Anemia and Iron Deficiency in Women: A Global and National Health Concern

By Mukul Singal, MD, FACP – Hematologist

Anemia is the most prevalent hematologic disorder worldwide, affecting approximately 1.92 billion people, or 24.3% of the global population. ¹ Iron deficiency is the leading cause, responsible for nearly two-thirds of all anemia cases.¹ In the U.S., iron deficiency affects nearly 40% of females ages 12 to 21, with 17.2% also meeting criteria for iron-deficiency anemia (IDA).² Among women ages 18 to 50, an estimated 34% are iron deficient.³

Despite their prevalence, iron deficiency and IDA are frequently underdiagnosed.^4,5 Symptoms such as fatigue, poor concentration, and tachycardia are often misattributed to hormonal or physiological changes. Early detection of iron deficiency and IDA are essential, and if left untreated, iron deficiency can impair physical and cognitive function as well as negatively impact maternal-fetal outcomes during pregnancy.

Etiology of Iron Deficiency

Iron deficiency arises from multiple causes ²:

• Blood loss: Menstrual bleeding is the most common cause in women, while gastrointestinal bleeding and frequent blood donations also impact iron stores. In developing regions, parasitic infections like hookworms are significant and can contribute to blood loss.
• Inadequate intake: Iron from red meat is more bioavailable than plant-based sources, putting vegetarians and vegans at higher risk for iron deficiency.
• Malabsorption: Conditions such as atrophic gastritis, gastric bypass, H. pylori infection, and use of proton pump inhibitors impair iron uptake.
• Increased demand: Daily iron absorption from Western diets averages only 1–5 mg³. Periods of rapid growth, such as puberty, and physiological stress can increase iron requirements. Almost 1 g of iron must be acquired during pregnancy to preserve the maternal iron balance and support fetoplacental development, with iron requirements increasing from 0.8 mg per day in the first trimester to 7.5 mg per day in the third.³

Presentation and Progression

Iron is stored primarily in red blood cells, muscle, liver, and macrophages. Iron deficiency progresses from depletion of storage pools to IDA.⁶ Iron is essential for cellular processes including mitochondrial function and redox reactions.⁶ Even non-anemic iron deficiency can impair health and fetal development.⁶ Symptoms may be nonspecific, and iron deficiency without anemia is often overlooked.

Common symptoms include :⁶

• Pale or sallow skin
• Fatigue and weakness
• Exercise intolerance
• Shortness of breath
• Rapid heart rate
• Headaches
• Pica (e.g., craving ice)
• Hair loss and brittle nails
• Sore or smooth tongue

Impact on Women

Iron deficiency disproportionately affects women, especially during reproductive years due to menstruation and pregnancy. Iron deficiency, with or without anemia, negatively affects women of all age groups.

In adolescents and younger women, iron deficiency can be associated with fatigue and impaired physical performance, as well as cognitive impairment and mood disturbances. Together, these lead to poor academic performance, and lost productivity. Iron deficiency also affects athletic performance, and a recent meta-analysis found iron deficiency in up to 31% of female athletes, with contributing factors including inadequate intake, gastrointestinal blood loss, sweat-related iron loss, and exercise-induced hemolysis.⁷

Iron deficiency in mothers is associated with adverse outcomes in both the mother (placental abruption, preterm birth, postpartum hemorrhage, maternal shock, and maternal intensive care unit admission and maternal mortality) as well as in the neonate (low birth weight, small-for-gestational age, arguably also cognitive development).^8-11

The repletion of iron stores antepartum may not only reduce the occurrence of PPH but also improve the ability to withstand hemorrhagic losses peripartum or from post-partum hemorrhage and reduce the need for PRBC transfusions.¹¹

Among older women (age >65 years), iron deficiency, with or without anemia, is associated with increased mortality.¹² This may reflect the added impact of functional iron deficiency, especially in patients with chronic inflammation, heart failure, and chronic kidney disease.¹³

Practitioners should therefore not dismiss these as ‘normal’ symptoms.

