Although iron is typically prescribed during pregnancy to prevent IDA,^[8][9] regardless of the mother’s iron levels, more studies should be conducted to verify its benefits throughout pregnancy and after childbirth.

One meta-analysis has assessed the effect of daily iron supplementation in pregnant iron-replete women and found that it may reduce both maternal IDA and maternal ID at term (i.e., at 37 weeks gestation or later). The results also suggested that daily oral iron supplementation may decrease the risk of newborns being small for gestational age (SGA) (i.e., having a birth weight below the 10th percentile for their gestational age) or low birthweight (LBW) (i.e., having a birth weight lower than 2500 g).^[9] Another meta-analysis, which included pregnant and non-pregnant women of reproductive age with IDA, found a significant increase in hemoglobin and ferritin levels following iron supplementation.^[8] However, both meta-analyses presented high heterogeneity, risk of bias, and low to moderate levels of evidence, leaving some questions about the benefits and safety of preventative iron supplementation unanswered.

Oral iron replacement therapy is typically the first-line treatment for IDA. Iron is available in different forms (e.g., tablets, liquid) and compounds (e.g., ferrous sulfate, ferrous fumarate, ferrous bisglycinate, etc.), each of which provides different amounts of elemental iron.^[23]

Here are some of the most common forms of iron found in supplements:

Formulations containing ferrous iron (Fe²⁺) are more bioavailable, but they are also more likely to cause side effects. In contrast, ferric iron (Fe³⁺) preparations are usually better-tolerated but not as effective.^[4]

Ferrous bisglycinate is another popular iron form found in supplements, wherein iron is chelated to two glycine molecules. Ferrous bisglycinate is marketed as more bioavailable than the other iron salts, and as having fewer gastrointestinal side effects. Furthermore, due to its stable chemical structure, ferrous bisglycinate is less affected by common iron absorption inhibitors (e.g., phytates found in cereals). However, although results from a meta-analysis showed that while iron bisglycinate was more effective than other iron salts in increasing hemoglobin levels in pregnant women, in children its effectiveness was comparable to other iron preparations.^[24]

Heme iron polypeptide (HIP) is another form of iron. It is commonly produced from swine or bovine blood using enzymatic hydrolysis, in which heme iron is bound to peptides derived from the digested hemoglobin.^[25] This form of iron has increased in popularity due to claims that it has enhanced bioavailability and fewer gastrointestinal side effects than other iron compounds. One study showed that when compared to ferrous fumarate, HIP taken with meals significantly increased iron absorption, but was not associated with side effects.^[26] However, larger studies should be conducted to compare its efficacy and safety to other iron preparations.

When iron is administered intravenously, IV ferric carboxymaltose and IV iron sucrose appear to be the most effective forms at increasing hemoglobin and ferritin levels within a period of four weeks.^[27]

Finally, one in vitro study compared modified-release iron supplements to immediate-release formulations and found that the slow-release tablets did not completely dissolve even after 24 hours, and iron uptake was considerably lower compared to regular tablets.^[28] Although modified-release iron preparations may be better tolerated, with fewer side effects, they may not be as effective. These findings need further clarification through in vivo clinical studies.

It remains unclear whether iron supplementation is beneficial for athletes with ID but not anemia, or for those with normal iron status. While there is some evidence that iron supplementation may improve fatigue in iron-deficient athletes and non-athletes,^[7] and intensive training is a potential cause of iron depletion,^[52] only a few studies have investigated the benefits of iron supplementation in athletes with adequate iron levels to replenish iron loss due to training.

In one study involving iron-sufficient soccer players during training, iron supplementation was found to maintain ferritin and iron store levels, and these levels decreased once the supplementation was interrupted.^[53] However, this study did not observe any significant difference in transferrin levels, which provide information on the iron levels required for erythropoiesis (red blood cell production), and it lacked a control group.

In another study, swimmers between the ages of 12 and 17 were either given an iron supplement (47 mg iron daily) or instructed to consume an iron-rich diet. Both interventions failed to significantly alter either the participants’ iron status (measured as iron, ferritin, and transferrin levels) or their athletic performance.^[54]

While most people obtain adequate iron from their diet, there are situations where iron supplementation may be required.^[1] For instance, the World Health Organization (WHO) recommends daily oral iron supplementation for all children living in areas where anemia prevalence exceeds 40%.

Frequent blood donation can also deplete iron levels, potentially leading to anemia, and therefore supplementation may be necessary, especially for people at high risk of deficiency, such as women.^[58][59] However, evidence that iron supplementation is effective in preserving iron levels is still weak.

Finally, individuals following a vegetarian or vegan diet may need to increase their iron intake,^[1] mainly because plant-based foods contain non-heme iron, which is not as bioavailable as the heme iron found in meat.

