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Health Benefits of Iron and Folic Acid Supplementation

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

Deadline for manuscript submissions: closed (22 November 2021) | Viewed by 75458

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Prof. Dr. Teresa Partearroyo

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Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, Madrid, Spain
Interests: dietary surveys; nutritional status; nutrition and metabolism, food reformulation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Gregorio Varela-Moreiras

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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, Collections and Topics 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

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Keywords

Micronutrients
Iron
Folic acid
Intervention studies
Health

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Published Papers (11 papers)

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Research

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12 pages, 1265 KiB

Open AccessArticle

Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study

by Thibaud Lefebvre, Muriel Coupaye, Marina Esposito-Farèse, Nathalie Gault, Neila Talbi, Caroline Quintin, Caroline Schmitt, Soumeya Bekri, André Bado, Hervé Puy, Simon Msika, Carole Brasse-Lagnel and Zoubida Karim

Nutrients 2021, 13(8), 2516; https://doi.org/10.3390/nu13082516 - 23 Jul 2021

Cited by 5 | Viewed by 2734

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 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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15 pages, 1354 KiB

Open AccessFeature PaperArticle

Acute Administration of Bioavailable Curcumin Alongside Ferrous Sulphate Supplements Does Not Impair Iron Absorption in Healthy Adults in a Randomised Trial

by Helena Tiekou Lorinczova, Gulshanara Begum, Derek Renshaw and Mohammed Gulrez Zariwala

Nutrients 2021, 13(7), 2300; https://doi.org/10.3390/nu13072300 - 3 Jul 2021

Cited by 5 | Viewed by 6936

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 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 (HydroCurc^TM; 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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9 pages, 265 KiB

Open AccessArticle

Temporal Relation between Double Fortification of Wheat Flour with Iron and Folic Acid, and Markers and Prevalence of Anemia in Children

by Flinle Danielle Biemi and Vijay Ganji

Nutrients 2021, 13(6), 2013; https://doi.org/10.3390/nu13062013 - 11 Jun 2021

Cited by 3 | Viewed by 2715

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 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)

13 pages, 787 KiB

Open AccessArticle

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

by Shannon L. Steele, Anthony Y. Y. Hsieh, Izabella Gadawski, Hou Kroeun, Susan I. Barr, Angela M. Devlin, Hélène C. F. Côté and Crystal D. Karakochuk

Nutrients 2021, 13(6), 1877; https://doi.org/10.3390/nu13061877 - 31 May 2021

Cited by 3 | Viewed by 3346

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 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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22 pages, 1475 KiB

Open AccessArticle

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

by Vijaya Kancherla, Manpreet Chadha, Laura Rowe, Andrew Thompson, Sakshi Jain, Dylan Walters and Homero Martinez

Nutrients 2021, 13(1), 244; https://doi.org/10.3390/nu13010244 - 16 Jan 2021

Cited by 15 | Viewed by 5304

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 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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24 pages, 409 KiB

Open AccessReview

Iron Supplementation at the Crossroads of Nutrition and Gut Microbiota: The State of the Art

by Ana M. Puga, María de Lourdes Samaniego-Vaesken, Ana Montero-Bravo, Mar Ruperto, Teresa Partearroyo and Gregorio Varela-Moreiras

Nutrients 2022, 14(9), 1926; https://doi.org/10.3390/nu14091926 - 4 May 2022

Cited by 21 | Viewed by 3904

Abstract

Gut microbiota has received significant attention owing to its decisive role in human health and disease. Diet exerts a significant influence on the variety and number of bacteria residing in the intestinal epithelium. On the other hand, as iron is a key micronutrient for blood formation and oxygen supply, its deficiency is highly prevalent worldwide. In fact, it is the most common cause of anemia and thus, iron supplementation is widespread. However, there is concern due to some potential risks linked to iron supplementation. Therefore, we have reviewed the available evidence of the effects that iron supplementation exerts on the gut microbiota as well as its potential benefits and risks. The compiled information suggests that iron supplementation is potentially harmful for gut microbiota. Therefore, it should be performed with caution, and by principle, recommended only to individuals with proven iron deficiency or iron-deficiency anemia to avoid potential adverse effects. In any case, large and long-term population studies are urgently needed to confirm or refute these results, mainly focused on vulnerable populations. Full article

