Protocol for a randomised, multicentre, four-arm, double-blinded, placebo-controlled trial to assess the benefits and safety of iron supplementation with malaria chemoprevention to children in Malawi: IRMA trial.

INTRODUCTION: Approximately 40% of children aged 6-59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development. METHODS AND ANALYSIS: IRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period. ETHICS AND DISSEMINATION: The trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders. TRIAL REGISTRATION NUMBER: ACTRN12620000386932.

Antenatal multiple micronutrient supplements versus iron-folic acid supplements and birth outcomes: Analysis by gestational age assessment method.

Meta-analyses consistently have found that antenatal multiple micronutrient supplementation (MMS) compared with iron and folic acid (IFA) alone reduce adverse birth outcomes. In 2020, the World Health Organization (WHO) placed a conditional recommendation for MMS and requested additional trials using ultrasounds to establish gestational age, because the evidence on low birthweight (LBW), preterm birth and small for gestational age (SGA) was considered inconsistent. We conducted meta-analyses to determine if the effects of MMS on LBW, preterm birth and SGA differed by gestational age assessment method. Using data from the 16 trials in the WHO analyses, we calculated the effect estimates of MMS versus IFA on birth outcomes (generic inverse variance method and random effects model) stratified by method of gestational age assessment: ultrasound, prospective collection of the date of last menstrual period (LMP) and confirmation of pregnancy by urine test and recall of LMP. The effects of MMS versus IFA on birthweight, preterm birth and SGA appeared consistent across subgroups with no evidence of subgroup differences (p > 0.05). When limited to the seven trials that used ultrasound, the beneficial effects of MMS were demonstrated: risk ratios of 0.87 (95% confidence interval [CI] 0.78-0.97) for LBW, 0.90 (95% CI, 0.79-1.03) for preterm birth and 0.9 (95% CI, 0.83-0.99) for SGA. Sensitivity analyses indicated consistency in the results. These results, together with recent analyses demonstrating comparable effects of MMS (vs. IFA) on maternal anaemia outcomes, strengthen the evidence to support a transition from IFA to MMS programmes in low- and middle-income countries.

Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial.

BACKGROUND: Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women. METHODS: In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks' gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks' gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to 4 weeks' post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up. FINDINGS: Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at 4 weeks' post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference -3·1 g [-75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34). INTERPRETATION: In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks' gestation or increase birthweight. FUNDING: Bill & Melinda Gates Foundation (INV-010612).

Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP - TT).

Background: Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care. Methods: This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin <10 g/dL - who are randomized to receive either parenteral iron - with FCM - or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester REVAMP trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin <11 g/dL - at 36 weeks' gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters. Discussion: This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.

Absorption of iron from edible house crickets: a randomized crossover stable-isotope study in humans.

BACKGROUND: Edible insects are a novel source of animal protein. Moreover, edible insects contain iron concentrations similar to meat, potentially making them a valuable iron source for human consumers. Yet, it is unknown to what extent iron from insects is absorbed in humans. OBJECTIVES: In this exploratory study, we assessed fractional iron absorption from house crickets (Acheta domesticus) consumed with refined (low-phytate, noninhibiting) or nonrefined (high-phytate, inhibiting) meals. METHODS: Intrinsically [57Fe]-labeled and control crickets were reared. Six iron-balanced experimental meals were randomly administered crossover to 20 iron-depleted females (serum ferritin <25 µg/L; 18-30 y old), in 2 time-blocks of 3 consecutive days, 2 wk apart. Three meals consisted of refined maize flour porridge with either [57Fe]-labeled crickets, [58Fe]SO4 (reference meal), or unlabeled crickets plus [54Fe]SO4. The other 3 meals consisted of nonrefined maize flour porridge with the same respective additions. Blood samples were drawn to assess the 14-d isotope enrichment in erythrocytes, and meal-specific fractional iron absorption was calculated. In vitro digestion was used to explore possible explanations for unexpected findings. RESULTS: Mean fractional iron absorption from 57Fe-labeled house crickets with refined maize porridge (3.06%) and from refined maize porridge with unlabeled crickets (4.92%) was lower than from the reference meal (14.2%), with respective mean differences of -11.1% (95% CI: -12.6%, -9.68%) and -9.29% (95% CI: -10.8%, -7.77%). Iron absorption from all meals based on unrefined maize porridge was low (<3%), and did not differ for the 2 meals with crickets compared with the reference meal. In vitro digestion showed that chitin, chitosan, and calcium limited iron bioaccessibility to a large extent. CONCLUSIONS: Iron absorption from house crickets and fortified maize porridge with crickets is low, which may be explained by the presence of chitin and other inhibitors in the cricket biomass.This trial was registered at https://www.trialregister.nl as NL6821.

