Ferric carboxymaltose for treatment of iron deficiency and iron deficiency anemia caused by abnormal uterine bleeding

Introduction

Women with heavy menstrual bleeding (HMB) lose 5–6 times more iron per cycle than those with normal menses [1]. Heavy menstrual bleeding leads to iron store depletion with subsequent iron deficiency (ID) [1, 2].

About two-thirds of the body’s iron is bound to hemoglobin (Hb) within the red blood cells (RBCs), and severe ID can subsequently lead to microcytic hypochromic iron deficiency anemia (IDA) [3].

Mild IDA can be asymptomatic, while symptomatic IDA can present with weakness, fatigue, headache, hair loss, brittle nails, and shortness of breath [3, 4]. Iron deficiency anemia can significantly reduce the quality of life, cognitive ability, and work productivity [5].

Evaluation of abnormal uterine bleeding (AUB) in women ≥ 40 years is crucial to exclude endometrial carcinoma. Dilatation and curettage (D&C) is the gold standard for endometrial sampling in AUB [6, 7].

Preoperative IDA is a risk factor for postoperative morbidity, including infection, prolonged hospital stays, and blood transfusion [1].

In addition, the risks associated with preoperative IDA were not eliminated by blood transfusions [8], and the preoperative transfusion corrects only the anemia (not the underlying cause) [9–11].

Studies have shown that correction of IDA prior to surgery reduces the postoperative blood transfusion, and improves the hematological parameters [12, 13].

Effective correction of ID/IDA in women with AUB improves the quality of life [14], while preoperative intravenous (IV) iron reduces the postoperative anemia and postoperative blood transfusion compared to no treatment [15].

Iron sucrose (IS) was approved in the United States and Europe for treatment of ID/IDA. The multiple infusion sessions are the main disadvantage of IS [11]. Ferric carboxymaltose (FCM) is a new IV iron, which can be used for correction of ID/IDA when there is clinical need to deliver iron for correction of ID/IDA rapidly. Froessler et al. found that FCM infusion significantly increased the Hb levels of pregnant women at 3, 6, and 8 weeks after infusion [16], and a randomized control trial (RCT) found that FCM was tolerable and effective for rapid correction of postpartum anemia [17]. Therefore, this study was designed to evaluate the efficacy and safety of FCM in treatment of ID/IDA caused by AUB.

Material and methods

One hundred and twenty women ≥ 40 years old with chronic AUB and ID/moderate IDA were included in this cohort study for correction of ID/IDA before D&C.

This study was conducted over one year (December 2019 to December 2020). Participants were included in this study after informed consent in accordance with the Helsinki Declaration, and after approval of the FCM for treatment of ID/IDA by the hospital’s drug committee.

Chronic AUB is defined as frequent uterine bleeding (recurs within < 24 days) over the last 6 months, > 80 ml in amount, and lasting > 8 days [18].

The International Federation of Gynecology and Obstetrics PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy including hyperplasia – coagulopathy, ovulatory, endometrial, iatrogenic, and not otherwise classified) classification of AUB facilitated accurate diagnosis and treatment. PALM defined the structural causes of AUB while COEIN defined the non-structural (functional) causes of AUB [18].

The Royal College of Obstetricians and Gynaecologists, and the American College of Obstetricians and Gynecologists prefer the patient-centered definition of HMB as excess menstrual blood loss which interferes with the women’s physical and social life and/or quality of life, and necessitates investigation and treatment [18]. The pictorial blood loss assessment chart was used in this study to assess the menstrual blood loss [19].

The diagnosis of ID was based on serum ferritin (< 30 µg/l), and the diagnosis of moderate IDA was based on serum ferritin (< 30 µg/l), Hb concentration (≥ 8 and < 12 g/dl), RBC mean corpuscular volume (MCV < 80 fl), and RBC mean corpuscular hemoglobin (MCH < 27 pg) [20–22].

Iron deficiency anemia in non-pregnant women was classified according to the WHO definition into severe anemia when Hb < 8 g/dl, moderate anemia ≥ 8 Hb < 12 g/dl, and mild anemia ≥ 11 Hb < 12 g/dl [20].