Diagnostic Recommendations

Despite its burden, IDA is often missed due to vague symptoms and inconsistent screening guidelines. While the European Hematology Association (EHA) and the International Federation of Gynecology and Obstetrics (FIGO) recommend screening high-risk individuals, the United States Preventive Services Task Force (USPSTF) and American College of Obstetricians and Gynecologists (ACOG) do not support routine screening for asymptomatic, non-anemic patients. However, both ACOG and CDC recommend screening at the first prenatal visit.

Serum ferritin is the primary diagnostic marker. A threshold of <30 ng/mL offers 92% sensitivity, compared to the traditional 57% at <15 ng/mL. There is a growing recognition of the need for a higher threshold of 50ng/mL, especially in women.^6,14,15 A transferrin saturation (TSAT) <20% also supports diagnosis. Functional iron deficiency should be considered when TSAT is <20% and ferritin is between 100–500 ng/mL.¹³

Additional tests like soluble transferrin receptor and the transferrin receptor–ferritin index can help differentiate IDA from anemia of inflammation. Bone marrow biopsy is the gold standard but not routinely indicated.

Management: Dosing and Delivery

Oral iron is first-line treatment and is inexpensive and very effective for the treatment of iron deficiency/ IDA in most patients. Common formulations include ferrous sulfate, fumarate, gluconate, and polysaccharide iron complex. No formulation has shown superior efficacy or lesser side effects, though polysaccharide iron complexes may be better tolerated, but at the risk of lesser bioavailability. There is some evidence that heme iron (red meat or as supplements) may be better absorbed from the GI tract.

Side effects of oral iron supplements include nausea, constipation, and diarrhea, and can lead to poor adherence in up to two-thirds of patients. Alternate-day dosing improves absorption and reduces side effects.¹⁶ Counseling and adjunctive therapies can also enhance adherence.

Parenteral iron is reserved for those intolerant or unresponsive to oral therapy. FDA approved IV formulations include low molecular weight iron dextran (InFeD®), iron sucrose (Venofer®), ferric carboxymaltose (Injectafer®), ferumoxytol (Feraheme®), and ferric derisomaltose (Monoferric®). The choice of parenteral preparation is often guided by physician, patient and insurance preference, as well as previous response to parenteral iron formulations. Consensus guidelines recommend the use of single dose iron formulations over formulations requiring multiple doses.¹⁵

The current parenteral formulations are all very safe. Completement activity related pseudo-allergy (more commonly known as Fishbaine reactions), which occur due to the tissue deposition of iron nanoparticles, are more common but are usually mild and short lived.¹⁵ True hypersensitivity reactions can occur, but are rare and pre-medication is generally unnecessary, unless there is prior history of hypersensitivity to other medications and/or other iron formulations.^15,17 A previous formulation, high molecular weight iron dextran, was associated with a higher risk of allergic reactions.   It is now well established that ferric carboxymaltose (FCM) carries a risk of hypophosphatemia and phosphorous levels should be followed, especially after repeated doses of FCM.^15,17,18

Routine prophylactic iron supplementation is not recommended outside of pregnancy. The CDC advises 30 mg daily of elemental iron for all pregnant individuals, except those at risk for hemochromatosis.

Dr. Mukul Singal is an adult hematologist at Innovative Hematology, parent of the Indiana Hemophilia & Thrombosis Center (IHTC) in Indianapolis. Dr. Singal’s special interests and expertise include bleeding and clotting disorders, especially bleeding issues in women. Dr. Singal also treats iron disorders with a special focus on hemochromatosis (iron overload).

References

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14. Tarancon-Diez L, Genebat M, Roman-Enry M, et al. Threshold Ferritin Concentrations Reflecting Early Iron Deficiency Based on Hepcidin and Soluble Transferrin Receptor Serum Levels in Patients with Absolute Iron Deficiency. Nutrients. Nov 10 2022;14(22)doi:10.3390/nu14224739
15. Van Doren L, Steinheiser M, Boykin K, Taylor KJ, Menendez M, Auerbach M. Expert consensus guidelines: Intravenous iron uses, formulations, administration, and management of reactions. Am J Hematol. Jul 2024;99(7):1338-1348. doi:10.1002/ajh.27220
16. von Siebenthal HK, Gessler S, Vallelian F, et al. Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomized double-blind placebo-controlled study. EClinicalMedicine. Nov 2023;65:102286. doi:10.1016/j.eclinm.2023.102286
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