Iron deficiency/iron deficiency anemia in women

Iron deficiency anemia

Disease progression

Anaemia exacerbates underlying disease in IBD,³ and increases the risk of disease progression in CKD and CHF^4,5

• greater risk of mortality, morbidity ^6–8

• Increased fatigue and decreased QoL⁹

Hospitalizations

We can associate IDA with hospitalization of patients or prolongation of hospital stay^{1-3, 6-8}

• Anemia increases the costs of managing CKD-ND patients by increasing patients’ risk of hospitalization and by hastening their progression to dialysis².
• We see increased healthcare costs in CHF and cancer patients with anemia, primarily driven by higher rates of hospitalisation^3,4.

Blood transfusion

Pre-operative IDA can be associated with increased blood transfusions

• Blood transfusions are frequently used to correct severe anemia, yet they are associated with increased mortality, morbidity, and length of hospitalisation^4–6 and have significant costs^13,14.

Decreased iron intake

• Vegetarian or otherwise unbalanced diet⁴
• Eating disorder⁵
• Disease-related anorexia⁶

Decreased iron absorption

• Coeliac disease⁷
• Malabsorption²
• Chronic inflammatory or malignant diseases²
• Concomitant intake of drugs²

Blood loss

• Heavy or prolonged menstrual bleeding (HMB)^1,2
• Delivery^2,3
• Gastrointestinal bleeding²
• Surgery²
• Blood donation²

Increased iron demand

• Pregnancy and lactation^2–4
• Infancy^2,4
• Adolescence^2,4
• Endurance sport⁸

All women of reproductive age are at risk of iron deficiency. It is estimated that 30% of women globally are anemic, with at least half of these cases arising from iron deficiency.

Among pregnant women, IDA has been associated with increased risks of low birth weight, prematurity, and maternal morbidity.

Iron deficiency and anemia reduce the work capacity of individuals and entire populations, bringing serious economic consequences and obstacles to national development.

• WHO. Preconception Care to Reduce Maternal & Childhood Mortality & Morbidity. 2012. http://apps.who.int/iris/bitstream/10665/78067/1/9789241505000_eng.pdf
• WHO. Guideline: Daily iron and folic acid supplementation in pregnant women. 2012. http://apps.who.int/iris/bitstream/10665/77770/1/9789241501996_eng.pdf
• WHO. Micronutrient deficiencies. 2013. http://www.who.int/nutrition/topics/ida/en/

Heavy menstrual bleeding is the leading cause of iron deficiency/iron deficiency anemia in women.

• The average iron content of the body is 2500–4000 mg, with women having a lower body iron content than men^1,2
• Most body iron (~1800 mg) is contained as hemoglobin in circulating red blood cells. Virtually all of the iron released after the breakdown of red blood cells is reused, and only 1–2 mg of iron is lost per day through shedding of cells in the gut or skin or menstrual blood loss¹
• Non-pregnant women require 1.5–2 mg iron/day from their diet to compensate for this loss of body iron compared with 1.0 mg iron/day for men¹
• Women are estimated to have a median dietary iron intake of 12 mg/day, which is lower than their RDA of 18 mg/day. The evidence of insufficient iron intake suggests that the additional iron demand from menstrual blood loss is not being met³

For clinical purposes, HMB should be defined as excessive menstrual blood loss which interferes with the woman’s physical, emotional, social and material quality of life, and which can occur alone or in combination with other symptoms. HMB should be recognized as having a major impact on a woman’s quality of life.

Any interventions should aim to improve quality-of-life measures.

NICE guideline. Heavy menstrual bleeding. 2007. http://www.nice.org.uk/nicemedia/live/11002/30404/30404.pdf

• There is a clear association between excessive menstrual blood loss and ID in women and adolescent girls^1,2
• As a result, several consequences of HMB are also causally related to ID^1,3-6
• Associations between HMB-associated factors (in particular, fatigue and impaired cognitive function) and ID are exemplified by improvements in these symptoms following iron supplementation^3,5

It is well established that ID/IDA exerts various negative effects^1,2. Specifically, ID/IDA has been shown to adversely influence physical and mental performance (exercise, physical activity, fatigue, mental and cognitive ability and performance)^1,3,4 physiological processes (enzymatic activity such as the respiratory chain; thermoregulation)¹ and immune (potential susceptibility to infections) and neurological function¹. ID/IDA also affects the ability to tolerate heavy blood loss⁵

• This schematic treatment algorithm illustrates recommended hemoglobin and serum ferritin thresholds dictating a diagnosis of ID/IDA and subsequent management in pre-menopausal (non-pregnant) women.¹
• Oral iron supplements at doses of 100 to 200 mg iron/day (IDA) or 60 to 100 mg iron/day (ID) are recommended as first-line treatment for women, with dosage adjusted according to ongoing diagnostic assessment.¹
• IV iron is advised as an alternative in cases of non-response or severe IDA; to get accurate measurements of treatment effect, serum ferritin levels should be assessed 12–16 weeks after initiation of IV treatment.¹
• Recent guidance from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) also recommends measures to minimize the risk of allergic reactions with IV iron use.²

