Cost-effectiveness of first-line IV vs oral iron for iron-deficiency anemia in women with heavy menstrual bleeding.

We developed a Markov simulation to compare the cost-effectiveness of first-line IV iron dextran, IV ferumoxytol, IV iron sucrose, and oral ferrous sulfate for treating IDA in reproductive-age women with HMB. Outcomes were modeled over a menstrual lifetime horizon, beginning at age 18 years and continuing through age 51 years, with model cycles of 3 months in length. 33 Costs and outcomes were assessed from a societal perspective, accounting for patient wages lost to infusion time, and discounted at 3% annually. 34 This analysis was conducted in accordance with the CHEERS guidelines (see the supplemental Material ). We assumed that women with HMB and IDA have an iron deficit of 1000 mg, with an average menstrual blood loss of 120 mL/mo in the base case. 35 Given an estimated iron loss of 0.5 mg/mL of blood with no coexisting gastrointestinal bleeding, this resulted in a monthly iron loss of 60 mg. 36 We assumed that dietary iron intake is sufficient to replete iron when menstrual blood losses are ≤50 mL/mo, based on population reference intervals and in the absence of malabsorption; in other words, an average of 25 mg of elemental iron is absorbed through diet each month. 37 Thus, in the base case of 120 mL average monthly menstrual losses, a patient will have a net monthly iron deficit of 35 mg requiring correction through iron supplementation. Patients who received and tolerated first-line treatment with IV iron dextran (single 2-hour 1000 mg dose), IV ferumoxytol (2 × 510 mg doses), or IV iron sucrose (5 × 200 mg doses) transitioned to the healthy state, defined as being free of IDA ( Figure 1 ). Importantly, we note that ferumoxytol may also be safely and effectively dosed as a 1-time 1020 mg infusion, and iron dextran may be dosed as a 1-time 1-hour 1000 mg infusion, both of which would decrease associated nursing and infusion costs while offering improved convenience to patients. 38 , 39 We examine these alternate infusion strategies in a separate scenario analysis below (see “Methods - Scenario and sensitivity analyses”). Patients remained in this state until they reaccumulated an iron deficit of 1000 mg due to continuing HMB. In the base case, this was estimated to occur over 30 months, based on the previously described assumptions. Upon reaching this threshold, patients transitioned back to the IDA state and received the same IV iron formulation as initially administered. This process of treatment, accumulating menstrual losses, and retreatment continued for the duration of the reproductive life span within our model, from ages 18 to 51 years. The probabilities of mild hypersensitivity reactions, encompassing Fishbane reactions, and anaphylaxis due to IV iron administration were derived from retrospective pharmacoepidemiologic studies based on data from Medicare Parts A and B in the United States, the World Health Organization safety surveillance database, and large retrospective studies of iron infusion reactions. 40 , 41 , 42 The probability of death due to anaphylaxis associated with IV iron products was estimated using data from the US Food and Drug Administration Adverse Event Reporting System database. 43 Figure 1. State-transition diagram for the treatment of IDA in women with HMB in the United States. Patients initiate treatment with either IV iron or oral iron. After completing treatment, all patients enter a healthy, IDA-free state. Ongoing iron losses from HMB after iron replenishment lead to the recurrence of IDA. Those starting with oral iron may switch to IV iron as second-line therapy due to GI adverse events. Patients who experienced GI adverse events with oral iron may directly switch to IV iron when treatment is restarted after recurrence of IDA. Death due to anaphylaxis from IV iron was also included. GI, gastrointestinal. State-transition diagram for the treatment of IDA in women with HMB in the United States. Patients initiate treatment with either IV iron or oral iron. After completing treatment, all patients enter a healthy, IDA-free state. Ongoing iron losses from HMB after iron replenishment lead to the recurrence of IDA. Those starting with oral iron may switch to IV iron as second-line therapy due to GI adverse events. Patients who experienced GI adverse events with oral iron may directly switch to IV iron when treatment is restarted after recurrence of IDA. Death due to anaphylaxis from IV iron was also included. GI, gastrointestinal. Patients receiving first-line treatment with alternate-day dosing of oral ferrous sulfate 325 mg (providing 65 mg elemental iron) were assumed to absorb 20.6% of the elemental iron, based on a previous radioisotope study. 