Diagnosis and management of iron deficiency in females

Key points

• Globally, females are disproportionately affected by iron deficiency, owing to biological, socioeconomic, and health system factors.

• Both nonanemic iron deficiency and iron-deficiency anemia cause substantial morbidity.

• Complete blood count and ferritin level are important initial investigations in those with history and examination findings suggestive of iron deficiency states; note that the lower limit of normal ferritin values has recently been raised, increasing identification of those who would benefit from treatment.

• Treatment is indicated when ferritin is below 50 μg/L in a pregnant person, below 30 μg/L in other adults, and below 20 μg/L in children.

• Oral iron and menstrual loss reduction are first-line treatments in females with heavy menstrual bleeding; intravenous iron is useful in malabsorption states, to avoid blood transfusion, and when oral iron cannot be tolerated.

Globally, females are disproportionately affected by iron deficiency, owing to biological and socioeconomic factors as well as health system factors that deprioritize prevention and treatment of iron deficiency among females. Iron is an essential element for humans. Numerous metabolic processes depend on it, including oxygen transport, DNA synthesis, and electron transport. While iron is key to the formation of hemoglobin and is rate limiting for erythrocyte production, it is also critical for function of myoglobin, cytochrome P450, and central nervous system function.^1,2

Both nonanemic iron deficiency (NAID) and iron-deficiency anemia (IDA) have important consequences. A German prospective cohort study of healthy adults aged 35–74 years found a positive relationship between absolute iron deficiency and mortality (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.3–2.8) after adjustment for hemoglobin and major cardiovascular risk factors. ³ Moreover, American data from the National Health and Nutrition Examination Survey showed that age-adjusted mortality rates with IDA as the underlying cause of death increased from 0.04 to 0.08 deaths per 100 000 people from 1999 to 2018, despite a greater than 25% decline in mortality rates with other types of anemia as the cause of death.⁴ Globally, in females IDA is the leading cause of years of life lost due to disability.⁵ Iron deficiency without resulting anemia, or NAID, is associated with fatigue, reduced work performance, and reduced cognitive function. Iron deficiency is the most common cause of anemia despite being preventable and easily treated.^6–13 Treatment of iron deficiency is usually straightforward and, given the burden of disease, its diagnosis and management should be prioritized. ^5,14 We discuss the diagnosis and management of iron deficiency in females, drawing on recent evidence, clinical guidelines, and consensus recommendations (Box 1).

Box 1: Literature search .

We searched PubMed from inception to February 2024 for randomized controlled trials, observational studies, and systematic and scoping reviews involving people with nonanemic iron deficiency (NAID) and iron-deficiency anemia (IDA), using search terms that included “iron deficiency,” “iron deficiency anemia,” “iron supplementation,” “oral iron,” and “intravenous iron.” We also reviewed guidelines, expert consensus recommendations, and expert commentaries on diagnosis and treatment of NAID and IDA.

What is iron deficiency and who is at risk?

Iron deficiency is defined as a state of decreased bodily iron stores. It is typically diagnosed when serum ferritin levels are below 30 μg/L in adults and below 20 μg/L in children.^15–17 Iron deficiency anemia occurs when iron deficiency results in diminished erythrocyte production; it is generally defined as a hemoglobin below 120 g/L in females and below 130 g/L in males.¹⁸

The body’s iron stores are depleted by inadequate dietary intake and blood loss, particularly owing to menstruation in nonpregnant females, as well as the high iron demand state of pregnancy and direct and indirect losses of iron during the postpartum period.¹⁹

Menstrual bleeding contributes overwhelmingly to iron deficiency. Normal menstrual cycles cause the loss of 10–20 mg of iron.^6,20 Blood loss greater than 80 mL per cycle is deemed heavy and associated with an increased risk of iron deficiency.^21,22 Among females, 18%–50% meet criteria for heavy menstrual bleeding, but it is underdiagnosed and undertreated.^19,20,23

The risk of iron deficiency increases during pregnancy owing to the high iron demands of fetal growth and development against a background of deficiencies from regular menstrual blood loss. Postpartum blood loss and lactation compound further iron losses.⁵

The 2021 Global Burden of Disease study estimated that in some low- and middle-income countries, almost 50% of the population is iron deficient.⁵ High-income countries also show high prevalence of iron deficiency among females; a 2022 study of screening blood samples sent to laboratories in Ontario estimated that 38% of nonpregnant females screened had NAID, and 13% had IDA.²⁴

