Comparative efficacy and safety of intravenous ferric carboxymaltose and iron sucrose for iron deficiency anemia in obstetric and gynecologic patients

Abstract Introduction: Iron deficiency anemia (IDA) is common among obstetric and gynecologic patients. This systematic review aimed to assess the comparative efficacy and safety of commonly used intravenous (IV) iron formulations, ferric carboxymaltose (FCM), and iron sucrose (IS) in the treatment of IDA in obstetric and gynecologic patients. Methods: We systematically searched PubMed, EMBASE, Cochrane CENTRAL, and Google Scholar for eligible randomized controlled trials (RCTs) comparing IV iron replacement using FCM and IS up to October 2019. The primary outcome was to compare the efficacy of FCM and IS, assessed by measuring serum hemoglobin (Hb) and ferritin levels before and after iron replacement. The secondary outcome was to compare the safety of FCM and IS, assessed by the incidence of adverse events during iron replacement. The meta-analysis was performed using RevMan 5.3. Results: We identified 9 RCTs with 910 patients (FCM group, n = 456; IS group, n = 454). Before iron replacement, FCM and IS group patients had similar baseline Hb (mean difference [MD], 0.04 g/dL; 95% confidence interval [CI], −0.07 to 015; I2 = 0%; P = 0.48) and ferritin levels (MD, −0.42 ng/mL; 95% CI, −1.61 to 0.78; I2 = 45%; P = 0.49). Following iron replacement, patients who received FCM had higher Hb (MD, 0.67; 95% CI, 0.25–1.08; I2 = 92%; P = 0.002) and ferritin levels (MD, 24.41; 95% CI, 12.06–36.76; I2 = 75%; P = 0.0001) than patients who received IS. FCM group showed a lower incidence of adverse events following iron replacement than IS group (risk ratio, 0.53; 95% CI, 0.35–0.80; I2 = 0%; P = 0.003). Serious adverse events were not reported in any group. Conclusion: FCM group showed better efficacy in increasing Hb and ferritin levels and a favorable safety profile with fewer adverse events compared with IS group for IDA treatment among obstetric and gynecologic patients. However, this meta-analysis was limited by the small number of RCTs and high heterogeneity. Trial registration: The review was prospectively registered with the International Prospective Registry of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, registration number CRD42019148905).


Introduction
Iron deficiency anemia (IDA) is common among women. In women of childbearing age, the most common cause of IDA is loss of iron due to menstrual blood loss or pregnancy. The risk factors related to IDA among women include low socio-economic status, social deprivation, teenage pregnancy, high parity, multiple pregnancies, and short inter-pregnancy intervals. [1] IDA is the final state of iron depletion due to inability to maintain physiologic balance of iron uptake and utilization. [2] Iron deficiency depresses the erythropoietic system resulting in decreased hemoglobin (Hb) levels. [3] Anemia in women is defined by the World Health Organization as an Hb level < 12 g/dL in nonpregnant women and < 11 g/dL in pregnant women. [4] The prevalence of IDA among pregnant women increases from 6.9% in the first trimester to 14.3% and 28.4% in the second and third trimesters, respectively. [5] Traditionally, oral iron replacement is used as the first-line therapy in patients with IDA due to its ease of administration, and early initiation of this treatment can correct anemia. However, oral iron has some disadvantages such as side-effects, poor compliance, and limited gastrointestinal absorption. [6,7] Sometimes, oral iron replacement even after prolonged treatment may fail to adequately correct anemia and iron reserves, before delivery in pregnant women. [7,8] This situation can be easily and efficiently remedied by the use of intravenous (IV) iron replacement, which can deliver the total amount of required iron over a short period. Currently, the most commonly used IV iron formulations are iron sucrose (IS) and ferric carboxymaltose (FCM). [1,[9][10][11][12][13] To date, there have been no systematic reviews comparing IV iron formulations, such as FCM and IS, in the treatment of IDA among obstetric and gynecologic patients.
Therefore, this study aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the efficacy and safety of most commonly used IV iron formulations, FCM and IS, in the treatment of IDA among obstetric and gynecologic patients.