18 This corresponds to a monthly iron uptake of ∼200.85 mg. After accounting for a monthly iron loss of 35 mg due to menstruation, the net monthly gain was 165.85 mg of elemental iron. Based on this rate, patients would replenish a 1000 mg iron deficit within 6 months. Combining this 6-month treatment duration with the previously estimated 30 months required to develop a 1000 mg iron deficit after completing treatment, we assumed that patients would return to the IDA state every 36 months. Patients who experienced gastrointestinal adverse events from oral iron could either continue oral therapy or switch to IV iron dextran as a second-line treatment. Patients receiving second-line IV iron dextran transitioned through subsequent health states in the same manner as those treated initially with IV iron. We assumed that 50% of patients who experienced gastrointestinal adverse events with oral iron reattempted oral supplementation, whereas 10.9% discontinued oral iron due to adverse events, based on the largest published meta-analysis studying oral iron discontinuation to date. 44 Background mortality was accounted for in all health states based on US Life Tables. 45 All model inputs are summarized in Table 1 . Table 1. Model input parameters and probability distributions Variable Base-case estimate Probabilistic sensitivity analysis Distribution and range References Clinical parameters  Cohort age at start, y 18 Fixed —  Age of menopause, y 51 Fixed 33  Discount rate 0.03 Fixed 34  Fractional absorption of per-oral iron 0.206 ß-PERT (0.165-0.247) 18  Probability of PO iron discontinuation due to adverse events 0.109 ß-PERT (0.0872-0.1308) 69  Probability of gastrointestinal adverse events due to per-oral iron treatment 0.069 ß-PERT (0.055-0.083) 18  Proportion of patients retrying per-oral iron after experiencing gastrointestinal adverse events 0.5 Fixed Assumption  Probability of IV iron anaphylactic reaction 2.0E−06 ß-PERT (1.6E−0.6 to 2.4E−06) 41  Probability of IV iron mild hypersensitivity, including Fishbane reactions 0.00437 ß-PERT (0.00350-0.00524) 41 , 42  Probability of death from anaphylaxis due to IV iron dextran 0.045 ß-PERT (0.036-0.054) 43  Background mortality Age specific ß-PERT 45 Utilities  Utility of healthy state Age specific ß-PERT 46  Utility of IDA state Age specific ß-PERT 47  Utility increment of moderate to no anemia 0.052 ß-PERT (0.0416-0.0624) 49  Utility increment of severe anemia to no anemia 0.149 ß-PERT (0.1192-0.1788) 49  Utility increment of severe to moderate anemia states 0.097 ß-PERT (0.0776-0.1164) 49  Disutility of GI adverse events due to PO iron −0.0878 ß-PERT (−0.07024 to −0.10536) 50 , 70  Disutility of IV iron hypersensitivity, including Fishbane reactions −0.000038 ß-PERT (−0.000046 to −0.000031) 71  Disutility of IV iron anaphylactic reaction −0.00074 ß-PERT (−0.00089 to −0.00059) 51 Costs (USD)  Mean annual health care expenditures, US women Age specific ß-PERT 52  Mean hourly earnings, United States 36.32 γ; α = 228.77, λ = 6.30 72  Monthly cost of once-daily oral iron sulfate 11.15 γ; α = 306.25, λ = 0.03 54  Cost of iron dextran per milligram 0.354 γ; α = 297.15, λ = 840.88 73  Cost of administration IV dextran (1000 mg) 173.20 γ; α = 361.38, λ = 0.76 74  Cost of iron sucrose per milligram 0.233 γ; α = 1083.04, λ = 4648.25 73  Cost of administering IV iron sucrose (1000 mg) 472.25 γ; α = 400.05, λ = 0.57 74  Cost of treating IV iron hypersensitivity reactions 11 696.26 γ; α = 306.25, λ = 0.03 43  Cost of treating anaphylaxis due to IV iron 11 696.26 γ; α = 306.25, λ = 0.03 43  Cost of ferumoxytol per milligram 0.308 γ; α = 400, λ = 1298.70 73  Cost of administering IV ferumoxytol (1020 mg) 188.90 γ; α = 399.58, λ = 2.16 74  Cost of menstrual hygiene product (single use) 0.33 γ; α = 225, λ = 676.90 75 GI, gastrointestinal; USD, US dollars. Model input parameters and probability distributions GI, gastrointestinal; USD, US dollars. Age-specific utility values for healthy women without IDA in the United States were derived from population norms based on the EuroQol-5D instrument. 