Reliability and validity of depression anxiety stress scale (DASS)-21 in screening for common mental disorders among postpartum women in Malawi.

BACKGROUND: Approximately one in five women who have recently given birth suffer from common mental disorder (CMD), particularly depression and/or anxiety. Most available CMD screening tools in most low- and middle-income countries do not screen for more than one mental health problem. Having a screening tool that is free to use, short in assessment time, and used to screen for more than one CMD is appealing in a resource-constrained setting. METHOD: We conducted a criterion validation study of the Chichewa translated and adapted DASS-21 instrument against gold standard diagnoses of depression and anxiety disorders using an independently administered Structured Clinical Interview for DSM-IV (SCID). We compared the performance of the DASS-depression subscale with the Edinburgh Postpartum Depression Scale (EPDS). Internal reliability was reported using both Cronbach's alpha and ordinal alpha. The DASS-21 and EPDS ability to discriminate cases from non-cases was assessed by receiver operating characteristics (ROC) analysis. We selected cut-off points for DASS-21 and EPDS that maximise both sensitivity and specificity. RESULTS: One hundred fifteen participants were administered all the measures. Approximately 11.3% and 14.8% had depression and anxiety diagnoses respectively using SCID. The overall Cronbach's alpha for the DASS-21 scale was 0.74. The DASS-21 subscales had Cronbach's alpha values of 0.66, 0.29 and 0.52 for depression (DASS-D), anxiety (DASS-A) and stress (DASS-S), respectively. The ordinal alpha for DASS-D, DASS-A and DASS-S subscales were 0.83, 0.74 and 0.87, respectively. The area under the ROC curve was 0.76 (95% CI: 0.61; 0.91) for DASS-D and 0.65 for DASS-A. At a cut-off point of one or more, the sensitivity and specificity for DASS-D were 69.2% and 75.5%, whilst DASS-A was 52.9% and 75.5%, respectively. Pearson correlation coefficient for the association between DASS-D and EPDS was r = 0.61, p < 0.001. CONCLUSION: The DASS-21 had good internal reliability (Cronbach's alpha), and its ordinal alpha demonstrated good internal reliability for all its sub-scales. Regarding the criterion validation, only the DASS-D and EPDS demonstrated a satisfactory ability to discriminate cases from non-cases. Our findings suggest that health practitioners can use DASS-D as an alternative tool in screening depression as it has fewer questions than EPDS.

Effect of postpartum anaemia on maternal health-related quality of life: a systematic review and meta-analysis.