Participants were evaluated thoroughly and subjected to transvaginal ultrasound (TVS) examination followed by laboratory investigation including serum ferritin (using UniCel DxI 800 analyzer, Beckman Coulter Inc., USA), complete blood count (using UniCel DxH 800 hematology analyzer, Beckman Coulter Inc., USA), coagu-lation profile [i.e., clotting, bleeding and activated partial thromboplastin (APTT) times], prolactin and thyroid hormones [using enzyme linked immunoassay (ELISA)], and liver function tests (i.e., alanine transaminase and aspartate transaminase using Synchron LX20, Beckman Coulter Inc., USA).

The transvaginal ultrasound was done for all participants by an expert sonographer blind to participants’ data (to avoid potential bias). The endometrium was evaluated in sagittal and axial planes for its thickness (uniform or localized thickness) and regularity. The normal atrophic postmenopausal endometrium appears thin and homogeneous [23]. Based on the current state of knowledge and cited diagnostic methodology, thickened endometrium is often indicative of endometrial pathology [23]. The presence of an endometrial complex favors a focal intracavitary process (i.e., polyp, or focal endometrial hyperplasia). The myometrium is also evaluated regarding its thickness, regularity, and contour [23].

Women included in this study were ≥ 40 years old (premenopausal or postmenopausal), diagnosed as chronic AUB associated with ID/moderate IDA, euthyroid, with normal prolactin, and liver function tests, normal bleeding, clotting, APTT times, and platelet count [6, 7].

Women with acute AUB (necessitates immediate action), intolerance or hypersensitivity to iron preparations, severe IDA, and/or anemia other than IDA [20–22], possibility of pregnancy, endocrine disturbance (i.e., hyper-prolactinemia or thyroid disorders), history of contraception, and/or hormonal replacement therapy (HRT) were excluded from this study [20–22].

Ferric carboxymaltose (Ferinject 50 mg iron/ml solution, Vifor Pharma, UK) is approved for treatment of ID/IDA when oral iron preparations are ineffective, contraindicated or when there is clinical need to deliver iron for correction of ID/IDA rapidly. The effect of FCM on IDA should not be assessed before 4 weeks after the last FCM infusion to allow adequate time for erythropoiesis, and iron utilization.

The needed iron dose of FCM to correct the ID/IDA was calculated when Hb was < 10 gm/dl according to participants` body weight: 500 mg of iron (< 35 kg), 1500 mg of iron (> 35 < 70 kg), and 2000 mg of iron (> 70 kg).

The calculated iron dose of FCM was diluted in 100 mL of 0.9% normal saline over 6 min when it was ≥ 500 mg, and in 250 mL of 0.9% normal saline over 15 min when it was > 500–1000 mg.

The total iron infusion dose of FCM should not exceed 20 mg iron/kg body weight, and the maximum recommended iron infusion dose of FCM was 1000 mg of iron/week. More than 1000 mg of iron was given in two infusion sessions [1000 mg in the first session, and the remaining amount in the second session (the two sessions scheduled one week apart)].

Participants were observed during the FCM infusion, and for at least 30 min following FCM infusion for signs of anaphylaxis, intolerance, and/or side effects (skin eruption, tachycardia, headache, abdominal or chest pain) to evaluate the safety of FCM (secondary outcome).

Participants also received oral folic acid tablets for 12 weeks to avoid folate deficiency. The pre-treatment ferritin, Hb, RBC MCV, and RBC MCH values were compared with the 6- and 12-week post-treatment values to evaluate the efficacy of FCM in treatment of ID/IDA caused by chronic AUB (primary outcome).

Results

One hundred and twenty women ≥ 40 years old with chronic AUB and ID/moderate IDA were included in this study for correction of ID/IDA before D&C using FCM. The pre-treatment ferritin, Hb, RBC MCV, and RBC MCH values were compared with the 6- and 12-week post-treatment values to evaluate the efficacy of FCM in treatment of ID/IDA caused by chronic AUB. Participants were observed during the FCM infusion, and for at least 30 min following FCM infusion for signs of anaphylaxis, intolerance, and/or side effects to evaluate the safety of FCM.

