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Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy.

ABSTRACT: Anaemia and malaria are both common in pregnant women in Sub-Saharan Africa. Previous evidence has shown that iron supplementation may increase malaria risk. In this observational cohort study, we evaluated P. falciparum pathogenesis in vitro in RBCs from pregnant women during their 2nd and 3rd trimesters. RBCs were collected and assayed before (n?=?327), 14 days (n?=?82), 49 days (n?=?112) and 84 days (n?=?115) after iron supplementation (60?mg iron as ferrous fumarate daily). P. falciparum erythrocytic stage growth in vitro is reduced in anaemic pregnant women at baseline, but increased during supplementation. The elevated growth rates parallel increases in circulating CD71-positive reticulocytes and other markers of young RBCs. We conclude that Plasmodium growth in vitro is associated with elevated erythropoiesis, an obligate step towards erythroid recovery in response to supplementation. Our findings support current World Health Organization recommendations that iron supplementation be given in combination with malaria prevention and treatment services in malaria endemic areas.

SUBMITTER: Goheen MM

PROVIDER: S-EPMC5732269 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy.

Goheen Morgan M MM Bah Amat A Wegmüller Rita R Verhoef Hans H Darboe Bakary B Danso Ebrima E Prentice Andrew M AM Cerami Carla C

Scientific reports 20171215 1

Anaemia and malaria are both common in pregnant women in Sub-Saharan Africa. Previous evidence has shown that iron supplementation may increase malaria risk. In this observational cohort study, we evaluated P. falciparum pathogenesis in vitro in RBCs from pregnant women during their 2nd and 3rd trimesters. RBCs were collected and assayed before (n = 327), 14 days (n = 82), 49 days (n = 112) and 84 days (n = 115) after iron supplementation (60 mg iron as ferrous fumarate daily). P. falciparum ery ...[more]

PMID: 29247172

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Project description:Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection.This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint.Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis.These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria.National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Project description:BackgroundIron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it may also improve other maternal and birth outcomes.ObjectivesTo assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention.Search methodsWe searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 July 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (2 July 2012) and contacted relevant organisations for the identification of ongoing and unpublished studies.Selection criteriaRandomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy.Data collection and analysisWe assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy.Main resultsWe included 60 trials. Forty-three trials, involving more than 27,402 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo.Overall, women taking iron supplements were less likely to have low birthweight newborns (below 2500 g) compared with controls (8.4% versus 10.2%, average risk ratio (RR) 0.81; 95% confidence interval (CI) 0.68 to 0.97, 11 trials, 8480 women) and mean birthweight was 30.81 g greater for those infants whose mothers received iron during pregnancy (average mean difference (MD) 30.81; 95% CI 5.94 to 55.68, 14 trials, 9385 women). Preventive iron supplementation reduced the risk of maternal anaemia at term by 70% (RR 0.30; 95% CI 0.19 to 0.46, 14 trials, 2199 women) and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women). Although the difference between groups did not reach statistical significance, women who received iron supplements were more likely than controls to report side effects (25.3% versus 9.91%) (RR 2.36; 95% CI 0.96 to 5.82, 11 trials, 4418 women), particularly at doses 60 mg of elemental iron or higher. Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130g/L during pregnancy and at term. Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%.Authors' conclusionsPrenatal supplementation with daily iron are effective to reduce the risk of low birthweight, and to prevent maternal anaemia and iron deficiency in pregnancy. Associated maternal side effects and particularly high Hb concentrations during pregnancy at currently used doses suggest the need to update recommendations on doses and regimens for routine iron supplementation.

Project description:Background. Pregnancy-associated malaria (PAM) remains a significant health concern in sub-Saharan Africa. Cross-sectional studies report that iron might be associated with increased malaria morbidity, raising fears that current iron supplementation policies will cause harm in the present context of increasing resistance against intermittent preventive treatment in pregnancy (IPTp). Therefore, it is necessary to assess the relation of iron levels with malaria risk during the entire pregnancy. Methods. To investigate the association of maternal iron levels on malaria risk in the context of an IPTp clinical trial, 1005 human immunodeficiency virus-negative, pregnant Beninese women were monitored throughout their pregnancy between January 2010 and May 2011. Multilevel models with random intercept at the individual levels and random slope for gestational age were used to analyze the factors associated with increased risk of a positive blood smear and increased Plasmodium falciparum density. Results. During the follow-up, 29% of the women had at least 1 episode of malaria. On average, women had 0.52 positive smears (95% confidence interval [CI], 0.44-0.60). High iron levels (measured by the log10 of ferritin corrected on inflammation) were significantly associated with increased risk of a positive blood smear (adjusted odds ratio = 1.75; 95% CI, 1.46-2.11; P < .001) and high P falciparum density (beta estimate = 0.22; 95% CI, 0.18-0.27; P < .001) during the follow-up period adjusted on pregnancy parameters, comorbidities, environmental and socioeconomic indicators, and IPTp regime. Furthermore, iron-deficient women were significantly less likely to have a positive blood smear and high P falciparum density (P < .001 in both cases). Conclusions. Iron levels were positively associated with increased PAM during pregnancy in the context of IPTp. Supplementary interventional studies are needed to determine the benefits and risks of differently dosed iron and folate supplements in malaria-endemic regions.

Project description:Abstract Objectives Vitamin D may have an adjunctive role in the prevention and treatment of iron deficiency (ID) through its proposed role in the regulation of erythropoiesis and circulating hepcidin concentrations. Observational studies have shown associations between low vitamin D and iron status; however, there are few data from intervention trials. In participants of the Maternal Vitamin D for Infant Growth Trial (MDIG; NCT01924013), among whom the baseline prevalence of vitamin D deficiency was 64%, we examined the effect of prenatal vitamin D supplementation on iron status during pregnancy by testing the effect of vitamin D supplementation on serum ferritin concentrations. Methods In this double-blind, dose-response, randomized trial in Dhaka, Bangladesh, women were recruited at 17–24 weeks’ gestation and randomly assigned to receive a prenatal vitamin D3 dose of 4200, 16,800, 28,000 IU/week or placebo. Serum ferritin was quantified using an electro-chemiluminescence immunoassay. Plasma C-reactive protein (CRP) was analysed by enzyme-linked immunoassay. Linear regression was used to test the hypothesized effect of vitamin D supplementation on serum ferritin (n = 1011 of 1300 enrolled). In a sensitivity analysis, we adjusted for concurrent CRP to correct for inflammation (n = 920). Regression correction was used to generate an inflammation-corrected estimate of the prevalence of ID (n = 920). Results Prevalence of ID (serum ferritin <15 µg/L) was high overall (27% corrected for inflammation; 12% uncorrected). Geometric mean (95% confidence interval) serum ferritin concentrations were lower in each of the vitamin D supplementation groups [43.1 (38.1, 48.7), 44.8 (40.4, 49.7) and 45.1 (41.5, 49.1) µg/L in the 4200, 16,800 and 28,000 IU/week groups, respectively] compared to the placebo group [50.3 µg/L (45.0, 56.2)], although none of the pairwise differences between each vitamin D group and placebo were statistically significant at the P < 0.05 threshold. Adjusting for CRP did not change the inferences. Conclusions In a population with concurrently high prevalence rates of iron and vitamin D deficiency, prenatal vitamin D supplementation did not lead to improvements in iron status by late gestation. The possibility of a negative effect of vitamin D supplementation on iron status should be further explored. Funding Sources The Bill and Melinda Gates Foundation.

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Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy.

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Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy.

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