Description of the condition
Over 1.6 billion people worldwide have anaemia, a condition in which haemoglobin production is diminished. Women of menstruating age account for approximately a third of all cases of anaemia worldwide, and approximately 468 million, or 30%, of all women aged 15 to 49 years are anaemic (WHO/CDC 2008). Iron deficiency (ID) is believed to contribute to at least half the worldwide burden of anaemia, especially in non-malaria-endemic countries (Stoltzfus 2001). Iron deficiency is thus considered the most prevalent nutritional deficiency in the world.
Iron deficiency occurs following negative iron balance. As body iron stores are exhausted, the production of red blood cells is impaired, and finally, iron deficiency anaemia (IDA) results (Suominen 1998). The major causes of negative iron balance include inadequate dietary iron intake (due to consumption of a diet with a low overall or bioavailable iron content); increased losses of iron due to chronic blood loss occasioned by intestinal hookworm infestations, which are endemic in many countries (Hotez 2005), and increased iron requirements (for example, during growth or pregnancy). Low dietary iron intake and bioavailability are considered key contributors to the burden of iron deficiency. This is especially so in populations consuming diets that are low in meat sources and high in cereals such as wheat, rice, maize and millet, which are rich in phytates, a type of compounds that bind to iron in the meal and prevent its absorption (Sharpe 1950). Other dietary components such as tannins (found in tea) and calcium (contained in milk products) also inhibit iron absorption.
Women beyond menarche and prior to menopause are at especially high risk of iron deficiency due to menstrual blood losses. The onset of menstrual blood losses accompanied by rapid growth, with an associated expansion of red cell mass and tissue iron requirements, means adolescent girls have a particularly high iron need compared with their male counterparts, and as this is compounded by inadequate dietary iron intake, these girls may be at especially high risk of iron deficiency (Dallman 1992). Other important causes of iron deficiency in women include intestinal malabsorptive conditions such as coeliac disease, chronic blood losses due to menorrhagia from uterine pathologies (such as fibroids), frequent blood donation and benign and malignant gastrointestinal lesions (Goddard 2011). Iron deficiency, with and without anaemia, has also been noted to be prevalent among female athletes and is thought to be due to diets deficient in iron, increased losses due to gastrointestinal tract bleeding and reduced iron absorption due to subclinical inflammation (Peeling 2008).
As well as being critical to the production of haemoglobin, iron has a critical role in many other aspects of human physiology as it is involved in a range of oxidation-reduction enzymatic reactions in the muscle and nervous tissue (Andrews 1999), as well as other organs. Iron deficiency and iron deficiency anaemia have been associated with a range of adverse physical, psychological and cognitive effects. On the one hand, animal models suggest a role for iron in brain development and function, with iron depletion being associated with dysregulated neurotransmitter levels (Lozoff 2007), and some, but not all, clinical studies have shown associations between iron supplementation and improvement in cognitive performance (Murray-Kolb 2007), mood and well being, with a reduction in fatigue (Verdon 2003). On the other hand, observational studies have suggested that iron deficiency in the absence of anaemia impairs exercise performance in women (Scholz 1997), while some, but not all, interventional studies of iron supplementation among the same population have shown variable improvements in maximal and submaximal exercise performance (LaManca 1993; Brownlie 2002), endurance (Hinton 2000; Brownlie 2004) and muscle fatigue (Brutsaert 2003). Observational and interventional studies have also suggested associations between iron status and haemoglobin concentrations and work productivity (Wolgemuth 1982; Li 1994: Scholz 1997). When anaemia is severe, it may cause lethargy, fatigue, irritability, pallor, breathlessness and reduced tolerance for exertion.
Alleviation of iron deficiency anaemia among menstruating women is thus considered a major public health priority, both to improve their existing health status and to enhance their health in preparation for future pregnancies (WHO 2009).
Other causes of anaemia important to distinguish from iron deficiency include anaemia of chronic disease (associated with inflammation which causes iron to be withheld from erythropoiesis (the process by which red blood cells are produced)), functional iron deficiency (associated with renal impairment), genetic conditions of the red cell (haemoglobin, enzymes and membrane) and infectious diseases (including malaria).
Description of the intervention
Strategies to improve iron intake and alleviate IDA include mass and point-of-use fortification of foods with iron, dietary diversification to increase iron intake, absorption and utilisation, iron supplementation and antihelminthic treatment. Supplementation is probably the most widespread intervention practiced clinically and in public health.