BACKGROUND: Postpartum anaemia remains a persistent and severe public health issue in many parts of the world. Studies have reported mixed findings on the effects of anaemia during the postpartum period on maternal health-related quality of life (HRQoL). We conducted this systematic review to summarise available evidence to inform public health practitioners on whether 1) anaemia negatively impact maternal health-related quality of life and 2) whether iron supplementation in anaemic women can improve maternal HRQoL during the postpartum period. METHODS: This review's protocol was registered online with PROSPERO (CRD42020206618). We extensively searched Embase, PubMed, Cochrane and Scopus through the HINARI website to identify studies that reported either association or effect of postpartum anaemia on fatigue, depression and mother-child interaction. We restricted our search to studies of human females published in English language from databases inception until August 2020. We followed a Cochrane guideline for reporting systematic reviews and meta-analysis to synthesise data. RESULTS: Twenty-seven studies were included in this systematic review, with some reporting all three domains (fatigue, depression and mother-child interaction) of HRQoL. Seven observational studies with pooled dichotomous outcomes showed that iron deficient or anaemic women were 1.66 times more likely to experience symptoms of depression than non-anaemic or iron-replete women [RR = 1.66 (95% CI: 1.28; 2.16), I2 = 67.0%, P < 0.01]. In three randomized controlled trials (RCTs), pooled continuous data showed statistically significant reduction in fatigue scores in women who received iron supplementation than the control group [MD: -1.85 (95% CI: -3.04; -0.67), I2 = 65.0%, p < 0.06]. Two of the four included studies showed that anaemic mothers were less responsive and had negative feelings towards their children than non-anaemic mothers. CONCLUSION: Evidence from this review suggests that postpartum anaemia negatively affects health-related quality of life and that iron replenishment improves both symptoms of fatigue and depression. Nevertheless, it remains unclear whether postpartum anaemia affects mother-child interaction.

Iron Bioavailability from Infant Cereals Containing Whole Grains and Pulses: A Stable Isotope Study in Malawian Children.

BACKGROUND: Compared with infant cereals based on refined grains, an infant cereal containing whole grains (WGs) and pulses with adequate amounts of ascorbic acid to protect against absorption inhibitors could be a healthier source of well-absorbed iron. However, iron absorption from such cereals is uncertain. OBJECTIVE: We measured iron bioavailability from ferrous fumarate (Fefum) added to commercial infant cereals containing 1) refined wheat flour (reference meal), 2) WG wheat and lentil flour (WG-wheat-lentil), 3) WG wheat and chickpea flour (WG-wheat-chickpeas), and 4) WG oat flour (WG-oat) and from ferrous bisglycinate (FeBG) added to the same oat-based cereal (WG-oat-FeBG). METHODS: In a prospective, single-blinded randomized crossover study, 6- to 14-mo-old Malawian children (n = 30) consumed 25-g servings of all 5 test meals containing 2.25 mg stable isotope-labeled iron and 13.5 mg ascorbic acid. Fractional iron absorption (FIA) was assessed by erythrocyte incorporation of isotopes after 14 d. Comparisons were made using linear mixed models. RESULTS: Seventy percent of the children were anemic and 67% were iron deficient. Geometric mean FIA percentages (-SD, +SD) from the cereals were as follows: 1) refined wheat, 12.1 (4.8, 30.6); 2) WG-wheat-lentil, 15.8 (6.6, 37.6); 3) WG-wheat-chickpeas, 12.8 (5.5, 29.8); and 4) WG-oat, 9.2 (3.9, 21.5) and 7.4 (2.9, 18.9) from WG-oat-FeBG. Meal predicted FIA (P ≤ 0.001), whereas in pairwise comparisons, only WG-oat-FeBG was significantly different compared with the refined wheat meal (P = 0.02). In addition, FIAs from WG-wheat-lentil and WG-wheat-chickpeas were significantly higher than from WG-oat (P = 0.002 and P = 0.04, respectively) and WG-oat-FeBG (P < 0.001 and P = 0.004, respectively). CONCLUSION: In Malawian children, when given with ascorbic acid at a molar ratio of 2:1, iron bioavailability from Fefum-fortified infant cereals containing WG wheat and pulses is ≈13-15%, whereas that from FeBG- and Fefum-fortified infant cereals based on WG oats is ≈7-9%.

Perceptions and experiences of intravenous iron treatment for anaemia in pregnancy in Malawi: a formative qualitative study.

