Heavy menstrual bleeding (HMB) is excessive menstrual blood loss which interferes with a woman’s physical, social, emotional and/or material quality of life [1]. It is a common gynaecological complaint that accounts for one-third of outpatient visits. Anemia resulting from abnormal uterine bleeding contributes to the overall health challenges faced by patients. In addition, anemia can delay or complicate the surgical procedure, and one might need to examine the underlying pathology of HMB. One of the major health issues worldwide is iron deficiency anemia, which affects up to 14% and 51% of the population in developed and developing countries, respectively [2]. In India, the prevalence of anemia among non-pregnant women is particularly high, standing at 51.5% [3]. While oral iron is the initial preference, the primary challenge associated with oral iron treatment lies in adherence due to gastrointestinal side effects such as bloating, diarrhea, heart-burn, nausea, and constipation. Consequently, parenteral iron therapy is the preferred alternative for these patients.

Available intravenous iron agents include iron dextran, ferric gluconate, and iron sucrose (ISC), and newer agents include ferric carboxymaltose (FCM), ferumoxytol, and iron isomaltose. The most recent inclusion in intravenous iron formulations is FCM. FCMs are classified as type I iron complexes devoid of dextran. FCM exhibits minimal side effects and better compliance, demonstrating an efficient and swift correction of anemia. Its main advantage over iron sucrose is that higher doses can be given per session (1,000 mg) [4]. The maximum permissible dose of iron sucrose is 300 mg/session or 600 mg/week. This results in an increase in the overall treatment cost due to the need for multiple visits [5].

However, a paucity of data on the use of FCM in perimenopausal women exists with limited prospective studies comparing FCM with ISC. This study assessed the impact of intravenous FCM and ISC on hematological parameters in perimenopausal women with HMB and anemia.

The present study was a prospective, open-label, randomized controlled trial with a parallel-group design conducted in a tertiary care hospital in North India. Patients were recruited from December 2016 to July 2018 after ethical clearance was obtained from the Institute Ethics Committee AIIMS/ IEC/18/262. The trial was registered with the Clinical Trial Registry of India (CTRI/2018/05/013854).

Perimenopausal women in the age group of 40 to 50 years attending gynecology outpatient department for heavy menstrual bleeding with hemoglobin (Hb) levels between 6-10 g/dL were screened. Women who were intolerant or non-compliant with oral iron therapy were enrolled after taking informed consent. Women with anemia due to causes other than iron deficiency anemia, chronic infections such as hepatcitis and human immunodeficiency virus, serum transaminase level greater than 1.5 times the upper limit of normal, serum creatinine level of more than 2.0 mg/dL, patients with a history of allergic reaction to intravenous iron infusion, and patients unlikely to follow up were excluded from the study. The cause of abnormal uterine bleeding (AUB) was classified based on the PALM-COEIN criteria [6].

Referring to a prior study by Christoph et al. [7], wherein the final Hb level after the administration of ISC increased from 9.56 to 11.04 gm/dL with a standard deviation of 1.19, the calculation for the estimated sample size considered a non-inferiority limit difference in mean Hb between the groups as 1 g/dL. Additional parameters, including an expected mean difference of 0, a standard deviation of 1.19, an alpha error of 5%, and a study power of 90%, led to an estimated sample size of 24 per group. Factoring in a 10% potential loss to follow-up, a minimum of 27 women with iron-deficiency anemia were required for inclusion in each study group.

Upon enrolment, the clinical history was obtained, including menstrual history, treatment history (including prior iron therapy), adherence to oral iron therapy, and the presence of chronic medical conditions. A thorough examination, including general physical and gynecological examinations, was performed. All findings were recorded in a structured proforma.

Baseline investigations including blood grouping and typing, hemoglobin levels, platelet count, total leukocyte count, fasting blood sugar, liver function tests, renal function tests, thyroid profile, routine urine microscopy, and culture sensitivity were performed. Anemia workup, including Hb, reticulocyte count, peripheral blood smear, red cell indices (mean corpuscular volume [MCV]; mean corpuscular hemoglobin [MCH]; and mean corpuscular hemoglobin concentration), Hb electrophoresis, stool examination for ova/parasites, and serum iron studies, including serum iron and ferritin levels, were performed.