46 The sex-specific baseline utility of the severe IDA health state was parameterized using EuroQol-5D index values from the largest (n = 236) prospective study of the effects of iron deficiency and anemia on the health-related quality of life in women of reproductive age, and adjusted for the US population, following the approach used in our previous cost-effectiveness analysis of iron-deficiency screening. 47 , 48 The utility increments of progressing from the state of severe to moderate anemia and severe to no anemia were then drawn from the multinational Global Burden of Disease study, informing the health-related quality of life benefit of undergoing iron supplementation for treatment of HMB-related IDA. 49 Disutilities associated with gastrointestinal adverse events from oral iron, as well as mild hypersensitivity reactions and anaphylaxis from IV iron products, were also incorporated. 50 , 51 Mean annual health care expenditure among women in the United States, based on data from the Medical Expenditure Panel Survey, was applied across all health states. 52 The costs of IV iron dextran and iron sucrose were obtained from the Centers for Medicare & Medicaid Services, whereas the cost of oral ferrous sulfate was sourced from GoodRx. 53 , 54 Median hourly nursing wages were incorporated in the cost of administering IV iron, and national mean hourly wages were used to account for income lost to iron infusion time; both were sourced from data from the US Bureau of Labor Statistics. 55 The cost of managing hypersensitivity reactions and anaphylaxis related to IV iron products was estimated using data from the US Food and Drug Administration Adverse Event Reporting System database. 43 Importantly, although the cost of management was applied to all hypersensitivity and anaphylactic reactions in the model for the sake of favoring the null hypothesis, we note the exceedingly rare incidence of true anaphylactic reactions to IV iron requiring epinephrine use documented extensively in the literature. Most reactions to IV iron are not immunoglobulin E-mediated but rather complement-mediated pseudo-allergy (also known as Fishbane) reactions, which are often self-limited, with hemodynamic instability more likely caused by the inappropriate administration of epinephrine or diphenhydramine rather than the reaction itself. 24 , 56 Finally, the cost of menstrual hygiene products was accounted for across the base case and all increasing monthly blood loss scenario analyses, and was sourced from the US Department of Health and Human Services Report, with the assumption that the average single-use menstrual pad or tampon will absorb 10 mL of blood before being changed, recognizing that this varies widely by individual preference. 57 , 58 The cost-effectiveness of each strategy was assessed using the incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB). The ICER was calculated as the difference in total cost divided by the difference in total quality-adjusted life years (QALYs) between strategies. The NMB was calculated as the product of total QALYs and the willingness-to-pay (WTP) threshold, minus total costs, for all commonly used WTP thresholds in the United States. 59 We explored alternative scenarios with average monthly menstrual blood losses of 240 mL and 420 mL. In these scenarios, after completing treatment, patients remained in the healthy state for 12 months and 6 months, respectively, compared with 30 months in the base-case scenario. An additional scenario analysis examined alternate, rapid dosing strategies of IV iron dextran (1-time, 1-hour infusion) and IV ferumoxytol (1-time, 30-minute infusion). A final scenario analysis examined changing levels of blood loss over time, specifically, assuming that all patients receive appropriate treatment for their bleeding symptoms with tranexamic acid and oral progestin, and decrease their monthly menstrual volume by one-half within 5 years of diagnosis. One-way deterministic sensitivity analyses were conducted to identify parameters with the greatest influence on the incremental NMB (iNMB) by varying all parameters by ±20% or their known 95% confidence intervals, including model starting age. Parameters that altered the iNMB by >10% are presented in a tornado diagram ( Figure 2 ). Probabilistic sensitivity analysis was also conducted using 10 000 Monte Carlo iterations, sampling from all distributions of probabilities, costs, and utilities simultaneously ( Table 1 ). Results of the probabilistic sensitivity analysis are presented as a cost-effectiveness acceptability curve ( Figure 3 ), showing the probability of each