Background: The study objective was to explore opinions, identify experiences, and describe perspectives on the acceptability of intravenous (IV) iron to treat anaemia in pregnancy and identify potential barriers and facilitators of introducing IV iron in the Malawian healthcare system. Methods: We conducted 15 in-depth interviews and two focus group discussions with pregnant women, and seven in-depth interviews with health workers at a community-based health centre in Blantyre and a tertiary hospital in Zomba. Results: Most women who used IV iron treatment during the second trimester of pregnancy reported feeling better and stronger after receiving the intervention. Women perceived that IV iron treatment worked faster and increased their haemoglobin count. However, cultural beliefs that IV iron treatment will cause miscarriage and the perception that study procedures involved Satanism and vampirism practices were barriers to acceptability. Health workers found IV iron treatment easy to administer because it is a single-dose treatment, simultaneously reducing the burden for pregnant women taking daily oral iron tablets. However, health workers expressed concerns about the costs and the need to train health workers before the large-scale implementation and integration of IV iron treatment into Malawi's routine care. Conclusions: Despite the perceived concerns and challenges experienced in participating in the first IV iron infusion trial in Malawi, participants' reflections suggest that IV iron infusion is acceptable for treating iron-deficiency anaemia in pregnancy. Participant advocate groups can offer a peer-to-peer education approach to sensitize and engage community members on the benefits of treatment and dispel concerns when the country contemplates integrating IV iron infusion for treating anaemia in pregnancy in Malawi.

Protocol for a multicentre, parallel-group, open-label randomised controlled trial comparing ferric carboxymaltose with the standard of care in anaemic Malawian pregnant women: the REVAMP trial.

INTRODUCTION: Anaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa and 49% in Asia. Oral iron therapy requires extended adherence to achieve correction of anaemia and replenishment of iron stores. Ferric carboxymaltose (FCM) is a recently established intravenous iron formulation associated with substantial advantages in safety, speed of delivery and total dose deliverable in a single infusion. We aim to determine whether FCM given once during the second trimester of pregnancy compared with standard oral iron distributed through routine antenatal services is effective and safe for treatment of moderate to severe maternal anaemia in sub-Saharan Africa. METHODS AND ANALYSIS: The randomized controlled trial of the effect of intravenous iron on anaemia in Malawian pregnant women (REVAMP) is a two-arm confirmatory individually randomised trial set in Blantyre and Zomba districts in Malawi. The trial will randomise 862 women in the second trimester of pregnancy with a capillary haemoglobin concentration below 100.0 g/L. The study comprises two arms: (a) intravenous FCM (20 mg/kg up to 1000 mg) given once at randomisation, and (b) standard of care oral iron (65 mg elemental iron two times per day) for 90 days (or the duration of pregnancy, whichever is shorter) provided according to local healthcare practices. Both arms receive sulfadoxine-pyrimethamine as intermittent preventive treatment in pregnancy. The primary outcome is the prevalence of anaemia (Hb <110.0 g/L) at 36 weeks' gestation. Secondary outcomes include birth weight, gestation duration and safety outcomes, including clinical malaria, serious perinatal events and postpartum haematologic and health-related outcomes in the mother and child. ETHICS AND DISSEMINATION: Ethical approval was granted by the Research Ethics Committee (COMREC P.02/18/2357) in Malawi and the Human Research Ethics Committee (WEHI: 18/02), Melbourne, Australia. The protocol is registered with the Australian and New Zealand Clinical Trials Registry. The results will be shared with the local community that enabled the research, and also to the international fora. TRIAL REGISTRATION NUMBER: ACTRN12618001268235; Pre-results.

Iron deficiency anaemia in sub-Saharan Africa: a review of current evidence and primary care recommendations for high-risk groups.