Ganzoni’s formula was used to calculate iron requirements. Iron requirement (mg)=BW (kg)×(target Hb (14)-actual Hb) (g/dL)×2.4+storage iron 1,000 mg.

The patients were randomized into two equal groups (1:1 allocation ratio) using a computer-generated random number table, with block randomization (block size: 4) employed to ensure balance between the groups throughout the study with allocation concealment ensured using sealed, opaque envelopes.

Patients in the FCM group were administered intravenous (IV) FCM (Inj Revofer; Lupin Pharmaceuticals Ltd., Pune, India). The maximum dose per session was 15 mg/kg (maximum: 1,000 mg). Subsequent doses were administered on day 7 and day 14. FCM was diluted in 200 mL of normal saline and administered as an IV infusion over 30 minutes.

Patients in the ISC group received IV ISC (Inj Orofer S; Emcure Pharmaceuticals Ltd., Pune, India) at 300 mg in 200 mL normal saline over 15-20 minutes bi-weekly until the prescribed dose was achieved (maximum 600 mg per week).

The overall health status of the patient, along with blood pressure and pulse rate, was assessed before the infusion and at 5-minute intervals during the infusion. Additionally, all women were provided anthelmintic therapy with a single 400 mg static dose of albendazole as part of the baseline treatment protocol to eliminate the potential confounding effects of helminthic infections on anemia correction. Oral iron therapy was discontinued at the time of recruitment. Minor or significant adverse events were documented. A record of dropouts, including premature terminations, was maintained.

All patients were followed up at 3, 6, and 12 weeks after treatment initiation. During follow-up, all hematological parameters-Hb, reticulocyte count, MCV, MCH, serum ferritin, and serum iron-were recorded, along with any adverse effects or events. MCV and MCH were measured to evaluate the overall status of red blood cells and provide a more comprehensive assessment of anemia. MCV assesses the average volume of red blood cells, whereas MCH measures the average amount of hemoglobin per red blood cell, helping to determine the severity of anemia and monitor the efficacy of the treatments administered.

A total of 166 perimenopausal women were assessed for eligibility. Among them, 60 perimenopausal women with moderate to severe anemia were recruited. After obtaining written informed consent, the patients were divided into two groups: FCM (n=30) and ISC (n=30). Fig. 1 depicts the study population flow chart.

The baseline characteristics of the patients are shown in Table 1. The mean was 44.0±3.4 years. Baseline characteristics were comparable between the groups. The most prevalent cause of AUB was AUB-L, accounting for 46.6% of patients, followed by AUB-O at 26.6%, AUB-M at 8.33%, and AUB-A at 6.66%. All patients received appropriate treatments tailored to their specific pathologies.

The study groups did not differ significantly in baseline hematological parameters, as shown in Table 2.

In the study population, 44% had moderate anemia, of which 26% and 60% were in the FCM and ISC groups, respectively. 56% of the patients had severe anemia, of whom 74% were in the FCM group and 40% were in the ISC group. The mean calculated iron requirement was 2,085±312 mg (range, 1,419-3,086) in the FCM group and 1,920±206 mg (range, 1,600-2,597) in the ISC group.

Although the mean deficits in both groups were comparable, the total number of doses required to deliver the calculated dose was significantly higher in the ISC group than in the FCM group (P<0.0001). This was because the maximum dose of ISC that can be given weekly is 600 mg, while for FCM, it was 1,000 mg. In the FCM group, most patients required only one or two doses, and only one patient required three doses. On the other hand, in the ISC group, the number of doses varied significantly, with some patients requiring as many as 8 to 13 doses. Specifically, four patients (13.33%) required eight doses, 13 (43.33%) required nine doses, nine (30%) required 10 doses, and a few patients required even more, with two patients (6.66%) requiring 11 doses and one patient each (3.33%) requiring 12 and 13 doses.