Table 1 shows the demographic data of participants, possible causes of AUB based on thorough evaluation (including history, TVS and laboratory findings), and pre-treatment ferritin, Hb, RBC MCV, and RBC MCH values.

The pre-treatment ferritin and Hb levels significantly increased from 13.2 ±7.4 µg/l and 8.8 ±0.8 g/dl, respectively, to 111.5 ±5.6 µg/l and 13.9 ±0.6 g/dl, respectively, 6 weeks after FCM (p = 0.001 and 0.0009, respectively). Also, the pre-treatment RBC MCV and RBC MCH values significantly increased from 74.3 ±2.3 fl and 26.6 ±5.3 pg, respectively, to 88.7 ±1.9 fl and 29.6 ±4.5 pg, respectively, 6 weeks after FCM (p = 0.01 and 0.03 respectively) (Table 2).

The pre-treatment ferritin and Hb levels significantly increased from 13.2 ±7.4 µg/l and 8.8 ±0.8 g/dl, respectively, to 98.7 ±6.1 µg/l and 12.9 ±0.65 g/dl, respectively, 12 weeks after FCM (p = 0.01 and 0.01, respectively). Also, the pre-treatment RBC MCV and RBC MCH values significantly increased from 74.3 ±2.3 fl and 26.6 ±5.3 pg, respectively, to 93.3 ±1.75 fl and 30.3 ±3.8 pg, respectively, 12 weeks after FCM (p = 0.001 and 0.0001, respe-ctively) (Table 3).

No anaphylaxis and/or intolerance to FCM was reported in this study, the only reported side effects were burning sensation at the infusion site [1.66% (2/120)] and mild headache during the infusion [0.83% (1/120)].

Discussion

The causes of chronic AUB in this study based on thorough evaluation (i.e., history, TVS and laboratory findings) were AUB-O (49.2%), AUB-P (19.2%), AUB-L (15.8%), AUB-A (7.5%), AUB-E (5.8%), and AUB-C (2.5%).

Similarly, Sun et al. studied the prevalence of chronic AUB causes among Chinese women using the PALM- COEIN classification system, and found that AUB-O was the most frequent cause of chronic AUB (57.7%), followed by AUB-P (16.2%), AUB-L (12%), AUB-A (4.94%), AUB-E (2%), and AUB-C (1%) [24].

AUB-O is commonly observed at the extremes of reproductive age, and commonly associated with endocrine disorders (i.e., hyperprolactinemia, hypothyroidism), obesity, and/or weight loss [18].

Whitaker et al.[18] found that the incidence of uterine polyps in chronic AUB varies widely among studies (3.7–65%), and this difference can be explained by the inclusion criteria and number of studied women [25].

Although > 50% of women with uterine fibroids are asymptomatic, some uterine fibroids can present with chronic AUB and ID/IDA [24]. The reported incidence of uterine fibroids as a cause of chronic AUB in this study was 15.8%, and was 12% in the Sun et al. study [24]. Similarly, Fraser et al. [26] and Shapley et al. [27] reported uterine fibroids (AUB-L) as a possible cause of AUB in 14–25% of women.

Although the reported incidence of adenomyosis as a cause of chronic AUB was 7.5% in this study, and was 4.94% in the Sun et al. study [24], Morassutto et al. reported a 20–30% prevalence for adenomyosis in AUB [28]. Morassutto et al. explained this difference by the diagnostic criteria (histological and radiological) used for diagnosis of adenomyosis [28].

The diagnosis of AUB-E depends on a careful history, and exclusion of other causes. The lack of available biomarkers for diagnosis of endometrial disorders indicates that the incidence of endometrial disorders in AUB (AUB-E) is underestimated [18].

Coagulopathies affect 13% of the women with HMB [18], and anticoagulants and antiplatelets have been considered as a part of AUB-C (rather than AUB-I) [18].

Iron deficiency anemia can significantly reduce the quality of life, cognitive ability, and work productivity [5]. Preoperative IDA is a risk factor for postoperative morbidity, including infection, prolonged hospital stays, and blood transfusion [1]. Correction of IDA prior to surgery reduces the post-operative blood transfusions, and improves the hematological parameters [8, 9].