Heme iron is more readily absorbed compared to non-heme iron, but the bioavailability of iron in the body can be influenced by several foods and dietary components. In individuals following a mixed diet, which includes fruit, vegetables, meat, and seafood, the bioavailability of iron ranges from approximately 14% to 18%. For vegetarian diets, iron bioavailability can range from 5% to 12%.^[1]

Animal protein appears to increase non-heme iron absorption from non-meat produce (e.g., vegetables, grains) when these foods are consumed in the same meal. However, this effect was less pronounced for wheat than for other plant-based foods.^[29][30] Additionally, studies have yielded mixed results regarding the combination of pork meat with meals high in phytates (which can be found in certain legumes and vegetables), indicating that phytate may counteract the positive effects of animal protein on non-heme iron absorption.^[31][32]

It’s often recommended that iron be taken with Vitamin C (ascorbic acid) supplements or vitamin C-rich foods. Theoretically, ascorbic acid can facilitate the reduction of ferric iron to its more bioavailable form (ferrous iron), and can chelate iron ions (i.e., bond with them) to enhance their solubility and absorption from the intestines into the bloodstream.^[33] Furthermore, ascorbate (a mineral salt of ascorbic acid) regulates the uptake of iron by transferrin, which is why scurvy (a disease resulting from a vitamin C deficiency) is often associated with some degree of iron-deficiency anemia.^[34] However, two meta-analyses both found no difference in hemoglobin and ferritin levels when iron was supplemented with vitamin C, compared to iron alone,^[33][35] suggesting that there is still limited clinical data on the benefits of combining iron and vitamin C.

Iron absorption can be reduced by other vitamins and minerals found both in supplements and foods.

Multiple studies have found that calcium is a strong inhibitor of iron absorption, and avoiding the simultaneous use of calcium and iron supplements may be beneficial. In one study, calcium phosphate inhibited iron absorption from a ferrous sulfate supplement, whether taken with or without food. In contrast, calcium carbonate only inhibited iron absorption when both supplements were consumed with food, suggesting that if a combined iron and calcium carbonate supplement is required, it should be taken between meals.^[36] Calcium citrate, on the other hand, reduced iron absorption both with and without food, but not to a statistically significant degree in one study^[36], and reduced absorption of non-heme iron without food in another study.^[37]. The impact of calcium chloride on iron absorption seems to vary depending on whether it’s taken with food^[38] or without food.^[39]

Furthermore, a wide variety of beverages with a high antioxidant content, including coffee and tea, have some acute inhibitory effects on non-heme iron absorption. Coffee may reduce iron absorption,^[40] possibly due to the presence of chlorogenic acid, a known iron chelator.^[41] This mechanism can be extended to green coffee extract, which is an even richer source of chlorogenic acid. Tea, whether green^[42] or black,^[40] might inhibit iron absorption, possibly due to the presence of catechins^[42] and theaflavins.^[43] Infusions of chamomile, lime flower, pennyroyal, peppermint, and vervain may also reduce non-heme iron absorption.^[40]

Rosemary (a source of rosmarinic acid), rich in phytic and phenolic acid, has also been shown to reduce non-heme iron absorption.^[42]

Additionally, in one randomized controlled trial, people with beta-thalassemia who took 500 mg of quercetin (a chelator of iron^[44]) per day for 12 weeks alleviated iron overload (a common complication of beta-thalassemia), notably reducing serum iron, ferritin, and inflammatory markers.^[45]

Lastly, although zinc has the potential to reduce the absorption of iron, the effect is inconsistent, and the strength of this effect is unclear, with different studies reporting varying results.^{[13][46][47][48][49]} The interaction between zinc and iron seems to be linked to competition for transporters in the liver, such as divalent metal transporter 1 (DMT1), human copper transporter 1 (hCTR1),^[50] and ZRT/IRT-like protein 14 (Zip14).^[51] Taking zinc between meals is likely a good way to prevent any interference with iron absorption.

It’s important to note that the typical Western diet is complex and rich in both iron absorption enhancers and inhibitors, whose effects may both be attenuated when these substances are consumed simultaneously.^[1]

Iron supplementation is often associated with gastrointestinal side effects, which may impact treatment adherence. As a result, researchers have explored different dosages and frequencies of supplementation.

One meta-analysis looked at intermittent (once, twice, or three times per week) iron supplementation vs. daily supplementation for improving iron status and preventing anemia in menstruating adolescent and adult women. Both had similar effects on hemoglobin levels and the risk of anemia. However, daily supplementation proved more effective in increasing ferritin levels (although with low quality of evidence), which may be especially significant in populations with a high prevalence of ID, which is characterized by adequate levels of hemoglobin but low ferritin and/or transferrin saturation.^[55] Moreover, there were no significant differences in treatment adherence or in the side effects experienced among participants in the two groups.^[18] There is currently no evidence that intermittent supplementation offers advantages in terms of fewer side effects or improved adherence compared to daily supplementation.

In another study, iron-depleted (but not deficient) participants took the same iron dose either daily or on alternate days for 14 and 28 days, respectively. The alternate-day dosing regimen resulted in reduced levels of hepcidin (a hormone responsible for regulating iron homeostasis in the body) and greater iron absorption. However, the impact on iron status remained unclear because there were no notable differences in serum iron, ferritin, or hemoglobin levels between the two groups at the end of the trial. Additionally, the alternate-day dosing group reported experiencing less nausea but more headaches.^[56] A subsequent study by the same author, including individuals with ID, confirmed these findings. However, the study’s duration was too short to assess the long-term effects on iron status.^[57]