Materials and methods
In this systematic review and meta-analysis of clinical trials, we evaluated the comparative efficacy and safety of IV FCM and IS in the treatment of IDA among obstetric and gynecologic patients. This analysis was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions, [14] and was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. [15] The review was prospectively registered with the International Prospective Register of Systematic Reviews (https://www.crd. york.ac.uk/prospero/, registration number CRD42019148905). This study did not require ethical approval since all analyses were based on previously published RCTs.

Literature search
We systematically searched the databases, including PubMed, EMBASE, Cochrane CENTRAL, and Google Scholar, to retrieve clinical trials involving adults (older than 18 years), which were published up to October 2019, with no language restrictions. As outlined in the Supplementary Information (S1, http://links.lww. com/MD/F671), the key words used during the search were "intravenous," "ferric carboxymaltose," "iron sucrose," "obstetric," "gynecologic," and "randomized."

Study selection
Peer-reviewed RCTs that evaluated the comparative efficacy and safety of IV FCM and IS in the treatment of IDA among obstetric and gynecologic patients were included in our analysis. Review articles, observational studies, case reports, letters to the editor, commentaries, proceedings, laboratory studies, and other nonrelevant studies were excluded. Two authors (DYG and YJC) independently assessed the articles for compliance with the inclusion/exclusion criteria. Disagreements were resolved by discussion or consultation with a third independent investigator (HWS).

Data extraction and assessment of outcomes
Several studies have assessed the efficacy of iron replacement therapy in patients with IDA by measuring the serum Hb and ferritin levels. Therefore, in our systematic review, the primary outcome was to compare the efficacy of IV FCM and IS by measuring serum Hb and ferritin levels before and after iron replacement. The secondary outcome was to compare the safety of IV FCM and IS based on the incidence of adverse events that occurred during iron replacement. We also compared the quality of life (QoL) and fatigue levels between the FCM and IS groups. Using standardized forms, two authors (HSY and SWL) extracted the following data independently: the name of the first author, year of publication, clinical inclusion criteria, country, number of patients who received IV iron replacement, serum Hb and ferritin levels, adverse events, and data on parameters for QoL and fatigue levels. The control group (IS group) included patients who received IV IS, while the intervention group (FCM group) included patients who received IV FCM as iron replacement therapy.

Assessment of bias risk
Two authors (YKJ and EJK) independently assessed the quality of the clinical trials. We used the Cochrane risk-of-bias tool to assess the quality of RCTs considering the following 7 potential sources of bias: random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and others.

Statistical analysis
Statistical analyses were performed using RevMan 5.3 (Cochrane Collaboration, London, UK). Mean differences (MDs) with their 95% confidence intervals (CIs) were calculated for continuous variables, and risk ratios (RR) with their corresponding 95% CIs were obtained for dichotomous outcome measures. The overall data were compared using a Z-test. All reported P values are 2sided, and P values < 0.05 were considered statistically significant. Statistical heterogeneity was estimated using the I 2 statistic, which was considered significant for I 2 values > 50%. The Mantel-Haenszel or inverse variance fixed-effects model was used for the study without significant heterogeneity, while the Mantel-Haenszel or inverse variance random-effects model was used for the study with significant heterogeneity. To assess the heterogeneity of the outcomes, we performed a sensitivity analysis by sequentially excluding one study in each turn to examine the influence of a single study on the overall estimate. We also performed a subgroup analysis of posttreatment Hb and ferritin levels according to patient types (obstetric, gynecologic, and obstetric and gynecologic). Funnel plots were used to assess Shin et al. Medicine (2021) 100: 20 Medicine the publication bias if more than 10 RCTs were included in a comparison. [14] 3. Results

Literature search
During the initial electronic search, 53 potential clinical trials were identified (11 from PubMed, 27 from EMBASE, 14 from Cochrane CENTRAL, and 1 from other sources), as described in Figure 1. We identified 9 RCTs [16][17][18][19][20][21][22][23][24] that compared the efficacy and safety of IV FCM and IS in the treatment of IDA among obstetric and gynecologic patients; these studies were published between 2015 and 2019.

Assessment for the risk of bias
The results of our assessment for the risk of bias regarding the quality of the included studies are summarized in Figure 2. All the studies described allocation concealment. However, 3 RCTs showed a high risk of bias, specifically due to the absence of blinding of participants or outcome assessments. [16,17,22] All other categories of bias were assessed as low risk or "no provided details" for the included studies.