Conventional iron salts (ferrous salts) are associated with gastric discomfort, vomiting, and constipation, which adversely affect compliance [29].

Iron sucrose was approved in the United States and Europe for treatment of ID/IDA. The reported incidence of anaphylaxis with IS is low (0.002%), and there are no hypersensitivity reactions reported with IS [29]. The multiple infusion sessions are the main disadvantage of IS (200 mg of IS in each session every other day) [11, 22].

Ferric carboxymaltose is a new IV iron, which can be used for correction of ID/IDA when oral iron preparations are ineffective, contraindicated or when there is a clinical need to deliver iron for correction of ID/IDA rapidly. Therefore, this study was designed to evaluate the efficacy and safety of FCM in treatment of ID/IDA caused by AUB. In the study, the pre-treatment ferritin and Hb levels significantly increased from 13.2 ±7.4 µg/l and 8.8 ±0.8 g/dl, respectively, to 111.5 ±5.6 µg/l and 13.9 ±0.6 g/dl, respectively, 6 weeks after FCM (p = 0.001 and 0.0009, respectively), and to 98.7 ±6.1 µg/l and 12.9 ±0.65 g/dl, respectively, 12 weeks after FCM (p = 0.01 and 0.01, respectively).

In addition, the pre-treatment RBC MCV and RBC MCH values significantly increased from 74.3 ±2.3 fl and 26.6 ±5.3 pg, respectively, to 88.7 ±1.9 fl and 29.6 ±4.5 pg, respectively, 6 weeks after FCM (p = 0.01 and 0.03, respectively), and to 93.3 ±1.75 fl and 30.3 ±3.8 pg, respectively, 12 weeks after FCM (p = 0.001 and 0.0001, respectively).

A systematic review found that IV iron is a safe alternative to address the problem of ID in women who require rapid replacement of iron stores [30].

An RCT found IV iron beneficial for pregnant women who presented with anemia at later gestation when rapid replacement of iron stores was required [31].

Froessler et al. studied the safety and efficacy of FCM in treatment of IDA during pregnancy, and found that FCM infusion significantly increased the Hb levels in all studied women at 3, 6, and 8 weeks after infusion. Froessler et al. reported minor side effects in 20% of studied women [16].

The reported side effects with FCM infusion in this study were burning sensation at the infusion site (1.66%) and mild headache during FCM infusion (0.83%).

An RCT was conducted by Van Wyck et al. to evaluate the effect of FCM infusion (≤1000 mg over 15 min) for treatment of postpartum anemia. Van Wyck et al. found that FCM was tolerable and effective for rapid correction of postpartum anemia [17].

Another RCT found that FCM infusion improved the iron stores of pregnant women with significant elevation of Hb levels within 12 weeks compared to IS. The convenient dosing and fewer infusion sessions result in better patient compliance with FCM infusion [32].

Overall, there is substantial evidence that FCM is effective in treating IDA in many acute and chronic conditions, with a favorable benefit-risk profile [33].

This study found that the pre-treatment ferritin and Hb levels significantly increased 6 and 12 weeks after FCM infusion. In addition, the pre-treatment RBC MCV and RBC MCH values significantly increased 6 and 12 weeks after FCM infusion. The only reported side effects with FCM infusion were burning sensation at the infusion site (1.66%) and mild headache during FCM infusion (0.83%).

This study concluded that the FCM was safe and effective for correction of ID/IDA caused by chronic AUB within 6 weeks. The serum ferritin and Hb levels and the RBC indices remained significantly high compared to the pre-treatment values 12 weeks after FCM infusion.

This study was the first cohort study conducted to evaluate the efficacy and safety of FCM in treatment of ID/IDA in women with chronic AUB.

Women who refused to participate and absence of postoperative follow-up after D&C were the limitations of this study. Further future studies comparing the efficacy and safety of FCM with other IV iron preparations including IS are needed.

Conclusions

Ferric carboxymaltose was safe and effective for correction of ID/IDA caused by chronic AUB within 6 weeks. The serum ferritin and Hb levels and the RBC indices remained significantly high compared to the pre-treatment values 12 weeks after FCM infusion.