Special Issue "Health Benefits of Iron and Folic Acid Supplementation"

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: 22 November 2021.

Special Issue Editors

Prof. Dr. Teresa Partearroyo
E-Mail Website
Guest Editor
Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, Madrid, Spain
Interests: Homocysteine; folates; hearing loss; dietary surveys; nutrition and metabolism; nutritional status
Special Issues and Collections in MDPI journals
Prof. Dr. Gregorio Varela-Moreiras
E-Mail Website
Guest Editor
Professor of Nutrition and Food Science, CEU San Pablo University (Madrid, Spain); President of the Spanish Nutrition Foundation (FEN)
Interests: folates; hearing; aging; dietary surveys; nutritional status
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Folic acid and iron are essential nutrients that are critical for many biological processes. Folic acid (FA) has been used for the prevention and treatment of macrocytic or megaloblastic anaemia. Recently, new potential functions were described, being the prevention of congenital malformations such as neural tube defects, the most demonstrated. Other new functions are regulation of homocysteine concentrations (a cardiovascular risk factor), the prevention or promotion of colorectal cancer depending on timeframe and the maintenance or improvement of cognitive function in seniors. Also, important to mention, is its role in immune function and more recently on osteoporosis prevention and hearing loss. On the other hand, iron is an essential nutrient of public health relevance required for many metabolic processes in the human body across the life and special physiological periods (e.g. pregnancy). In addition, iron deficiency is the most common and widespread nutritional disorder in the world. However, despite the well-recognized health benefits for both nutrients, there is still controversy about potential adverse consequences due to supplementation or the optimal dose to be used.

This Special Issue of Nutrients is therefore intended to highlight some of the recent dietary and nutrition studies utilizing experimental models or humans studies with these micronutrients, and highlight research investigating the various mechanisms by which folic acid and iron supplementation influence human health across the lifespan. Therefore, this issue welcomes the submission of manuscripts either describing original research or reviewing the scientific literature on this topic.

Prof. Dr. Teresa Partearroyo
Prof. Dr. Gregorio Varela-Moreira
Guest Editors

Manuscript Submission Information

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Keywords

  • Micronutrients
  • Iron
  • Folic acid
  • Intervention studies
  • Health

Published Papers (9 papers)