Oral administration is the preferred route of administration for iron in the treatment of anemia. It often causes unwarranted gastrointestinal side effects that decrease the adherence to iron therapy. Parenteral iron has the advantages of certainty of administration and better compliance [8]. They offer a higher and more rapid supply of iron than oral iron therapy, eliminating the gastrointestinal side effects associated with oral substitution. Additionally, it leads to decreased blood transfusion and the avoidance of associated risks [9]. Recent studies have also shown that oral iron therapy requires more time to increase hemoglobin levels than its parenteral counterpart [10].

Intravenous iron sucrose has recently replaced most parenteral preparations. However, the main disadvantage is the limited dose per session, which ultimately increases the total treatment costs. On the other hand, FCM is designed to be administered in large doses via IV injection. Once in the body, iron is released gradually, avoiding acute toxicity, but allowing large amounts of iron to be delivered, resulting in a much wider therapeutic window. The complex has a molecular weight of approximately 150,000 Da. Unlike other smaller iron complexes, little of the product is lost through renal elimination. FCM prevents dextran-induced hypersensitivity reactions. It has a neutral pH and physiological osmolarity and can be given via rapid infusion because it is dextran-free [11]. It has a structure similar to ferritin and promotes iron deposition in the reticuloendothelial system of the liver. Therefore, iron can be provided without inducing oxidative stress [12,13]. The Food and Drug Administration approved FCM in August 2013. The International Federation of Gynecology and Obstetrics PALM-COEIN classification system for AUB in non-pregnant women separates structural causes (PALM) from medical conditions (COEIN). Structural issues are identified via imaging or histopathology and medical conditions are clinically assessed. This system was used in this study. The mean baseline Hb in the present study was 7.85±1.05 g/dL (range, 6-10 g/dL). This was lower than that reported by Van Wyck et al. [10] and Breymann et al. [14]. Other hematological parameters, such as serum ferritin, were also lower in our population than in Western studies. This can be attributed to the lack of early treatment awareness, already depleted iron stores, and limited access to medical facilities in our population compared to Western populations.

In a study by Van Wyck et al. [10], patients with abnormal uterine bleeding with anemia were randomized to receive either IV FCM or oral iron. More patients in the FCM group achieved an Hb rise of 2 g (82% vs. 62%), rise of 3 g (53% vs. 36%), and a target Hb of 12 g (73% vs. 50%) as compared to the oral iron group. Also, Bisbe et al. [15], in a multicenter comparative study on the efficacy of intravenous FCM and iron sucrose for correcting preoperative anemia in patients undergoing major elective surgery, found that in the FCM group, patients attained replenishment of iron more frequently (82% vs. 62%; P=0.007 respectively). Similarly, in the present study, at 12 weeks a higher proportion of patients in the FCM group attained correction of anemia (Hb ≥12 g) compared to the ISC group (75.9% vs. 65.5%). Additionally, the increase in Hb levels in the FCM group was significantly greater compared to that in the ISC group (P=0.003). Although a higher proportion of the FCM group had severe anemia compared to the ISC group (73% vs. 40%) at the baseline, the mean Hb levels achieved at the 3-week follow-up were comparable between the groups. This rapid rise may be beneficial in patients awaiting surgery.

Evstatiev et al. [16] compared FCM and ISC in patients with inflammatory bowel disease. A higher proportion of patients in the FCM group compared to the ISC group achieved Hb normalization (72.8% vs. 61.8%; P=0.015). This study highlights that FCM requires fewer doses and a shorter treatment duration compared to ISC. Consequently, this can lead to greater cost-effectiveness of FCM, making it a more efficient option for managing iron deficiency. It showed a saving of USD 238 per patient and a 12% higher response rate. However, in the present study, the cost of therapy with FCM was significantly higher than that with ISC, as this assessment excluded expenses related to travel, potential loss of working days, and the subsequent loss of wages. Considering the significantly higher number of visits in the ISC group, the overall cost of therapy may be higher. Our findings were consistent with the study by Jose et al. [17], which reported a cost that was INR 306.1 higher in the FCM group.

