 77% of iron deficient children would have received supplements while 80% of children with P. falciparum and 86% of children with anemia of inflammation would have avoided iron. Conclusions: In African children, hepcidin ascertains iron status, distinguishes iron deficiency anemia from anemia of inflammation, and hence could guide iron supplementation toward groups in whom it will likely be beneficial and safe.

Efficacy and Safety of Daily Iron Supplementation in Children: Lessons from Three Systematic Reviews and Meta-analyses of Randomized Controlled Trials.

Objectives: 47% of pre-school children and 25% of school-aged children are anaemic. Daily iron supplementation remains a key anaemia control intervention, but benefits and safety in children are debated. We systematically reviewed evidence for daily iron supplementation in 4–23m, 2-5y and 5-12y children. Methods: Separate searches and systematic-reviews/meta-analyses were performed for each age-group. Electronic databases and other sources were searched for randomized controlled trials comparing daily iron supplementation with control. Random-effects meta-analysis was used. Risk-of-bias was estimated using the Cochrane tool. Results: For children 4-23m, 2-5y and 5-12y respectively we identified 9533, 9169 and 16501 citations, from which 35, 15 and 32 eligible studies were identified, of which 9, 0 and 4 were at low overall risk-of-bias. Iron improved haemoglobin and ferritin and, in 4-23 m and 5-12y, reduced anaemia and iron deficiency. In 5-12y, iron improved global cognitive scores (SMD 0.50 [0.11, 0.90], p = 0.01) and in anaemic children, IQ (MD 4.55 [0.16, 8.94], p = 0.04). In 2-5y, limited data suggested a small improvement from iron in cognitive performance. No benefit was evident in 4-23 m (Bayley’s mental development index: MD 1·65 [–0·63, 3·94]) overall but was seen in iron deficient children (MD 5.90 [1.91, 10.00], p=0.005). Iron did not benefit growth in 4-23 m or 2-5y, but did improve growth in 5-12y. Vomiting and fever were increased in 4-23m receiving iron. Conclusions: Although supplementation iron improves cognition in older children or children with ID, evidence of non-haematologic benefit in pre-school children is inadequate. Further research is needed to enable guideline development.

Effects of Daily Iron Supplementation on Physical Performance in Women of Reproductive Age: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Objectives: Animal and human observational studies suggest iron deficiency impairs physical exercise performance but findings from randomized trials are conflicting. Iron deficiency and anaemia are especially common in women of reproductive age (WRA). We therefore performed a systematic review and meta-analysis to determine the effect of iron supplementation on exercise performance in WRA. Methods: We searched the Cochrane Central Register of Clinical Trials, MEDLINE, Scopus (comprising Embase and MEDLINE), WHO regional databases and other sources in July 2013. Randomised controlled trials that measured exercise outcomes in WRA randomized to daily oral iron supplementation versus control were eligible. Random-effects meta-analysis was used to calculate Mean Differences (MD) and Standardised MDs (SMD). Risk of bias was assessed using the Cochrane risk-of-bias tool. Results: Of 6757 titles screened, 22 eligible studies contained extractable data. Only 3 were at overall low risk of bias. Iron supplementation improved both maximal exercise performance, demonstrated by an increase in VO2 max (relative VO2 max: MD 2.35 mL/kg/min [95% CI 0.82, 3.88], P=0.003, 18 studies; absolute VO2 max: MD 0.11 L/min [0.03, 0.20], P=0.01, 9 studies; overall VO2 max: SMD 0.37 [0.11, 0.62] P=0.005, 20 studies), and submaximal exercise performance demonstrated by a lower heart rate (MD -4.05 beats per minute [-7.25, -0.85], P=0.01, 6 studies) and proportion of VO2 max (MD -2.68% [-4.94, -0.41], P=0.02, 6 studies) required to achieve defined workloads. Conclusions: Daily iron supplementation improves maximal and submaximal exercise performance in WRA, providing a rationale to prevent and treat iron deficiency in this group.