• Normal hemoglobin levels vary with age, sex and physiological status, e.g. during pregnancy. Anemia occurs when hemoglobin levels fall below. For example, the WHO recommended threshold¹
• Since conditions other than ID, e.g. vitamin B12 or folate deficiency, can also cause anemia, definitive diagnosis of IDA includes laboratory evidence of ID,² such as levels of the following parameters:
  • A low serum ferritin value shows absolute ID, although levels may not solely reflect iron stores in all cases.³ Serum ferritin is also an acute-phase reactant that is elevated, independently of body iron, in response to inflammatory processes⁴
  • TSAT reflects the availability of iron in the plasma,⁴ and is the percentage of occupied iron-binding sites on transferrin which is presented as the ratio of serum iron and total iron-binding capacity (TIBC)
  • Serum (or soluble) transferrin receptor (sTfR) is the serum concentration of transferrin receptor shed from reticulocytes; it shows iron-deficient erythropoiesis and tissue iron deficiency, and is unaffected by inflammation.⁵ In ID, the numbers of transferrin receptors increase significantly,⁴ but sTfR is the only diagnostic marker of ID that appears to remain at normal levels during pregnancy⁶

Anemia has a profound effect on the quality of life. Therefore, normalisation of the Hb level and iron status is a goal in the overall management of underlying diseases (Van Assche 2013, McMurray 2012). 

Notably, a retrospective analysis of patients with inflammatory bowel disease who were treated for anemia and achieved normal Hb levels showed a 50% recurrence after 10 months (Kulnigg 2009). Iron deficiency, defined as ferritin <30 μg/L, recurred within a median time of 19 months, and iron deficiency recurred faster in patients with a post-treatment ferritin level <100 μg/L (median 4 months) than in patients with ferritin levels between 100-400 μg/L (median 11 months) and ferritin >400 μg/L (median 49 months; p<0.001).

Sufficient iron repletion (ferritin 100-400 μg/L) can prevent or delay anemia recurrence (Evstatiev 2013, Kulnigg 2009).

Since over 90% of ingested iron remains unabsorbed, oral iron preparations frequently lead to the occurrence of GI adverse effects, including nausea, flatulence, diarrhea and gastric erosion (Van Assche 2013).

Animal and human studies show that the generation of reactive oxygen species (Fenton reaction) by non-absorbed iron might lead to the exacerbation of IBD.

Several studies have shown that I.V. iron is at least as effective as oral iron, delivers faster response rates, and is safer in all but a very few patients who may experience side-effects.

Intravenous iron therapy is advisable in the following cases: for iron-deficient patients who are intolerant or unresponsive to oral iron supplementation (i.e., those showing an insufficient increase in serum iron parameters within the first 2 weeks of treatment); for patients with severe anemia (Hb <10 g/dL); for patients with pronounced disease activity; and for patients who are being treated with erythropoiesis-stimulating agents. Patients with mild anemia (Hb >10 g/dL) can be adequately treated with 100 mg/day iron sulphate.

Limited effectiveness – Impaired intestinaliron absorption

• Poor absorption (~90% not absorbed)
• Absorption and efficacy do not increase proportionally with higher doses. 2
• May not compensate for ongoing chronic blood loss1
• Long therapy, mostly, needs to be continued for 5-6 months or at for least 3 months after replenishment of iron stores
• Concomitant food or medication (e.g. phosphate binders, H2 blockers, proton pump inhibitors)

Compliance

• Frequent intolerance because of GI side effects
• Pill burden: usually 2 or 3 tablets per day
• Low dose (100mg/day) may help to mimic the GI side effects and improve tolerance

May be inadequateduring ESA therapy

·Accelerated erythropoiesis can increase demand for iron beyond the amount supplied orally

Oxidative stress

High oral iron doses can saturate the iron transport system if it rapidly released the iron, resulting in oxidative stress

Oral iron may not compensate for ongoing blood loss in IBD.¹ Studies in animal models of inflammatory bowel disease (IBD) consistently show an increase in oxidative stress, disease activity, intestinal inflammation and colorectal cancer development through oral iron supplementation.² This is not surprising, as approximately 90% of ingested iron is not absorbed, passes the sites of intestinal inflammation and induces local oxidative stress at sites of active inflammation (through the Fenton reaction).

Further studies show that nutritional iron may be one of the exogenous factors responsible for the onset of colitis.^3,4 In patients with IBD, oral iron induces oxidative stress,⁵ increases local disease activity, particularly in patients with ulcerative colitis,⁶ and in patients with Crohn’s disease, the absorption of oral iron is inhibited, possibly through a hepcidin-mediated mechanism.⁷

If oral iron is used, there is limited data available to differentiate between products.

A study comparing iron polymaltose complex⁸ and ferrous sulphate showed that ferrous sulphate increased markers for lipid peroxidation more than iron polymaltose complex.