Serum ferritin is considered a marker for iron stores. However, it is nonspecific and can increase in conditions such as systemic illnesses and inflammation. In the present study, the Ganzoni formula was used to calculate the total required dose; accordingly, 1,000 mg of iron was given to replenish the stores. For most Indian women, this amount may not be sufficient to replenish their stores. At the end of the study, serum ferritin levels were 278.6±95 μg/L and 252±53 μg/L in the FCM and ISC groups, respectively. Although these measurements were within the normal range, they were lower than those reported in Western studies [10,14,16]. Thus, patients must be encouraged to consume an iron-rich diet following treatment to maintain these stores and prevent recurrence. Sharma et al. [18] conducted a prospective comparative study in which 120 postpartum women with iron deficiency anemia (Hb <10%) were administered a fixed dose of 1,000 mg of FCM or ISC within 10 days of delivery, and Hb and serum ferritin were repeated after 14 days. There were significant mean increases in Hb and ferritin levels in both groups. FCM was superior to iron sucrose (P<0.001). They concluded that FCM was very effective in improving hemoglobin concentration and early restoration of iron reserves in patients with postpartum anemia, which is consistent with the results of the present study. Large doses given within a short time save hospital resources and improve patient satisfaction.

In the present study, side effects were minimal in both groups and were not statistically significant. Hyperferritinemia at the end of 12 weeks was observed in one patient receiving FCM (600 μg/L). No patients in the ISC group had hyperferritinemia. Evstatiev et al. [16] reported an incidence of hyperferritinemia in 2.9% and 0.4% of individuals administered FCM and ISC, respectively. 5% of the individuals reported asymptomatic hypophosphatemia, 4% in the FCM group and 6% in the ISC group, which recovered within 6 to 12 weeks. Van Wyck et al. [10,19] reported asymptomatic hypophosphatemia in 70% of individuals assigned to IV FCM. In acute hemolytic anemia, an association has been found between enhanced erythropoiesis and selective hypophosphatemia [20] and hematopoietic reconstitution after allogeneic peripheral blood stem cell transplantation [21]. Blazevic et al. [22] documented four cases of severe and symptomatic hypophosphatemia when administering IV FCM or ISC. Pre-existing disorders related to phosphate homeostasis, such as secondary or tertiary hyperparathyroidism, were observed in three of these cases. The observed symptoms were generalized weakness, vertigo, nausea, and diarrhea. The patients were treated with intravenous sodium glycerophosphate. Therefore, serum phosphate levels should be assessed before starting intravenous iron administration.

Mahey et al. [23] conducted a randomized controlled trial comparing FCM and ISC in the treatment of iron deficiency anemia due to abnormal uterine bleeding and found a significant increase in mean hemoglobin levels from baseline in the FCM group at 6 weeks (P=0.005). However, there was no difference between the groups at 12 weeks (P=0.11), with similar side effects. IV FCM leads to a rapid increase in Hb levels in patients with anemia due to AUB.

Thus, FCM results in a rapid rise in hemoglobin causes better build-up of iron stores, and is well tolerated with minimal side effects. Other advantages include a lower number of doses, fewer needle pricks, and fewer hospital visits compared with ISC.

The strength of the present study lies in the well-designed study model used to analyze the benefits of FCM and ISC and to effectively analyze and compare the impact of FCM and ISC on hemoglobin levels. A notable limitation of this study was the small sample size of 30 patients per group, which may affect the generalizability of the results. Future research with larger sample sizes is necessary to further assess the efficacy and safety of these treatments in perimenopausal women with heavy menstrual bleeding.

In conclusion, FCM and ISC have comparable efficacy in increasing hemoglobin levels in perimenopausal women with heavy menstrual bleeding and iron deficiency anemia. A greater number of patients receiving FCM achieved correction of anemia than those receiving ISC, with similar side-effect profiles. This study adds to the growing body of literature on intravenous iron formulations, offering a basis for future studies to explore the broader implications of these therapies in diverse patient populations.