(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)

35 pages, 676 KiB

Open AccessEditor’s ChoiceReview

Iron Status, Anemia, and Iron Interventions and Their Associations with Cognitive and Academic Performance in Adolescents: A Systematic Review

by Kaitlyn L. I. Samson, Jordie A. J. Fischer and Marion L. Roche

Nutrients 2022, 14(1), 224; https://doi.org/10.3390/nu14010224 - 5 Jan 2022

Cited by 37 | Viewed by 12434

Abstract

In adolescents, iron-deficiency anemia is the leading cause of disability-adjusted life years lost. The World Health Organization recommends delivering iron supplementation through school-based platforms, requiring partnerships with the education sector. This anemia-reduction intervention is valued for the perceived benefits of improved learning and school performance. This article aims to systematically review the available evidence on the relationship between iron status and anemia and impacts of iron interventions on cognitive and academic performance in adolescents. Fifty studies were included: n = 26 cross-sectional and n = 24 iron-containing interventions. Our review suggests that iron status and anemia may be associated with academic performance in some contexts and that iron supplementation during adolescence may improve school performance, attention, and concentration. However, nearly all supplementation trials were judged to have moderate or high risk of bias. We did not find evidence suggesting that iron status and anemia influenced or were associated with attention, intelligence, nor memory in adolescents. Further, iron supplementation did not improve memory and recall or intelligence. Overall, more high-quality research is needed to guide programmers and policy makers to understand the relationships between anemia and educational performance and the potential impacts of iron interventions, which effectively reduce anemia, on adolescents’ learning and school performance. Full article

(This article belongs to the Special Issue Health Benefits of Iron and Folic Acid Supplementation)

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18 pages, 339 KiB

Open AccessReview

Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer’s Disease: A Narrative Review

by Ana M. Puga, Mar Ruperto, Mª de Lourdes Samaniego-Vaesken, Ana Montero-Bravo, Teresa Partearroyo and Gregorio Varela-Moreiras

Nutrients 2021, 13(9), 2966; https://doi.org/10.3390/nu13092966 - 26 Aug 2021

Cited by 13 | Viewed by 5746

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 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)

25 pages, 2276 KiB

Open AccessReview

Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials

by Omid Asbaghi, Damoon Ashtary-Larky, Reza Bagheri, Seyedeh Parisa Moosavian, Hadi Pourmirzaei Olyaei, Behzad Nazarian, Mahnaz Rezaei Kelishadi, Alexei Wong, Darren G. Candow, Frédéric Dutheil, Katsuhiko Suzuki and Amirmansour Alavi Naeini

Nutrients 2021, 13(7), 2355; https://doi.org/10.3390/nu13072355 - 9 Jul 2021

Cited by 34 | Viewed by 7799

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 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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13 pages, 615 KiB

Open AccessReview

Iron-Containing Oral Contraceptives and Their Effect on Hemoglobin and Biomarkers of Iron Status: A Narrative Review

by Jordie A. J. Fischer, Carolina S. Sasai and Crystal D. Karakochuk

Nutrients 2021, 13(7), 2340; https://doi.org/10.3390/nu13072340 - 9 Jul 2021

Cited by 5 | Viewed by 7522

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 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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16 pages, 1764 KiB

Open AccessReview

Effects of Folic Acid Supplementation on Inflammatory Markers: A Grade-Assessed Systematic Review and Dose–Response Meta-Analysis of Randomized Controlled Trials

by Omid Asbaghi, Damoon Ashtary-Larky, Reza Bagheri, Seyedeh Parisa Moosavian, Behzad Nazarian, Reza Afrisham, Mahnaz Rezaei Kelishadi, Alexei Wong, Frédéric Dutheil, Katsuhiko Suzuki and Amirmansour Alavi Naeini

Nutrients 2021, 13(7), 2327; https://doi.org/10.3390/nu13072327 - 6 Jul 2021

Cited by 32 | Viewed by 5081

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 (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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