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Research

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Article
Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study
Nutrients 2021, 13(8), 2516; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13082516 - 23 Jul 2021
Viewed by 628
Abstract
Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who [...] Read more.
Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Article
Acute Administration of Bioavailable Curcumin Alongside Ferrous Sulphate Supplements Does Not Impair Iron Absorption in Healthy Adults in a Randomised Trial
Nutrients 2021, 13(7), 2300; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072300 - 03 Jul 2021
Viewed by 1025
Abstract
Ferrous sulphate (FS) is a cost effective, readily available iron supplement for iron deficiency (ID). The pro-oxidant effect of oral ferrous iron is known to induce inflammation, causing gastric side-effects and resulting in poor compliance. Curcumin is a potent antioxidant and has also [...] Read more.
Ferrous sulphate (FS) is a cost effective, readily available iron supplement for iron deficiency (ID). The pro-oxidant effect of oral ferrous iron is known to induce inflammation, causing gastric side-effects and resulting in poor compliance. Curcumin is a potent antioxidant and has also been shown to exhibit iron chelation in-vitro, although it is not established whether these effects are retained in-vivo. The aim of this study was therefore to assess the influence of a formulated bioavailable form of curcumin (HydroCurcTM; 500 mg) on acute iron absorption and status in a double blind, placebo-controlled randomized trial recruiting 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54). Participants were randomly allocated to five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Participants were provided with the supplements according to their relevant treatment groups at baseline (0 min), and blood collection was carried out at 0 min and at 180 min following supplementation. In the treatment groups, significant difference was observed in mean serum iron between baseline (0 min) and at end-point (180 min) (F (1, 144) = 331.9, p < 0.0001) with statistically significant intra-group increases after 180 min (p < 0.0001) in the FS18_Plac (8.79 µmol/L), FS18_Curc (11.41 µmol/L), FS65_Plac (19.09 µmol/L), and FS65_Curc (16.39 µmol/L) groups. A significant difference was also observed between the two time points in serum TIBC levels and in whole blood haemoglobin (HGB) in the treatment groups, with a significant increase (1.55%/2.04 g/L) in HGB levels from baseline to end-point observed in the FS65_Curc group (p < 0.05). All groups receiving iron demonstrated an increase in transferrin saturation (TS%) in a dose-related manner, demonstrating that increases in serum iron are translated into increases in physiological iron transportation. This study demonstrates, for the first time, that regardless of ferrous dose, formulated curcumin in the form of HydroCurc™ does not negatively influence acute iron absorption in healthy humans. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Article
Temporal Relation between Double Fortification of Wheat Flour with Iron and Folic Acid, and Markers and Prevalence of Anemia in Children
Nutrients 2021, 13(6), 2013; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13062013 - 11 Jun 2021
Viewed by 782
Abstract
Fortification of wheat flour with iron and folic acid became mandatory in Ivory Coast in 2007. The purpose of this study was to determine the time trend relation between mandatory double fortification of wheat flour with iron and folic acid and markers and [...] Read more.
Fortification of wheat flour with iron and folic acid became mandatory in Ivory Coast in 2007. The purpose of this study was to determine the time trend relation between mandatory double fortification of wheat flour with iron and folic acid and markers and prevalence of anemia by comparing the data between pre- and post-fortification periods in Ivory Coast children. Data were derived from the pediatric unit of the University Hospital of Treichville, Abidjan, Ivory Coast. Medical records of 467 children from 5 to 14 years old were analyzed from the years 2004 through 2010. Periods from 1 January 2004 to 31 December 2006 and 1 January 2008 to 31 December 2010 were considered as pre- and post-fortification periods, respectively. Data on hemoglobin, hematocrit, red blood cell count (RBC), mean corpuscular volume (MCV), and anemia between pre- and post-fortification periods were compared. There were no significant differences in hemoglobin, hematocrit, RBC, and prevalence of anemia between pre- and post-fortification periods. However, MCV in post-fortification period was significantly higher compared to pre-fortification period in all subjects (77.6 fL vs. 76.8 fL; p = 0.02) and in young girls (79.1 fL vs. 75.2 fL; p = 0.01). Lack of significant differences in anemia and in markers of anemia between pre- and post-fortification periods need further investigation in children of Ivory Coast. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
Article
Daily Oral Supplementation with 60 mg of Elemental Iron for 12 Weeks Alters Blood Mitochondrial DNA Content, but Not Leukocyte Telomere Length in Cambodian Women
Nutrients 2021, 13(6), 1877; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13061877 - 31 May 2021
Viewed by 966
Abstract
There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect [...] Read more.
There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18–45 years) who received 60 mg of elemental iron as ferrous sulfate (n = 190) or a placebo (n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: −0.04 [95% CI: −0.16, 0.08]; p = 0.50 and ß-coefficient: −0.96 [95% CI: −2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: −11 [95% CI: −20, −2]; p = 0.02 and ß-coefficient: −11 [95% CI: −20, −1]; p= 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Article
Reducing the Burden of Anemia and Neural Tube Defects in Low- and Middle-Income Countries: An Analysis to Identify Countries with an Immediate Potential to Benefit from Large-Scale Mandatory Fortification of Wheat Flour and Rice
Nutrients 2021, 13(1), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13010244 - 16 Jan 2021
Cited by 1 | Viewed by 1465
Abstract
Using a predetermined set of criteria, including burden of anemia and neural tube defects (NTDs) and an enabling environment for large-scale fortification, this paper identifies 18 low- and middle-income countries with the highest and most immediate potential for large-scale wheat flour and/or rice [...] Read more.
Using a predetermined set of criteria, including burden of anemia and neural tube defects (NTDs) and an enabling environment for large-scale fortification, this paper identifies 18 low- and middle-income countries with the highest and most immediate potential for large-scale wheat flour and/or rice fortification in terms of health impact and economic benefit. Adequately fortified staples, delivered at estimated coverage rates in these countries, have the potential to avert 72.1 million cases of anemia among non-pregnant women of reproductive age; 51,636 live births associated with folic acid-preventable NTDs (i.e., spina bifida, anencephaly); and 46,378 child deaths associated with NTDs annually. This equates to a 34% reduction in the number of cases of anemia and 38% reduction in the number of NTDs in the 18 countries identified. An estimated 5.4 million disability-adjusted life years (DALYs) could be averted annually, and an economic value of 31.8 billion United States dollars (USD) generated from 1 year of fortification at scale in women and children beneficiaries. This paper presents a missed opportunity and warrants an urgent call to action for the countries identified to potentially avert a significant number of preventable birth defects, anemia, and under-five child mortality and move closer to achieving health equity by 2030 for the Sustainable Development Goals. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Review