The epidemiology of iron deficiency anaemia in sub-Saharan Africa differs from that in other parts of the world. The low-quality diets prevalent in this region are a poor source of iron, the population is frequently exposed to infection, and demographic characteristics result in a greater prevalence of people at high risk of iron deficiency anaemia than in other parts of the world. We herein review the causes, disease burden, and consequences of iron deficiency anaemia in the general population in this region, and current policies and interventions for its control. The current debate is dominated by concerns about the safety of iron interventions, namely regarding its effects on malaria and other infectious diseases. However, universal antenatal iron supplementation and delayed cord clamping are safe interventions and stand out for their potential to improve maternal and infant health. Effective infection control is a precondition to safe and efficacious iron interventions in children. Greater emphasis should be given to approaches aiming to reduce iron loss due to helminth infections and menstruation, alongside interventions to increase iron intake. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Preanalytic and analytic factors affecting the measurement of haemoglobin concentration: impact on global estimates of anaemia prevalence.

The accuracy of haemoglobin concentration measurements is crucial for deriving global anaemia prevalence estimates and monitoring anaemia reduction strategies. In this analysis, we examined and quantified the factors affecting preanalytic and analytic variation in haemoglobin concentrations. Using cross-sectional data from three field studies (in children, pregnant and nonpregnant women), we examined the difference in haemoglobin concentration between venous-drawn and capillary-drawn blood measured by HemoCue (ie, preanalytic) and modelled how the bias observed may affect anaemia prevalence estimates in population surveys and anaemia public health severity classification across countries. Using data from an international quality assurance programme, we examined differences due to instrumentation from 16 different haematology analyzers (ie, analytic). Results indicated that capillary and venous haemoglobin concentrations are not in agreement (bias +5.7 g/L (limits of agreement (LoA) -11.2, 22.6) in preschool age children; range from -28 g/L to +20 g/L in pregnant women; bias +8.8 g/L (LoA -5.2, 22.9) in non-pregnant women). The bias observed could introduce changes in population survey estimates of anaemia of up to -20.7 percentage points in children and -28.2 percentage points in non-pregnant women after venous adjustment. Analytic variation was minimal and unlikely to influence the diagnosis of anaemia. These findings suggest that global estimates of anaemia prevalence derived from capillary haemoglobin, as they often are, may be inaccurate and lead to erroneous public health severity classification, but that point-of-care, or other, instruments should not introduce variation if properly used.

Antenatal iron supplementation, FGF23, and bone metabolism in Kenyan women and their offspring: secondary analysis of a randomized controlled trial.

BACKGROUND: Fibroblast growth factor-23 (FGF23) regulates body phosphate homeostasis primarily by increasing phosphaturia. It also acts as a vitamin D-regulating hormone. Maternal iron deficiency is associated with perturbed expression and/or regulation of FGF23 and hence might be implicated in the pathogenesis of hypophosphatemia-driven rickets in their offspring. OBJECTIVES: We aimed to determine the effect of antenatal oral iron supplementation on FGF23 concentration and maternal and infant markers of bone-mineral regulation. METHODS: We performed a secondary analysis of a trial in which 470 rural Kenyan women with singleton pregnancies and hemoglobin concentrations ≥ 90 g/L were randomly allocated to daily, supervised supplementation with 60 mg elemental iron as ferrous fumarate or placebo from 13-23 weeks of gestation until 1 mo postpartum. As previously reported, iron supplementation improved iron status in mothers and neonates. For the present study, we reanalyzed all available plasma samples collected in mothers and neonates at birth, with primary outcomes being concentrations of FGF23, measured by 2 assays: 1 that detects intact hormone and C-terminal cleavage products (total-FGF23) and another that detects the intact hormone only (intact-FGF23). RESULTS: Analysis was performed on 433 women (n = 216, iron group; n = 217, placebo group) and 414 neonates (n = 207, iron group; n = 207, placebo group). Antenatal iron supplementation reduced geometric mean total-FGF23 concentrations in mothers and neonates by 62.6% (95% CI: 53.0%, 70.3%) and 15.2% (95% CI: -0.3%, 28.4%, P = 0.06), respectively. In addition, it increased geometric mean neonatal intact-FGF23 concentrations by 21.6% (95% CI: 1.2%, 46.1%), increased geometric mean maternal hepcidin concentrations by 136.4% (95% CI: 86.1%, 200.3%), and decreased mean maternal 25-hydroxyvitamin D concentrations by 6.1 nmol/L (95% CI: -11.0, -1.2 nmol/L). CONCLUSIONS: Analysis of this randomized trial confirms that iron supplementation can reverse elevated FGF23 production caused by iron deficiency in iron-deficient mothers and their neonates. Further investigations are warranted to assess to what extent iron supplementation can prevent FGF23-mediated hypophosphatemic rickets or osteomalacia.