A 2022 retrospective study of pregnant females aged 13–54 years in Ontario, Canada, with laboratory samples obtained between January 2013 and June 2018, found that 53% of pregnant outpatients had iron deficiency and 8% had a hemoglobin level below 105 g/L.²⁵ Anemia in pregnancy affects both the pregnant person and their offspring, with potential for lasting consequences. Anemia in pregnancy has been associated with increased risk of preterm labour (odds ratio [OR] 1.54, 95% CI 1.36–1.76),²⁶ postpartum hemorrhage owing to the role of erythrocytes in hemostasis (OR 1.29, 95% CI 1.21–1.38),^14,27,28 peripartum death (OR 2.36, 95% CI 1.60–3.48),²⁹ and postpartum depression (risk ratio [RR] 2.25, 95% CI 1.22–4.16),³⁰ as well as intellectual disability (OR 2.20, 95% CI 1.61–3.01), autism spectrum disorder (OR 1.44, 95% CI 1.13–1.84), and attention-deficit/hyperactivity disorder (OR 1.37, 95% CI 1.14–1.64)³¹ in exposed offspring in early childhood.

A cross-sectional study from the United States using National Health and Nutrition Examination Survey data showed that Black females have a prevalence of IDA 4–7 times (p < 0.0001) higher than that of White females.³² In a retrospective cohort study using the National Inpatient Sample from the Agency for Healthcare Research and Quality, Black females were 5 times more likely to die from postpartum hemorrhage (RR 5.1, 95% CI 3.6–7.1) than females of other races and ethnicities.³³ Postpartum females of lower socioeconomic status in Ontario are also disproportionately affected, more often requiring blood transfusions due to uncorrected antenatal anemia than those of higher socioeconomic status.^24,25,34

The prevalence of NAID varies depending on geographic region, population studied, and laboratory parameters used for diagnosis.¹⁵ In a prospective cohort study of 5000 patients, NAID was independently associated with risk of all-cause mortality (HR 1.3, 95% CI 1.0–1.6) after adjustment for age, sex, hemoglobin, and major cardiovascular risk factors.³ Moreover, treatment of NAID has been shown to improve exercise performance, reduce fatigue, and decrease the risk of anemia.^3,35

How are iron deficiency states diagnosed?

The signs and symptoms of NAID and IDA are summarized in Figure 1.

Figure 1:

Symptoms and signs of nonanemic iron deficiency (NAID) and iron deficiency anemia (IDA). Percentages in brackets refer to the reported estimated point prevalence of NAID or IDA symptoms in the literature.^36–38 Note: IQ = intelligence quotient. See Related Content tab for accessible version. Illustration by Carine Bekdache.

Patients with IDA may complain of severe fatigue, shortness of breath, chest discomfort, and orthostatic dizziness. Patients with NAID may also report fatigue, as well as hair and nail changes, restless legs, poor exercise tolerance, pica (urge to eat inedible things), abnormal mood, brain fog, and cognitive impairment owing to negative impact on memory, attention, and thought processes.^19,36–38

Clinicians should obtain a thorough medication history for nonsteroidal anti-inflammatory drugs (NSAIDs) or antithrombotics. Discussion on dietary consumption of iron, changes in bowel habits, abdominal discomfort, dyspepsia, change in appetite, or weight loss is important, to ascertain the possibility of gastrointestinal causes of iron loss, including malignancy.^15,39,40

Taking a detailed menstrual history is important. Patients may not realize their bleeding is abnormal or may not report heavy bleeding owing to perceived stigma.^41,42 The American College of Obstetricians and Gynecologists defines heavy menstrual bleeding as any 1 of the following: bleeding that lasts more than 7 days; bleeding that soaks through 1 or more tampons or pads every hour for several hours in a row; a need to wear more than 1 pad at a time to control menstrual flow; a need to change pads or tampons during the night; or menstrual flow with blood clots that are as big as a quarter or larger. It is helpful to use a modified pictorial blood assessment chart⁴³ to more accurately quantify blood lost per cycle. Asking about the type of tampons and pads being used is important, because the level of absorbency influences perception of the amount of blood lost. Saturating 2 heavy pads (100 mL) or 3 heavy tampons (90 mL) over a menstrual cycle immediately meets criteria for heavy menstrual bleeding.⁴⁴

The physical examination should note any changes that could indicate iron deficiency or anemia, such as pallor, koilonychia, angular cheilitis, hair thinning, orthostatic changes in vital signs, and signs suggesting heart failure. A pelvic and rectal examination may be useful to suggest an underlying cause, guided by history.^15,39