Adverse events according to the intravenous iron formulation (number of events/person)
Eight studies [17][18][19][20][21][22][23][24] provided data regarding adverse events according to the formulation used in IV iron replacement. The FCM group had a lower incidence of adverse events than the IS group (RR, 0.53; 95% CI, 0.35-0.80; I 2 = 0%; P = 0.003) (Fig. 5). The sensitivity analysis for the comparison of adverse events between groups did not yield a change in the overall result. We also recorded the adverse effects reported in the 2 groups in the included studies (Table 2). Hypophosphatemia was reported in 2 studies. [17,20] No serious adverse events were reported in the included studies.

QoL and fatigue levels according to the formulation of intravenous iron therapy
QoL and fatigue levels were reported in 5 RCTs [16][17][18]20,24] using diverse measurements methods such as a Short Form-12 Health Survey, [16] Short Form-36 Health Survey, [18] Linear Analogue Scale Assessment, [17] and Scale of General Well-Being. [24] Regarding QoL and fatigue levels, 4 studies [16][17][18]24] showed favorable outcomes with the FCM group outcomes being more favorable than the IS group.

Discussion
In the present meta-analysis, we found that IV FCM was superior compared with IV IS as an iron replacement agent for the treatment of IDA among obstetric and gynecologic patients. IV FCM yielded higher Hb and ferritin levels, as well as demonstrated a more favorable safety profile with fewer adverse events among obstetric and gynecologic patients with IDA compared with IV IS. IDA is widespread worldwide, but mostly overlooked. IDA primarily results in fatigue, poor work capacity, diminished QoL, and even infertility in women. [27] IDA in pregnancy may lead to preterm labor, low birth weight, and perinatal maternal mortality. [27] Therefore, active treatment of IDA among obstetric and gynecologic patients is very important in the prevention of morbidity and mortality of women. [28]  Oral iron is a convenient mode of iron replacement. However, oral iron is insufficient for the treatment of IDA, particularly in the third trimester of pregnancy. [8] Oral iron may take 3 to 6 months to replete body iron stores and normalize the ferritin levels. [29] In a study on the dosage of oral iron (1 or 2 capsules/d) in the treatment of IDA during pregnancy, there were no differences in Hb and ferritin levels based on the oral iron dose. [30] This might be due to increased hepcidin level caused by frequent oral iron intake in high doses. Hepcidin regulates iron homeostasis and inhibits iron absorption for up to 24 hours after the last administration of oral iron formulation. [31] The Network for the Advancement of Patient Blood Management, Haemostasis, and Thrombosis recommends consideration of IV iron in pregnant women who fail to respond to oral iron supplementation within 2 to 4 weeks of initiation of therapy, those with severe anemia (Hb < 8.0 g/dL), or newly diagnosed IDA beyond 34 weeks of gestation. [32] In general, IV iron formulations resulted in adverse effects such as hot flushes, chest tightness, headache, nausea, vomiting, mild fever, arthralgia, and anaphylaxis caused by the toxic reaction of free iron. High molecular weight iron dextran formulations also demonstrated concerning adverse effects, specifically, anaphylactic reaction, and circulatory collapse. [33,34] FCM and IS are dextran-free IV iron formulations that are commonly used for IDA. IS has been the standard formulation used in IDA treatment for the past 20 years. [17] It has few adverse events and requires no test dose. The disadvantages of IS are the necessity of multiple infusions and prolonged infusion time (at a dose of up to 300 mg per dose or 600 mg per week). FCM is the newest iron formulation approved by the Food and Drug Administration in 2013. FCM can be administered at large iron doses as a single infusion over 15 minutes (usual doses of 750 mg in the USA and up to 1000 mg in the European Union). [35] The efficacy and tolerability of FCM have been validated in the treatment of IDA in patients with irritable bowel disease, [36] and most recently in chronic heart failure. [37] In our meta-analysis, posttreatment Hb and ferritin levels were higher in FCM group compared with the IS group. In a previous observational study on 863 pregnant women, Froessler et al [38] documented significantly increased Hb and ferritin levels after IV FCM treatment. In the studies conducted by Lee et al and Jose et al, FCM led to a significantly higher and rapid increase in the Hb levels compared with IS, following significantly fewer treatment sessions. [16,17] In the sensitivity analysis of posttreatment Hb levels in our study, heterogeneity (I 2 ) among the studies was decreased to 0% when we excluded the study by Naqash et al. [18] This may be