The contribution of provitamin A biofortified cassava to vitamin A intake in Nigerian pre-schoolchildren.

Biofortified yellow cassava has been developed to alleviate vitamin A deficiency. We examined the potential contribution of yellow cassava to total retinol activity equivalent (RAE) intake if replacing white by yellow cassava among pre-school Nigerian children. Dietary intake was assessed as part of a randomised controlled trial. Pre-schoolchildren (n 176) were randomly assigned to receive either white cassava (WC) or yellow cassava (YC) for 17 weeks. Dietary intake assessments were conducted during the intervention and 1 month after, when children had resumed their habitual diet. Differences in RAE intake between groups and time points were compared using a linear mixed model regression analysis. During intervention, median RAE intake was 536 µg/d in the YC group and 301 µg/d in the WC group (P < 0·0001). YC contributed approximately 40 % to total RAE intake. Of the children, 9 % in the YC group and 29 % in the WC group had RAE intake below the Estimated Average Requirement. After intervention, median RAE intake was 300 µg/d and did not differ between intervention groups (P = 0·5). The interaction effect of group and time showed a 37 % decrease in RAE intake in the YC group after the intervention (Exp(ß) = 0·63; 95 % CI 0·56, 0·72). If WC was replaced by YC after intervention, the potential contribution of YC to total RAE intake was estimated to be approximately 32 %. YC increased total RAE intake and showed a substantially lower inadequacy of intake. It is therefore recommended as a good source of provitamin A in cassava-consuming regions.

A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan.

Background: Anaemia affects more than half of Africa's pregnancies. Standard care, with oral iron tablets, often fails to achieve results, with compliance and gastrointestinal side-effects being a significant issue. In recent years, intravenous iron formulations have become safe, effective, and quick to administer, allowing the complete iron requirements of pregnancy to be provided in one 15-minute infusion. The Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP) will evaluate whether a modern intravenous iron formulation, ferric carboxymaltose (FCM), given once during the second trimester is effective and safe in improving maternal and neonatal outcomes for treatment of moderate to severe anaemia in sub-Saharan Africa.   The objective was to publish the detailed statistical analysis plan for the REVAMP trial prior to unblinding the allocated treatments and performing the analysis.   Methods: REVAMP is a multicentre, two-arm, open-label, parallel-group randomized control trial (RCT) in 862 pregnant women in their second trimester. The trial statistician developed the statistical analysis plan in consultation with the trial management team based on the protocol, data collection forms, and study outcomes available in the blinded study database.   Results: The detailed statistical analysis plan will support the statistical analyses and reporting of the REVAMP trial after unblinding the treatment allocations.   Conclusions: A statistical analysis plan allows for transparency as well as reproducibility of reporting and statistical analyses.

Daily consumption of pro-vitamin A biofortified (yellow) cassava improves serum retinol concentrations in preschool children in Nigeria: a randomized controlled trial.

