Sex, Lies, and Iron Deficiency in 2024: Cost-Effectiveness of Screening Ferritin Thresholds for the Treatment of Iron Deficiency in Women of Reproductive Age

Introduction: Iron deficiency (ID) is the most common micronutrient deficiency globally and one of the top five causes of years lived with disability in every country around the world. Epidemiologically, this health burden disproportionately affects persons with the capacity to menstruate. If unaddressed, ID may progress to IDA, further impacting the social, emotional, and health-related well-being of affected individuals. In the United States (US), the burden of ID is exacerbated by underdiagnosis and undertreatment due, in part, to low ferritin thresholds for diagnosis (i.e., 15µg/L per the US Centers for Disease Control and Prevention and the World Health Organization). These thresholds are argued to be inappropriately low based on physiologic studies of iron status and metabolism, which suggest a ferritin threshold of no less than ~25-30µg/L (and perhaps upwards of 50µg/L) as more sensitive for ID diagnosis. Given the current absence of universal screening for ID in the US, we performed the first cost-effectiveness analysis of varying ferritin thresholds for ID diagnosis and treatment.

Methods: We built a Markov simulation model of adult women in the US to examine the cost-effectiveness of screening all women for iron deficiency with the following strategies: 1) ferritin threshold <25µg/L, 2) ferritin threshold <15µg/L, and 3) status quo (i.e., no screening). The analysis was conducted over a lifetime time horizon with a willingness-to-pay (WTP) threshold of $100,000 per quality-adjusted-life-year (QALY). Costs were assessed in 2024 US dollars, with age- and sex- specific average annual healthcare costs informed by the US Medical Expenditures Panel Survey. The epidemiologic prevalence of ID in the US was informed by National Health and Nutrition Examination Survey data (across 2003-2010 and 2015-2020). The probability of iron-related adverse events including iron anaphylaxis was sourced from randomized clinical trials of oral and intravenous iron, as well as World Health Organization Vigibase data from 2008-2017. Adult women entered the model at age 18 and, if found to be iron deficient, were treated with iron supplementation, undergoing hematology follow-up and retreatment in accordance with average menstrual blood losses until age 51, the median age of menopause in the US. Once daily oral ferrous sulfate was used as the base-case iron supplement for treatment of ID, and a scenario analysis examined treatment with intravenous iron dextran. Effectiveness was measured in quality-adjusted life-years and parameterized using age-, sex-, and ID-specific utilities. The primary outcome was the incremental cost-effectiveness ratio (ICER) of screening vs no screening. We concluded by conducting deterministic and probabilistic sensitivity analyses, utilizing beta-PERT distributions to parameterize transition probabilities and utilities, and gamma distributions for costs, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo iterations.

Results: In the base case, screening for ID with a ferritin threshold <25µg/L is the cost-effective strategy in 100% of 10,000 Monte Carlo iterations, accruing $212,000 in costs and generating 24.3 QALYs, versus $211,000 and 23.3 QALYs (threshold of 15µg/L), and $210,000 and 22.3 QALYs (no screening). The incremental cost-effectiveness ratio of 25µg/L compared to no screening is $940/QALY, well under all accepted WTP thresholds in the US. Similar cost-effectiveness was found in the scenario analysis when patients with ID are treated with iron dextran (ICER = $1,700/QALY). Deterministic sensitivity analysis revealed that no parameter variations change the conclusion (i.e., that screening with a ferritin threshold of <25µg/L is the cost-effective strategy).

Conclusion: Identifying and treating women with ID at a ferritin threshold of <25µg/L is a cost-effective intervention, regardless of whether treatment is given with oral or intravenous iron supplementation. These results fill a critical gap in women’s health and align with a priority area (i.e., iron deficiency) for the American Society of Hematology.