Oral iron supplementation, administered once a day or more frequently, is the standard clinical practice of many physicians in the treatment of iron deficiency in women (Goddard 2011). Daily iron and folic acid supplementation for three months has also been widely recommended for the prophylaxis of iron deficiency in populations where the prevalence of anaemia exceeds 40% (WHO/UNICEF/UNU 2001). In addition to its haematological effects, the use of folic acid during the periconceptional period helps prevent babies being born with neural tube defects (WHO/UNICEF/UNU 2001).
Iron is generally administered as a salt compound in a tablet, capsule, liquid or dispersible formulation. The most commonly prescribed salts include ferrous sulphate, fumarate and gluconate (Pasricha 2010). Commonly reported side effects of iron supplements include gastrointestinal disturbances (especially constipation and nausea) and dark stools. In those using liquid formulations, tooth staining can occur. Slow or sustained release formulations, in which iron is surrounded by a coating, aim to alleviate gastrointestinal side effects by delaying delivery of iron to a more distal point in the gastrointestinal tract, but their efficacy has been questioned.
How the intervention might work
Iron is absorbed by intestinal cell luminal and basal transporters, transported bound to proteins to the bone marrow, muscle and other tissue, where it is taken up by specific receptors and used for biologic functions or stored (Andrews 1999). Textbooks advise that in an iron deficient anaemic individual, haemoglobin concentrations should rise by 1g/dL per week, with early evidence of red blood cell formation discernible in the peripheral blood after 72 hours of supplementation (Mahoney 2011).
There is an inverse relationship between iron status and the ability to absorb iron. Iron deficiency induces changes in intestinal iron transport that can double absorption of iron from the diet (Thankachan 2008). Thus, as with dietary sources of iron, absorption from supplements depends on the baseline iron status of the individual and the co-consumption of iron absorption enhancers (such as vitamin C, other acidic foods and meat) and inhibitors (calcium, phytates and tannins) (Hurrell 2010).
As mentioned above, the ubiquitous presence of iron in the human body is such that its deficiency impairs a number of physiological functions, and iron supplementation may thus benefit, physical, psychological and cognitive health. Improvements in haemoglobin and myoglobin concentrations may ensure adequate tissue oxygenation and performance (Umbreit 2005). Iron is also present in the brain in relatively large amounts and is involved in neurotransmitter function (Burhans 2005); an adequate supply may contribute to maintain a normal cognitive and psychological health, although the mechanisms are not completely elucidated as yet.
Despite the known and potential benefits of this intervention, it has been reported that daily iron supplementation in anaemic women increases their oxidative stress (King 2008; Tiwari 2011), although the clinical significance of this phenomenon in the short and long term remains unclear. Perhaps the most important side effect of iron supplements is the risk of severe toxicity of iron in overdose, albeit this is uncommon in women.
An additional consideration when providing supplements at population level is the endemicity of malaria in a given region. Approximately 40% of the world population is exposed to the malaria parasite and it is endemic in over 100 countries, causing more than a million deaths per year (WHO 2010). Provision of iron in malaria-endemic areas, particularly to children, has been controversial due to concerns that iron therapy may exacerbate infections, in particular malaria (Oppenheimer 2001; Okabe 2011), although it is still not completely clear whether iron produces the same effects among older populations or whether subclinical malaria alters the response to iron supplementation.
Why it is important to do this review
Daily oral supplementation in women has been a longstanding intervention both in the public health and clinical fields. Many patients and clinicians ascribe adverse health outcomes (including fatigue and lethargy, impaired cognitive performance and psychological dysfunction) to iron deficiency, even in the absence of anaemia, and attribute improvement in these symptoms to iron supplementation. In addition, many sporting authorities (including the International Olympic Committee (IOC 2009)) recommend screening of female athletes for iron deficiency in order to target iron supplementation, with a view to improving performance.
Several intervention trials have evaluated improvements in haemoglobin and iron status, as well as non-haematologic outcomes such as physical, cognitive and psychological health, in menstruating women receiving iron supplementation. However, evaluation of this intervention has not been subject to systematic review and it is thus difficult to estimate the benefits and risks associated with the daily use of iron supplements in menstruating women.
This review will complement the findings of other Cochrane systematic reviews assessing the use of iron supplements alone, or in combination with other vitamins and minerals, in different female populations: intermittent supplementation in children (De-Regil 2011), iron supplementation among children in malaria-endemic areas (Okabe 2011), intermittent iron supplementation in menstruating women (Fernandez-Gaxiola 2011), daily and intermittent iron and folic acid supplementation in pregnant women (Pena-Rosas 2009), multiple micronutrient supplementation in pregnancy (Haider 2006) and iron supplementation during the postpartum period (Dodd 2004).