strategy being cost-effective across all accepted WTP thresholds in the United States. Figure 2. Tornado diagram showing 1-way sensitivity analysis of iNMB for IV iron dextran vs oral ferrous sulfate in the base case. Each row represents the range of outcomes resulting from changes in 1 parameter. Only parameters that produced a >10% change in iNMB are shown. Blue bars indicate iNMB changes associated with lower parameter values; red bars indicate changes with higher values. EV, expected value; USD, US dollars. Figure 3. Cost-effectiveness acceptability curve showing the probability that each treatment strategy is cost-effective across all accepted WTP thresholds in the United States ($50 000-$150 000 per QALY). The dashed line indicates the base-case threshold of $100 000 per QALY. USD, US dollars. Tornado diagram showing 1-way sensitivity analysis of iNMB for IV iron dextran vs oral ferrous sulfate in the base case. Each row represents the range of outcomes resulting from changes in 1 parameter. Only parameters that produced a >10% change in iNMB are shown. Blue bars indicate iNMB changes associated with lower parameter values; red bars indicate changes with higher values. EV, expected value; USD, US dollars. Cost-effectiveness acceptability curve showing the probability that each treatment strategy is cost-effective across all accepted WTP thresholds in the United States ($50 000-$150 000 per QALY). The dashed line indicates the base-case threshold of $100 000 per QALY. USD, US dollars.

In the base-case analysis, IV iron sucrose incurred the highest total cost ($163 500), followed by IV ferumoxytol ($158 300), IV iron dextran ($157 500), and oral ferrous sulfate ($152 900). The total QALYs gained were 19.26 with IV iron dextran, IV ferumoxytol, and IV iron sucrose, compared with 19.10 with oral ferrous sulfate. Thus, first-line treatment with IV iron dextran was the cost-effective strategy, with an ICER of $28 600 per QALY (95% credible interval [CI], $19 200-$55 500 per QALY) and an iNMB of $11 500 compared with oral ferrous sulfate ( Table 2 ). Table 2. Reproductive lifetime costs, effectiveness, and economic outcomes for first-line treatment with IV iron dextran, IV iron sucrose, IV ferumoxytol, and oral ferrous sulfate Strategy Cost, USD Incremental cost, USD Effectiveness, QALYs Incremental effectiveness, QALYs NMB, USD Monthly blood loss of 120 mL (base case)  Oral ferrous sulfate 152 900 Ref 19.10 Ref 1 757 000  IV iron dextran 157 500 4600 19.26 0.16 1 768 000  IV ferumoxytol 158 300 5400 19.26 0.16 1 768 000  IV iron sucrose 163 500 10 600 19.26 0.16 1 762 000 ICER = $28 600 (95% CI, $19 200-$55 500 per QALY) Monthly blood loss of 240 mL  Oral ferrous sulfate 156 400 Ref 18.30 Ref 1 674 000  IV iron dextran 165 200 8 800 18.70 0.39 1 705 000  IV ferumoxytol 167 300 10 900 18.70 0.39 1 702 000  IV iron sucrose 178 200 21 900 18.70 0.39 1 691 000 ICER = $22 500 (95% CI, $14 300-$52 500 per QALY) Monthly blood loss of 420 mL  Oral ferrous sulfate 157 000 Ref 17.19 Ref 1 562 000  IV iron dextran 174 400 17 400 18.91 1.72 1 716 000  IV ferumoxytol 177 800 20 800 18.91 1.72 1 713 000  IV iron sucrose 195 500 38 500 18.91 1.72 1 695 000 ICER = $10 100 (95% CI, $8 600-$12 300 per QALY) Results are shown for the base case and scenarios with increased menstrual blood loss. NMB is calculated at a WTP threshold of $100 000 per QALY. The ICER is calculated for IV iron dextran compared with oral ferrous sulfate. Ref, reference value; USD, US dollars. Reproductive lifetime costs, effectiveness, and economic outcomes for first-line treatment with IV iron dextran, IV iron sucrose, IV ferumoxytol, and oral ferrous sulfate Results are shown for the base case and scenarios with increased menstrual blood loss. NMB is calculated at a WTP threshold of $100 000 per QALY. The ICER is calculated for IV iron dextran compared with oral ferrous sulfate. Ref, reference value; USD, US dollars. First-line treatment with IV iron dextran remained cost-effective in alternative scenarios with monthly menstrual bleeding of 240 mL and 420 mL, yielding ICERs of $22 500 per QALY (95% CI, $14 300-$52 500 per QALY) and $10 100 per QALY (95% CI, $8600-$12 300 per QALY) compared with oral ferrous sulfate, respectively ( Table 2 ). A variable blood loss scenario analysis examining the effect of a 50% reduction in total menstrual volume across all patients at model year 5 revealed that IV iron dextran remains the preferred treatment at an ICER of $22 500 per QALY (95% CI, $15 400-$41 100 per QALY). A final scenario analysis examining rapid infusion dosing of IV iron dextran and IV ferumoxytol demonstrated that these alternate, consolidated infusion strategies lowered costs while generating equivalent QALY gain, with 1-time, 30-minute dosing of IV ferumoxytol being the cost-effective strategy with an ICER of $23 400 per QALY (95% CI, $15 500-$45 400 per QALY; supplemental Table 1 ). The 1-way deterministic sensitivity analyses showed that the model was most sensitive to the utility gain from severe anemia to no anemia, followed by the gain from severe to moderate anemia ( Figure 2 ). First-line IV iron dextran remained the cost-effective strategy across the full range of all parameter uncertainty. The probabilistic sensitivity analysis indicated that first-line treatment with IV iron dextran had the highest probability of being cost-effective across all accepted US WTP thresholds ($50 000-$150 000 per QALY; Figure 3 ), being preferred in 99.9% of 10 000 base-case Monte Carlo iterations.

Over the reproductive life span, we found that first-line treatment with IV iron dextran is the cost-effective treatment for women with HMB and IDA. With an ICER of $28 600 per QALY, IV iron dextran remained the cost-effective treatment strategy across all commonly accepted WTP thresholds in the United States. 59 Our scenario analyses showed that IV iron dextran had a progressively decreasing ICER and thus was even more cost-effective for women with heavier monthly menstrual bleeding. Our findings support the use of IV iron formulations as first-line therapy in the treatment of patients with HMB, as IV iron dextran, IV ferumoxytol, and IV iron sucrose strategies accrue increased quality-adjusted life-expectancy compared with oral ferrous sulfate across the reproductive life span. This is secondary to the improved patient adherence and tolerability seen with IV iron treatment, and the low incidence of adverse events (eg, hypersensitivity and anaphylaxis) compared with the gastrointestinal side effects seen in oral regimens, commonly associated with premature treatment termination. 44 , 60 , 61 These findings are consistent with previous cost-effectiveness studies that have shown IV iron to be cost-effective (rather than oral iron) for treating IDA during pregnancy in the LMIC context. 29 Importantly, our results account for wages lost to time spent commuting to and from and undergoing iron infusion, which represents both a personal and economic burden that differs between formulations requiring single (IV iron dextran) vs multiple (IV ferumoxytol and IV iron sucrose) infusion appointments to replete 1 g of elemental iron. 62 , 63 Thus, the requirement for iron sucrose to be administered over multiple (5) doses contributes to its increased cost burden. Similarly, rapid infusion dosing strategies of IV iron dextran and IV ferumoxytol compared favorably against their base-case counterparts in a scenario analysis, generating fewer costs with equivalent QALY gain, with 1-time ferumoxytol dosing being the most favorable of all examined strategies. This is relevant as patients have highlighted the time commitment and difficulty in securing appointments for IV iron therapy as major barriers to treatment. 17 The 1-way sensitivity analysis identified the utility gain from treating IDA as the most influential parameter affecting cost-effectiveness estimates. Nevertheless, IV iron dextran remained cost-effective compared with oral ferrous sulfate across the full range of utility values. To our knowledge, this is the first study to model iron metabolism over decades of menstrual blood loss and treatment cycles for women with HMB. The model captures the chronic, relapsing nature of IDA in women with HMB, and provides evidence to guide both clinical recommendations and insurance coverage. We linked transitions in health states to monthly menstrual loss, dietary iron intake, and the efficacy of iron supplementation. This structure permits straightforward adaptation to other populations, and allows clinicians and policymakers to apply our findings to individual patients or local settings. We also integrated adverse event rates from large pharmacovigilance databases, enabling more accurate estimation of costs and utility decrements associated with these events. Additionally, we account for the cost of menstrual hygiene products across levels of monthly blood loss, recognizing that this further contributes to the economic