An initial complete blood count (CBC) and ferritin level test will guide further workup. The CBC is typically normal in the case of NAID. The hemoglobin concentration will be decreased when IDA is present. The mean corpuscular volume (MCV) may be normal in IDA; a retrospective study of nonpregnant females in Ontario found that 56% with IDA have a normal MCV.²⁴ When the MCV is low, it suggests chronicity of the iron deficiency.⁴⁵ Ferritin is an acute-phase reactant that rises with inflammatory states (e.g., infection, malignancy, chronic kidney disease), even in the presence of iron deficiency.⁴⁶ Full iron studies should be ordered (i.e., serum iron, total iron binding capacity, and transferrin saturation) for patients with inflammation who have symptoms of iron deficiency with a serum ferritin of 30 μg/L or higher. In this context, a transferrin saturation below 20%⁶ (or 30%–40% in some cases)⁴⁷ is in keeping with iron deficiency. Iron studies should be drawn in a fasting state, because blood iron levels are susceptible to recent dietary intake; serum ferritin, however, is not affected by recent dietary intake. In patients with concomitant inflammation, the serum ferritin may rise above the laboratory upper limit of normal. Different disease states may have different serum ferritin ceiling thresholds in keeping with iron deficiency; for example, guidelines on chronic kidney disease and heart failure suggest a ceiling serum ferritin of 300 μg/L.⁴⁷ Both serum ferritin and iron studies testing are relatively inexpensive and widely available.

Any underlying causes of blood loss causing iron deficiency or anemia should be identified, investigated, and addressed. Patients with a hemoglobin below 100 g/L should be referred to a hematologist, gynecologist, gastroenterologist, or other specialist as indicated.

Should females be screened for iron deficiency?

No national recommendations exist in Canada for routine screening for NAID or IDA in nonpregnant females of reproductive age. The International Federation of Gynecology and Obstetrics⁴⁸ and the European Hematology Association⁴⁹ recommend screening for iron deficiency in all females of reproductive age and all females in first trimester of pregnancy. Choosing Wisely Canada recommends that screening tests in general be done according to the risk profile of the patient.⁵⁰ The 2024 US Preventive Services Task Force statement on screening for iron deficiency during pregnancy concluded there was not enough level 1 evidence to decide for or against screening during pregnancy, ⁵¹ despite decades of observational data on its high prevalence and known association with harms to the maternal–fetal dyad.

In this context of unaligned guidelines, it would be reasonable to carry out CBC and ferritin testing for asymptomatic females and females of reproductive age every 3 years, especially for those with heavy menstrual bleeding or who are planning to become pregnant. Testing of asymptomatic females and females at risk for iron deficiency is appropriate given the subtle nature of some symptoms, which will sometimes be accepted as normal by patients.⁴²

A CBC will be helpful in detecting anemia, and serum is the best screening test for iron deficiency states because it most accurately reflects iron stores and is not sensitive to recent dietary intake.¹⁶ A serum ferritin below 30 μg/L has long been used as the threshold to mark iron deficiency in adults, as it accurately reflects low iron stores (sensitivity of about 92% and specificity about 98%).^15–17,52 However, there is a pathophysiological progression to iron deficiency, and a serum ferritin value below 50 μg/L corresponds with abnormal biochemical markers of iron deficiency and is associated with increased gastrointestinal absorption of iron, which suggests physiologic relevance of this threshold.^53–57

In 2024, the lower limit of normal for ferritin was raised in the largest Canadian community laboratories and some hospitals to guide evidence-based clinical decisions (Table 1 and Box 2). Previously, the lower limit of normal of ferritin was 12–15 μg/L (depending on community laboratory), and this has been increased to 30 μg/L for adults and 20 μg/L for children. The previous ranges for the most common ferritin assays were based on biased population samples, which did not exclude those with NAID or IDA, and did not adhere to the Clinical and Laboratory Standards Institute reference interval guideline when establishing their normal ranges for ferritin.⁵⁹

Table 1:

Recommended screening and treatment algorithm for iron deficiency in nonpregnant people

Patient population	Laboratory value	Interpretation	Suggested management
Adult (age ≥ 18 yr) patients	Ferritin < 30 μg/L	Iron deficiency	Initiation of iron therapy with reassessment of ferritin in 3 months
Adult patients with concomitant inflammation	Ferritin ≥ 30 μg /L AND transferrin saturation < 20%*	Iron deficiency	Initiation of iron therapy with reassessment of ferritin and iron studies in 3 months
Pediatric (age < 18 yr) patients	Ferritin < 20 μg /L	Iron deficiency	Initiation of iron therapy with reassessment of ferritin in 3 months
Pediatric patients with concomitant inflammation	Ferritin ≥ 20 μg /L AND transferrin saturation < 20%*	Iron deficiency	Initiation of iron therapy with reassessment of ferritin and iron studies in 3 months

^*If adult patients have concomitant inflammation (e.g., active cancer, autoimmune disease, infection, chronic kidney disease, heart failure) with ferritin ≥ 30 μg/L, iron studies (serum iron, total iron binding capacity, transferrin saturation) should be ordered in the fasting state. For pediatric patients with concomitant inflammation and ferritin ≥ 20 μg/L, iron studies or soluble transferrin receptor should be ordered in the fasting state.