BACKGROUND: Vitamin A deficiency is a public health problem in sub-Saharan Africa. Pro-vitamin A biofortified (yellow) cassava has the potential to contribute significantly to improve vitamin A status, especially in populations that are difficult to reach with other strategies. OBJECTIVES: The study aimed at determining the efficacy of biofortified cassava to improve vitamin A status of Nigerian preschool children. METHODS: An open-label randomized controlled trial was conducted in southwestern Nigeria. In total, 176 preschool children (aged 3-5 y) were randomized into 2 parallel arms comprising an experimental group (n = 88), fed foods prepared from biofortified (yellow) cassava, and a control group (n = 88), fed foods prepared from white cassava, twice a day, 6 d a week for 93 d. RESULTS: A total of 159 children completed the trial (yellow cassava group, n = 80; white cassava group, n = 79). Children consumed 221 and 74 µg/d retinol activity equivalents from intervention foods in the yellow and white cassava groups, respectively. The treatment effect on serum retinol concentrations at the end of the feeding trial was 0.06 µmol/L (95% CI: 0.004, 0.124 µmol/L), after adjustment for baseline retinol concentrations, inflammation, and asymptomatic malaria status. No significant treatment effects were detected for serum ß-carotene (adjusted effect: 3.9%; 95% CI: -0.6%, 8.6%) and gut permeability (adjusted effect: 0.002; 95% CI: -0.089, 0.092), but a significant effect was detected for hemoglobin concentrations (adjusted effect: 3.08 g/L; 95% CI: 0.38, 5.78 g/L). CONCLUSIONS: Daily consumption of ß-carotene from biofortified cassava improved serum retinol and hemoglobin concentrations modestly in Nigerian preschool children. This study was registered with clinicaltrials.gov as NCT02627222.

Iron Absorption from Iron-Biofortified Sweetpotato Is Higher Than Regular Sweetpotato in Malawian Women while Iron Absorption from Regular and Iron-Biofortified Potatoes Is High in Peruvian Women.

BACKGROUND: Sweetpotato and potato are fast-maturing staple crops and widely consumed in low- and middle-income countries. Conventional breeding to biofortify these crops with iron could improve iron intakes. To our knowledge, iron absorption from sweetpotato and potato has not been assessed. OBJECTIVE: The aim was to assess iron absorption from regular and iron-biofortified orange-fleshed sweetpotato in Malawi and yellow-fleshed potato and iron-biofortified purple-fleshed potato in Peru. METHODS: We conducted 2 randomized, multiple-meal studies in generally healthy, iron-depleted women of reproductive age. Malawian women (n = 24) received 400 g regular or biofortified sweetpotato test meals and Peruvian women (n = 35) received 500 g regular or biofortified potato test meals. Women consumed the meals at breakfast for 2 wk and were then crossed over to the other variety. We labeled the test meals with 57Fe or 58Fe and measured cumulative erythrocyte incorporation of the labels 14 d after completion of each test-meal sequence to calculate iron absorption. Iron absorption was compared by paired-sample t tests. RESULTS: The regular and biofortified orange-fleshed sweetpotato test meals contained 0.55 and 0.97 mg Fe/100 g. Geometric mean (95% CI) fractional iron absorption (FIA) was 5.82% (3.79%, 8.95%) and 6.02% (4.51%, 8.05%), respectively (P = 0.81), resulting in 1.9-fold higher total iron absorption (TIA) from biofortified sweetpotato (P < 0.001). The regular and biofortified potato test meals contained 0.33 and 0.69 mg Fe/100 g. FIA was 28.4% (23.5%, 34.2%) from the regular yellow-fleshed and 13.3% (10.6%, 16.6%) from the biofortified purple-fleshed potato meals, respectively (P < 0.001), resulting in no significant difference in TIA (P = 0.88). CONCLUSIONS: FIA from regular yellow-fleshed potato was remarkably high, at 28%. Iron absorbed from both potato test meals covered 33% of the daily absorbed iron requirement for women of reproductive age, while the biofortified orange-fleshed sweetpotato test meal covered 18% of this requirement. High polyphenol concentrations were likely the major inhibitors of iron absorption. These trials were registered at www.clinicaltrials.gov as NCT03840031 (Malawi) and NCT04216030 (Peru).

Antenatal iron supplementation and birth weight in conditions of high exposure to infectious diseases.