attributed to differences in the study population; the study by Naqash et al included a mixed group of obstetric and gynecologic patients in variable disease states, whereas the other studies included either obstetric or gynecologic patients alone. The advantage of using FCM is the prompt correction of IDA. [16,24,39] The treatment time required to administer a 1000 mg dosage of iron was a single day in the FCM group, and about 2 weeks in the IS group. Therapy with FCM is beneficial in pregnant women at risk of postpartum hemorrhage and gynecologic patients requiring urgent surgery for uncontrolled menorrhagia. [16] In a study by Koch et al [26] on the ideal iron dose in IDA, 1500 mg IV iron was more effective compared with the commonly used dose of 1000 mg IV iron. Therefore, FCM is essential for rapid iron replacement in IDA.
In a meta-analysis on the safety of IV iron replacement therapy conducted by Avni et al, which included 103 RCTs, IV iron replacement was not associated with severe cardiovascular, respiratory, or neurologic adverse effects. However, infusion reactions at the IV site occurred after IV iron administration. In our meta-analysis, the incidence of adverse events was lower in the FCM group than in the IS group. This may be because the carboxymaltose shell of FCM minimizes the release of free iron, resulting in the delivery of greater amounts of iron to the tissues. [39] As an adverse effect of IV iron, hypophosphatemia was noted in 2 RCTs in our meta-analysis. [17,20] Van Wyck et al [40] observed transient, asymptomatic hypophosphatemia in 70% of patients undergoing IV iron replacement with FCM, whereas Blazevic et al [41] reported symptomatic hypophosphatemia in 4 patients  receiving IV FCM and IS. IDA stimulates the transcription of fibroblast growth factor-23 (FGF23) in osteocytes, which results in hypophosphatemia due to the induction of phosphaturia. [42] IV iron also induces hypophosphatemia by inhibiting the cleavage of intact FGF23. In general, hypophosphatemia is observed among 70% of gynecological patients receiving treatment for IDA. [43,44] Therefore, serum phosphate levels should be monitored during IV iron replacement. Regarding QoL and fatigue level, the findings of our metaanalysis were consistent with the studies by Van Wyck et al. [40,43] This may be due to patient-friendly dosing, fewer hospital visits, and the rapid effect on Hb level associated with FCM therapy.
The choice of iron formulation is determined by the cost and convenience of administration. [10] The controversy on the choice of IV iron formulation (FCM and IS) based on the lower versus higher cost [17,20,36] has been highlighted previously. In general, IS requires multiple infusions that amount to added travel costs and lost-working days, compared with those with a single infusion of FCM.
In a meta-analysis by Qassim et al [10] involving the comparison of IV iron formulations (IS, FCM, and iron polymaltose), there was no evidence that a single formulation was superior. This may be due to the omission of a few studies on IV IS and FCM therapies and the difference in the types of studies included (21 RCTs and 26 observational studies).
This meta-analysis had the following strengths. The included studies were restricted to RCTs, and there were no restrictions on language or type of publication. However, our review had several limitations. First, we included some blinded studies with a high risk of bias. Second, almost all the included studies were conducted in the same country. Third, there were differences in time points of measurement of Hb and ferritin levels among the studies. Fourth, the number of included studies was small, and the study population comprised women alone.
Animal studies have shown evidence of embryotoxicity and an increase in fetal skeletal abnormalities at maternally toxic doses of IV iron ("Product Information, Injectafer [ferric carboxymal-tose]," American Regent Laboratories Inc, Shirley, NY). However, no published human data are available on developmental adverse outcomes associated with the use of IV FCM or IS. Therefore, there is a need for caution regarding the use of IV iron replacement for the treatment of IDA in the first trimester of pregnancy; however, IV iron replacement may be recommended in the second and third trimesters.

Conclusions
In our meta-analysis, FCM therapy showed better efficacy in increasing Hb and ferritin levels, as well as a more favorable safety profile with fewer adverse events than IS therapy in IDA among obstetric and gynecologic patients. However, our study had the limitation of a small number of included RCTs with a high heterogeneity. Therefore, further well-designed RCTs with a low risk of bias are necessary to validate our results.  (2), itching (2), rash (1), hypophosphatemia (15) IS Fever (2), gastritis (2), vomiting (2)