Box 2: Further clinical resources .

• Raise the Bar (https://www.hemequity.com/raise-the-bar-home) helps health care providers diagnoses and treat nonanemic iron deficiency (NAID) and iron-deficiency anemia (IDA), and is led by Canadian researchers.

• First Exposure (https://firstexposure.ca/non-anemic-iron-deficiency-and-iron-deficiency-anemia-in-pregnancy/) at the University of Toronto is a digital information hub and research network providing evidence-based information to the public and health care providers on the safety of medications and other exposures during pregnancy and lactation).

How are NAID and IDA treated in females?

Maintaining erythrocyte production requires 20 mg of iron daily.⁶⁰ Dietary modifications alone do not provide adequate amounts of elemental iron to treat iron deficiency, especially in menstruating or pregnant people who are experiencing ongoing iron losses or high iron demands.⁶¹ However, following an iron-rich diet in addition to replacement and other strategies is reasonable.

Management of abnormal uterine bleeding in affected females is of critical importance to address NAID and IDA. Menstrual blood loss reduction strategies include use of tranexamic acid, NSAIDs, oral contraception, and progesterone-releasing intrauterine devices.⁶²

Oral iron is first-line therapy for NAID and for IDA if hemoglobin is above 100 g/L.^56,63 Iron salts (ferrous gluconate, sulfate, or fumarate) should be used as first-line oral iron therapy, as they are less expensive and there is no robust evidence that their more expensive counterparts (polysaccharide, heme-based, or liposomal iron preparations) are more effective.⁶⁴ They should be taken only once daily (Table 2), and ferrous gluconate and sulfate may be better tolerated than ferrous fumarate, owing to their lower elemental iron content.^56,65 Oral supplements should ideally be taken on an empty stomach to avoid interference with absorption. Gastrointestinal adverse effects (nausea, constipation, diarrhea, indigestion, and metallic taste) reduce treatment adherence.⁶⁴ The best oral iron supplement is the one that a patient tolerates and takes consistently. Randomized controlled trials found that every-other-day therapy may be better tolerated than daily therapy, but intermittent dosing may reduce compliance.^66–69

Table 2:

Oral iron preparations⁵⁸

Generic name	Daily or alternate day dosing	Dose per tab, mg	Elemental iron, mg/tab	Daily estimated cost, $
Ferrous gluconate	1 tab	300	35	0.10
Ferrous sulfate	1 tab	300	60	0.20
Ferrous fumarate	1 tab	300	100	0.25
Ferrous bisglycinate	1 tab	25	25	0.30
Polysaccharide iron complex	1 tab	150	150	0.75
Liposomal iron	1 tab	30	30	1.75
Heme iron polypeptide	2 to 3 tabs	11	11	2.40

If oral supplements are well tolerated and effective for the degree of ongoing iron losses with underlying causes addressed, improvements in hemoglobin should begin within days to weeks with oral iron. Improvements in iron stores, as assessed by ferritin, will typically occur in about 3–6 months.

Some patients will not be able to tolerate an effective dose of oral iron. Oral iron may be ineffective if the causes of blood loss are insufficiently addressed (this can happen when sources of blood loss are unclear, such as in occult gastrointestinal bleeding), or if patients have malabsorptive states, and should likely trigger additional investigations. Intravenous (IV) iron can be used in any patient who does not tolerate oral iron, when a trial of oral iron has been ineffective, in a patient with severe anemia to avoid the need for transfusion, or in the context of malabsorption. Total dose requirements can be approximated using iron deficit calculations (i.e., the Ganzoni formula) or dosing regimens suggested by simplified product monographs, but must consider ongoing losses of iron.⁷⁰ In most cases, replacement therapy is best monitored with serial ferritin determinations.