cost of HMB, acknowledging that patterns of use also vary widely by personal preference. The cost of managing hypersensitivity and anaphylactic reactions was applied broadly across our model to conservatively favor the null hypothesis; however, given the rare incidence of true anaphylactic reactions to IV iron products, in clinical practice the cost-effectiveness of IV iron is likely to compare even more favorably against oral iron supplementation. Furthermore, although our results are specific to the United States context, our work provides an important backbone for the development of future models toward addressing the worldwide prevalence of IDA, particularly in the LMIC context, aligning with the United Nations Sustainable Development Goal 2.2.3 of halving the prevalence of anemia in women of reproductive age by 2030. 64 Although no signatory country is likely to achieve this goal, region-specific health-economic analyses can be used to illuminate high-value interventions and feasible goals in the treatment of IDA around the world. 65 Despite the strengths of our model, several limitations should be noted. Estimates for oral iron discontinuation and re-initiation rates were based on the best available limited empirical data or, when data were not available, clinical expert opinion. We also assumed that women undergo uniform menstrual loss across the reproductive lifetime and after diagnosis of HMB in the base case, which does not include patient treatment for the underlying cause of HMB (eg, uterine polyps, leiomyomas, etc), treatment to reduce menstrual volume (eg, hormonal contraceptives), or possible pregnancy. We addressed this with a scenario analysis examining the effect of patients undergoing proper diagnosis and treatment of their HMB with a 50% reduction in monthly menstrual volume by model year 5, which demonstrated that IV iron dextran remains the preferred treatment across all strategies. Additionally, although our analyses compared the use of oral ferrous sulfate, IV iron dextran, IV ferumoxytol, and IV iron sucrose, we recognize other oral and IV iron formulations may be chosen by patients and clinicians based on cost, coverage, and personal preference, which lie outside the scope of this study. Some patients may switch between iron products, which was not incorporated into our study. As the total number of IV infusions is a determinant of cost-effectiveness, IV ferric derisomaltose and ferric carboxymaltose, administered as single infusion treatments, may demonstrate similar cost-effectiveness compared with oral iron (though ferric carboxymaltose use entails added costs due to phosphate monitoring and, at times, the need for phosphorus repletion). Furthermore, as highlighted in our scenario analysis, 1-time dosing of ferumoxytol is similarly favored from a societal perspective. We also recognize that productivity loss experienced by women with HMB is not limited to time taken away from work for iron infusions, but encompasses both absenteeism and presenteeism due to symptoms of bleeding and anemia; indeed, self-reported surveys indicate that menstruating women missed an average of 1.3 days of work and experienced 23.2 days of presenteeism per year due to menstruation. 66 Although beyond the scope of this current work, future analyses incorporating this productivity loss from HMB symptoms are likely to demonstrate an even greater cost-effectiveness for IV iron than with oral supplementation, particularly at higher levels of monthly blood loss, which preclude rapid repletion and adequate symptom relief by oral supplementation alone. It is also important to note that the cost of IV iron formulations may vary by insurer and across jurisdictions. In addition, our current analysis does not account for the cost of hospital outpatient facility fees, which vary significantly by health care system and jurisdiction, and for which there is enormous heterogeneity in insurance coverage, although their inclusion would further favor single-dose infusion with iron dextran over competing multiple-dose IV iron strategies. 67 , 68 In conclusion, first-line IV iron dextran is a cost-effective strategy for managing IDA in women with HMB. Its long-term economic value supports efforts to increase access to infusion centers, decrease insurance barriers, and reduce disparities in the receipt of IV iron. Future studies are needed to quantify the real-world gain in quality of life and adherence, and efficacy of various IV iron formulations.