BACKGROUND: A recent cohort study among Papua New Guinean women surprisingly showed iron deficiency during pregnancy to be associated with increased birth weight. These findings seemingly contradict previous trial evidence that iron supplementation leads to increased birth weight, particularly in iron-deficient women, and hence require explanation. MAIN TEXT: We have re-analysed data from a previous trial in Kenya and demonstrated that, because women who were initially iron deficient respond better to iron supplementation, they show an increase in birthweight. There is evidence that this benefit is decreased in iron-replete women, possibly due to the adverse effects of haemoconcentration that can impair oxygen and nutrient transfer across the placenta. The Papua New Guinean results might be explained by a similar differential response to the iron supplements that they all received. CONCLUSIONS: Antenatal iron supplementation should ideally be administered in conjunction with measures to prevent, diagnose and treat malaria given the propensity of pathogenic microorganisms to proliferate in iron-supplemented individuals. However, even where services to prevent and treat malaria are poor, current evidence supports the conclusion that the benefits of universal iron supplementation outweigh its risks. Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1146-z. Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1376-8.

Iron Status of Kenyan Pregnant Women after Adjusting for Inflammation Using BRINDA Regression Analysis and Other Correction Methods.

Serum ferritin concentration is the preferred biomarker to assess population iron status in the absence of inflammation. Interpretation of this biomarker is complicated in populations with a high burden of infection, however, because inflammation increases serum ferritin concentration independently of iron status. We aimed to compare estimates of iron status of Kenyan pregnant women, with circulating ferritin concentrations adjusted for inflammation using newly proposed methods by the BRINDA project, or using previously proposed adjustment methods. We re-analyzed data from pregnant Kenyan women living in a rural area where malaria is highly endemic (n = 470) or in an urban area (n = 402). As proposed by the BRINDA group, we adjusted individual ferritin concentration by internal regression for circulating concentrations of C-reactive protein (CRP) and α1-acid glycoprotein (AGP). Other adjustment methods comprised: (a) arithmetic correction factors based on CRP or AGP; (b) exclusion of subjects with inflammation (CRP >5 mg/L or AGP >1 g/L); and (c) higher ferritin cut-off value (<30 µg/L). We additionally adjusted for Plasmodium infection as appropriate. Lastly, we assessed iron status without adjustment for inflammation. All correction methods increased prevalence of iron deficiency compared to the unadjusted estimates. This increase was more pronounced with the internal regression correction method. The iron deficiency prevalence estimate increased from 53% to 87% in rural Kisumu study and from 30% to 41% in the urban Nairobi study after adjusting for inflammation (CRP and AGP) using the BRINDA internal regression method. When we corrected for both inflammation and Plasmodium infection using the regression correction, it resulted in lower prevalence estimates compared to uninfected women. Application of linear regression methods to adjust circulating ferritin concentration for inflammation leads to markedly decreased point estimates for ferritin concentration and increased estimates for the prevalence of iron deficiency in pregnancy.

Insects as sources of iron and zinc in human nutrition.

Dietary deficiencies in Fe and Zn are globally widespread, causing serious health problems such as anaemia, poor pregnancy outcomes, increased risk of morbidity and mortality, stunted growth and impaired physical and cognitive development. Edible insects, of which a diversity of over 2000 species is available, are dietary components for about 2 billion individuals and are a valuable source of animal protein. In the present paper, we review the available information on Fe and Zn in edible insects and their potential as a source of these micronutrients for the rapidly growing human population. The levels of Fe and Zn present in eleven edible insect species that are mass-reared and six species that are collected from nature are similar to or higher than in other animal-based food sources. High protein levels in edible insect species are associated with high Fe and Zn levels. Fe and Zn levels are significantly positively correlated. Biochemically, Fe and Zn in insects occur predominantly in non-haem forms, bound to the proteins ferritin, transferrin and other transport and storage proteins. Knowledge gaps exist for bioavailability in the human alimentary tract, the effect of anti-nutritional factors in other dietary components such as grains on Fe and Zn absorption and the effect of food preparation methods. We conclude that edible insects present unique opportunities for improving the micronutrient status of both resource-poor and Western populations.