Adverse effects with IV iron are rare (about in 1 in 200) and include self-limited acute “Fishbane” reactions, such as flushing and acute chest or back tightness, without hypotension, wheezing, stridor, or periorbital edema.⁷¹ Most occur within 1–2 hours of the IV iron infusion and resolve once the infusion is stopped. Fishbane reactions are distinct from anaphylaxis and rarely recur with rechallenge.⁷¹ Reactions do not recur when the infusion is reinitiated at a slower rate after an infusion pause with resolution of symptoms.⁷¹ Risk of anaphylaxis after IV infusion of iron is rare (< 1 in 200 000).⁷¹ No evidence exists to suggest that one currently available formulation of IV iron is safer than another; formulations administered as single total dose infusions (e.g., ferric derisomaltose) are recommended, to minimize health resource utilization and patient convenience.^56,72

Response to IV iron treatment should be assessed with CBC and ferritin level testing in most patients. Administration of IV iron will immediately affect ferritin values and therefore should not be rechecked within 4 weeks of IV iron administration, as the result will be misleadingly high. Ferritin treatment targets are 50 μg/L or higher for patients on oral iron supplementation and 100 μg/L or higher for patients on IV iron, given that those on IV iron are typically at greater risk of rapid iron store depletion. In patients with a hemoglobin level between 70 and 100 g/L, CBC and ferritin should be reassessed in 1 month. In patients with a hemoglobin level above 100 g/L, CBC and ferritin can be reassessed in 2–3 months.

Patients who remain symptomatic should be retested every 3–6 months (Table 1). In many jurisdictions, parenteral iron is now available for administration through infusion clinics, no longer requiring referral to a specialist or hospital for administration. Importantly, blood transfusions for IDA should be reserved for emergent indications only (e.g., hypotension, massive hemorrhage).

What about iron deficiency in pregnancy?

Many females have suboptimal iron stores as they enter pregnancy, and pregnancies occurring in rapid succession increase the risk of iron deficiency. During gestation and postpartum, it takes about 1000 mg of iron to support the growth of the fetus, the placenta, and the increase in maternal blood volume, and to account for lochial losses.⁷³

The World Health Organization recommends 30–60 mg of elemental iron per day during pregnancy.⁷⁴ Given that 1000 mg of iron is equivalent to 177 large steaks,⁷⁵ it is impossible to “eat your way out” of iron deficiency in pregnancy.

A Canadian clinical practice guideline for pregnant patients recommends therapeutic doses of iron if the serum ferritin is less than 30 μg/L.⁷⁶ Pregnant females should have a serum ferritin included in initial antenatal blood work (Figure 2), as the CBC alone is not an effective screening test for IDA.²⁴ This guidance contrasts with 2024 guidance issued by the US Preventive Services Task Force, which recommends against routine screening for iron deficiency in asymptomatic pregnant females; the task force cited insufficient population-level screening data, in their view, to support screening in asymptomatic pregnant people, and limited evidence to guide the use of iron replacement during pregnancy in this group.⁵² Since then, an international panel of experts has developed best practice recommendations for managing iron deficiency, and suggested screening and treatment of iron deficiency in pregnancy according to Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)–based appraisal of the literature and expert consensus.⁵⁶

Figure 2:

Recommended screening and treatment algorithm for iron deficiency in pregnancy (based on the Unity Health Toronto policy on iron deficiency anemia treatment in pregnancy; developed with input from experts across Toronto academic hospitals). Note: CBC = complete blood count, Hb = hemoglobin, IV = intravenous. See Related Content tab for accessible version.

Iron replacement therapy during pregnancy can be limited by adverse effects; decreased bowel motility caused by elevated progesterone and the pressure of the uterus on the rectum often lead to constipation, which is made worse by oral ingestion of iron.⁷⁷ Combination prenatal vitamins generally contain calcium and magnesium in addition to iron, and these elements directly interfere with iron absorption. Patients should take iron supplements at a different time of day from any prenatal vitamin supplements.

Oral iron supplementation is unlikely to meaningfully increase ferritin levels during pregnancy, because pregnancy is a time of iron utilization, not storage. Intravenous iron can be used in pregnant females in the second and third trimester of pregnancy, but safety has not been evaluated in the first trimester.^56,72

Conclusion

In Canada and globally, NAID and IDA are highly prevalent, especially among people with the biological capacity to menstruate, become pregnant, and lactate. Targeted treatment corrects these conditions and appears to correct their negative effects. Females of reproductive age are at high risk of NAID and IDA; thus, regular screening and prompting of treatment using knowledge translation tools enables care when necessary. Important clinical questions remain unanswered and should be addressed by future research (Box 3). Canada can lead by example to structurally transform care and address this glaring example of health inequity.

Box 3: Unanswered questions .

• How should guidelines on nonanemic iron deficiency and iron deficiency anemia in females be harmonized in partnership with hematologists, obstetricians, gynecologists, family medicine physicians, and patients?

• What are the ideal screening indications for females of reproductive age?

• What is the ideal oral iron regimen for first-line management of iron deficiency?