Effect of IV ferric carboxy maltose for moderate/severe anemia: a systematic review and meta-analysis

Introduction Anemia remains a prevalent global health issue with varying severity. Intravenous iron supplementation, particularly with ferric carboxymaltose (FCM), has appeared as a possible therapeutic intervention for individuals with moderate to severe anemia. The study aimed to assess the efficacy and safety of ferric carboxymaltose (FCM) in reducing anemia. Methods We searched electronic databases, registries, websites, e-libraries, reference lists of reviews, citations, etc. We included randomized control trials (RCTs), non-RCTs, and single-arm studies, while observational studies, case series, and case studies were excluded. Two reviewers independently screened the studies and extracted the data. We included studies of moderate-to-severely anemic Indians and excluded Indians with other comorbidities. We assessed the risk of bias and the overall quality of evidence (QoE) using GRADE GDT. Result We identified 255 studies and included 14 studies (11 RCT, one non-RCT, and two single-arm studies) with 1,972 participants for qualitative analysis and 10 studies in the meta-analysis. All the included studies detailed the use of FCM for anemia. The primary outcomes assessed in the included studies were anemia, hemoglobin, and adverse events. The outcomes assessed ranged from 2 weeks to 12 weeks. The risk of bias varied across different studies with different outcomes. FCM is consistent with a fewer number of adverse events as compared to other interventions and provides “moderate” to “very low” QoE. Conclusion A slow single infusion of 1 gram of FCM is well-tolerated, safe, and effective in treating iron deficiency anemia (IDA) and surpasses other interventions (Iron Sucrose Complex (ISC), Iron sucrose, and ferrous ascorbate) in elevating hemoglobin levels and replenishing iron stores. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=459363, CRD42023459363.