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Review
Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer’s Disease: A Narrative Review
Nutrients 2021, 13(9), 2966; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13092966 - 26 Aug 2021
Viewed by 765
Abstract
Cognitive impairment and Alzheimer’s Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and [...] Read more.
Cognitive impairment and Alzheimer’s Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer’s Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer’s Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
Review
Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials
Nutrients 2021, 13(7), 2355; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072355 - 09 Jul 2021
Cited by 1 | Viewed by 954
Abstract
Background: There is a growing interest in the considerable benefits of dietary supplementations, such as folic acid, on the glycemic profile. We aimed to investigate the effects of folic acid supplementation on glycemic control markers in adults. Methods: Randomized controlled trials examining the [...] Read more.
Background: There is a growing interest in the considerable benefits of dietary supplementations, such as folic acid, on the glycemic profile. We aimed to investigate the effects of folic acid supplementation on glycemic control markers in adults. Methods: Randomized controlled trials examining the effects of folic acid supplementation on glycemic control markers published up to March 2021 were detected by searching online databases, including Scopus, PubMed, Embase, and ISI web of science, using a combination of related keywords. Mean change and standard deviation (SD) of the outcome measures were used to estimate the mean difference between the intervention and control groups at follow-up. Meta-regression and non-linear dose-response analysis were conducted to evaluate the association between pooled effect size and folic acid dosage (mg/day) and duration of the intervention (week). From 1814 detected studies, twenty-four studies reported fasting blood glucose (FBG), fasting insulin, hemoglobin A1C (HbA1C), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) as an outcome measure. Results: Results revealed significant reductions in FBG (weighted mean difference (WMD): −2.17 mg/dL, 95% CI: −3.69, −0.65, p = 0.005), fasting insulin (WMD: −1.63 pmol/L, 95% CI: −2.53, −0.73, p < 0.001), and HOMA-IR (WMD: −0.40, 95% CI: −0.70, −0.09, p = 0.011) following folic acid supplementation. No significant effect was detected for HbA1C (WMD: −0.27%, 95% CI: −0.73, 0.18, p = 0.246). The dose-response analysis showed that folic acid supplementation significantly changed HOMA-IR (r = −1.30, p-nonlinearity = 0.045) in non-linear fashion. However, meta-regression analysis did not indicate a linear relationship between dose, duration, and absolute changes in FBG, HOMA-IR, and fasting insulin concentrations. Conclusions: Folic acid supplementation significantly reduces some markers of glycemic control in adults. These reductions were small, which may limit clinical applications for adults with type II diabetes. Further research is necessary to confirm our findings. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Review
Iron-Containing Oral Contraceptives and Their Effect on Hemoglobin and Biomarkers of Iron Status: A Narrative Review
Nutrients 2021, 13(7), 2340; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072340 - 09 Jul 2021
Viewed by 694
Abstract
Oral contraceptive use has been associated with decreased menstrual blood losses; thus, can independently reduce the risk of anemia and iron deficiency in women. Manufacturers have recently started to include supplemental iron in the non-hormonal placebo tablets of some contraceptives. The aims of [...] Read more.
Oral contraceptive use has been associated with decreased menstrual blood losses; thus, can independently reduce the risk of anemia and iron deficiency in women. Manufacturers have recently started to include supplemental iron in the non-hormonal placebo tablets of some contraceptives. The aims of this narrative review are: (i) to describe the relationship between oral contraceptive use and both anemia and iron status in women; (ii) to describe the current formulations of iron-containing oral contraceptives (ICOC) available on the market; and (iii) to systematically review the existing literature on the effect of ICOC on biomarkers of anemia and iron status in women. We discovered 21 brands of ICOC, most commonly including 25 mg elemental iron as ferrous fumarate, for seven days, per monthly tablet package. Our search identified one randomized trial evaluating the effectiveness of ICOC use compared to two non-ICOC on increasing hemoglobin (Hb) and iron status biomarker concentrations in women; whereafter 12 months of contraception use, there were no significant differences in Hb concentration nor markers of iron status between the groups. ICOC has the potential to be a cost-effective solution to address both family planning needs and iron deficiency anemia. Yet, more rigorous trials evaluating the effectiveness of ICOC on improving markers of anemia and iron deficiency, as well as investigating the safety of its consumption among iron-replete populations, are warranted. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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Review
Effects of Folic Acid Supplementation on Inflammatory Markers: A Grade-Assessed Systematic Review and Dose–Response Meta-Analysis of Randomized Controlled Trials
Nutrients 2021, 13(7), 2327; https://0-doi-org.brum.beds.ac.uk/10.3390/nu13072327 - 06 Jul 2021
Viewed by 926
Abstract
It has been theorized that folic acid supplementation improves inflammation. However, its proven effects on inflammatory markers are unclear as clinical studies on this topic have produced inconsistent results. To bridge this knowledge gap, this systematic review and meta-analysis of randomized controlled trials [...] Read more.
It has been theorized that folic acid supplementation improves inflammation. However, its proven effects on inflammatory markers are unclear as clinical studies on this topic have produced inconsistent results. To bridge this knowledge gap, this systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effects of folic acid supplementation on serum concentrations of the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Methods: To identify eligible RCTs, a systematic search up to April 2021 was completed in PubMed/Medline, Scopus, Web of Science, EMBASE, Cochrane databases, and Google Scholar using relevant keywords. A fix or random-effects model was utilized to estimate the weighted mean difference (WMD) and 95% confidence interval (95% CI). Results: Twelve RCTs were included in the present meta-analysis. The pooled analysis revealed that serum concentrations of CRP (WMD: −0.59 mg/L, 95% CI −0.85 to −0.33, p < 0.001) were significantly reduced following folic acid supplementation compared to placebo, but did not affect serum concentrations of IL-6 (WMD: −0.12, 95% CI −0.95 to 0.72 pg/mL, p = 0.780) or TNF-α (WMD: −0.18, 95% CI −0.86 to 0.49 pg/mL, p = 0.594). The dose–response analysis demonstrated a significant relationship between an elevated dosage of folic acid supplementation and lower CRP concentrations (p = 0.002). Conclusions: We found that folic acid supplementation may improve inflammation by attenuating serum concentrations of CRP but without significant effects on IL-6 and TNF-α. Future RCTs including a larger number of participants and more diverse populations are needed to confirm and expand our findings. Full article
(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)
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