Globally, 31.2% of women experience iron-deficiency anemia (IDA), which leads to an estimated 926 years lived with disability per 100 000 women. 1 Gynecological disorders, such as uterine polyps, fibroids, adenomyosis, gynecological malignancies or hyperplasia, and ovulatory dysfunction, as well as coagulopathies, are a significant risk factor for IDA in women of reproductive age, especially in high-income countries, where the prevalence of dietary iron deficiency is lower than in low- and middle-income countries (LMIC). 2 , 3 It is estimated that within the United States, ∼16 million women experience heavy menstrual bleeding (HMB), defined as any level of menstrual blood loss that significantly affects one’s social, material, mental, or health-related quality of life, and classically established as >80 mL menstrual blood losses per month. 4 , 5 Importantly, many individuals also experience vaginal blood loss outside of menstruation, which may similarly contribute to reduced quality of life. 6 Decades of societal, familial, and health care professional normalization have contributed to most patients with HMB receiving delayed or suboptimal care. 4 , 7 , 8 In fact, in high-income countries, where such data are readily available, HMB represents the most common cause of IDA, affecting up to one-third of menstruating women, though women in LMIC are also known to suffer decreased health-related quality of life due to HMB. 8 , 9 , 10 Multinational surveys across the United States, Canada, France, Russia, and Brazil indicate that only one-fifth of women receive proper care for HMB. 11 Patient surveys from Finland reported that 63% of individuals with HMB had IDA, yet only half received treatment. 12 This co-occurrence of HMB and IDA is associated with substantial reductions in quality of life manifested by fatigue, cognitive impairment, potential complications in pregnancy, and productivity loss. 13 , 14 The treatment of HMB not only involves addressing the underlying cause of HMB, but also timely identification and treatment of IDA. 4 , 15 , 16 Iron supplementation can be provided either orally (PO) or through intravenous (IV) formulations, with differences in efficacy, safety, cost, and availability between the 2 approaches. 15 Oral iron therapy is the most commonly recommended first-line treatment among HMB treatment guidelines due to its low cost and wide availability. 4 , 17 However, challenges with treatment adherence and variable effectiveness are common in clinical practice, largely due to gastrointestinal adverse effects, such as nausea, constipation, and abdominal discomfort, and inconsistent absorption of oral iron. 15 , 18 Additionally, individual patients may experience different severity and frequency of adverse events in response to the variety of available oral iron formulations and dosages, while noting that randomized studies are consistent with improved tolerability and equivalent efficacy of alternate day dosing compared with daily dosing. 19 , 20 , 21 , 22 In contrast, IV iron formulations are associated with higher treatment adherence, but involve greater upfront costs and carry a small risk of infusion reactions. 22 , 23 , 24 Current treatment recommendations indicate that there is a substantial evidence gap regarding the optimal first-line treatment for IDA. 25 , 26 However, IV iron treatment is often not offered upfront, and typically reserved for only after intolerance or inadequate response to oral iron is demonstrated. In the United States, individuals with HMB and IDA receive their first IV iron infusion an average of 4.4 years after symptom onset and 1.4 years after IDA diagnosis. 17 This delay significantly compromises care, especially as most women with IDA report a preference for IV iron over oral therapy. 27 Given the substantial economic burden of IDA due to HMB, there is a need to identify cost-effective treatment strategies. 28 Although previous studies have examined the cost-effectiveness of different iron supplementation strategies for anemia during pregnancy or during the post-partum period, data on the cost-effectiveness of IV vs oral iron therapies in reproductive-age women outside of pregnancy are lacking. 29 , 30 Cost-effectiveness analyses conducted across the reproductive life span are particularly important for patients with HMB and IDA as they often remain iron-deficient for extended periods before diagnosis, underscoring the need for early initiation of optimal therapy. 31 , 32 Additionally, they may require long-term iron supplementation, which can result in a substantial financial burden. Against this background, we conducted a cost-effectiveness analysis comparing first-line treatment with IV vs oral iron formulations for managing IDA in women with HMB across the reproductive life span.

Conflict-of-interest disclosure: A.C. has served as a consultant for MingSight, New York Blood Center, Pfizer, Sanofi, and Synergy; and has received authorship royalties from UpToDate. The remaining authors declare no competing financial interests.