Introduction
Anemia is indicated by a deficiency in the number of red blood cells or below-average hemoglobin levels within these cells (1).This condition presents a noteworthy public health challenge, influencing not just individual well-being but also significantly impacting societal and economic advancement (2).As per WHO 2023 estimates, 42% of children under five and 40% of pregnant women are anemic globally (1).According to National Family Health Survey (NFHS-5) data organized in India (between 2019 and 2021), 57% of women and 25% of men in the age group of 15-49 years are anemic in India (3).Despite the availability of treatments and guidelines (Anemia Mukt Bharat), the slightest improvement is observed in the anemia status in India (4).
Causes of anemia can often be distinct but frequently coexist.The primary cause of anemia encompasses nutritional deficiencies, hemoglobinopathies, and infectious diseases (like malaria, tuberculosis, HIV, and parasitic infections).While it's mostly presumed that around 50% of anemia cases stem from iron deficiency, this ratio might vary among different population groups and regions (5).Acknowledging the multifaceted nature of this ailment, rectifying anemia necessitates a comprehensive strategy (5).An integrated approach is crucial to combat it effectively, identifying and mitigating contributing factors.
Iron deficiency typically evolves gradually, often without evident symptoms or clinical manifestations.As iron reserves are gradually exhausted, iron availability to tissues diminishes, resulting in symptomatic anemia (6).This includes fatigue, weakness, dizziness and shortness of breath (6).
Although anemia can occur at any stage of life, pregnant women and young children are more inclined.The health effects of anemia include a high risk of maternal and child mortality, a negative impact on children's cognitive development, physical development, physical performance, and increased susceptibility to infections in adults.Anemia during the antepartum period distinctly impacts both maternal and fetal well-being.It is intricately associated with more significant morbidity and risk of several challenges throughout pregnancy, such as greater susceptibility towards infection, increased need for blood transfusion during delivery, cardiovascular complications, intrauterine growth retardation, preterm delivery, and perinatal mortality and morbidity (7,8).During the first trimester, IDA harms fetal growth more than during late pregnancy (6,7,9).Anemia during the post-partum period inflicts a significant disease burden at a vital phase of maternal-infant interaction and may result in developmental impairments in afflicted mothers' newborns (6).
In regions where Iron Deficiency Anemia (IDA) is the predominant cause of anemia (especially in low-income contexts), supplementary iron is often administered through supplements to vulnerable groups.Strategies like fortifying food and diversifying diets to enhance iron consumption emerge as crucial and sustainable methods to combat IDA within the broader aspects.However, a comprehensive approach incorporating iron interventions alongside other strategies becomes imperative when anemia is not solely attributed to iron deficiency.
The primary approach to addressing it involves oral or intravenous (IV) iron supplementation, targeting the underlying cause of IDA, and restoring iron levels to normal.The initial method of choice is oral iron supplementation.However, challenges related to compliance and the potential for iron depletion undermine the efficacy of oral iron treatment (10).Oral interventions prove inadequate in cases of moderate to severe anemia, necessitating prompt elevation of hemoglobin levels and rapid iron store replenishment.Instead, expedited remedies like parenteral therapies become imperative (11).Notably, parenteral options, including intravenous iron preparations, facilitate swifter iron restoration compared to oral methods, and their tolerability during pregnancy is notable.Among the commonly utilized parenteral preparations, Iron Sucrose Complex (ISC) and iron dextran are dosed according to the level of iron deficiency.Nevertheless, it's crucial to acknowledge that intravenous iron dextran formulations risk allergic reactions, whereas intravenous iron polymaltose mandates a lengthier infusion time.
Ferric carboxymaltose (FCM) is a third-generation intravenous dextran-free, intravenous iron formulation given in a single dose over a small duration, which overcomes the limitations of existing treatments and has a greater capacity for restoring iron (12).It minimizes the dose frequency but also has few drug-related side effects.Clinical findings have shown intravenous FCM's efficacy is effective in spanning conditions like uterine bleeding, post-partum iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease, irrespective of hemodialysis (13).
Ferric carboxymaltose is an innovative iron complex composed of a ferric hydroxide core, facilitating controlled iron delivery to reticuloendothelial cells and subsequently to iron-binding proteins like ferritin and transferring (13).This complex minimizes the risk of releasing excessive ionic iron into the serum.It is swiftly eliminated through the bloodstream and predominantly circulated to the bone marrow, liver, and spleen (13).This deliberate gradual release mechanism contributes to the low toxicity of FCM, establishing a substantial safety margin between standard and lethal doses.Furthermore, the FCM formulation's neutral pH and physiological osmolarity permit the administration of elevated doses with favorable local tolerance.As long as the iron dosage is tailored to the patient's needs, the likelihood of FCM-induced toxicity during clinical use remains relatively low.Additionally, FCM stands out for its absence of dextran ferumoxytol and iron isomaltose, minimizing the risk of dextran-induced anaphylactic reactions.Its exceptional safety profile, remarkably low immunogenicity, and often singular-dose regimen enhance its cost-effectiveness, particularly in most cases.Though studies (8,(14)(15)(16)(17)(18)(19)(20)(21) have demonstrated positive and encouraging effects of FCM in anemic individuals, there exists an urge to generate evidence for patients, practitioners and policymakers to determine the potential integration of intravenous FCM in the management of moderate to severely anemic individuals and, if data permits, to figure out the most appropriate drug dosage for this group of patients.Therefore, we plan to systematically review existing literature that reports intravenous FCM's effectiveness in treating moderate-to-severe anemia.This systematic review aimed to assess the efficacy and safety of ferric carboxymaltose in reducing anemia.

Methods
The systematic review was conducted using a standard methodology suggested in the Cochrane Handbook of Systematic Reviews (22).The protocol of this systematic review was registered in Prospero.The registration number of the proposed protocol is https:// www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023459363.This systematic review was funded by Indian Council of Medical Research (ICMR), India.

Types of studies
Inclusion criteria encompassed Randomized Control Trials (RCTs), non-RCTs, and single-arm studies while observational studies, case series, and case studies were excluded.Full journal publication was mandatory for inclusion, though extended abstracts of otherwise unpublished clinical trials were accepted.

Types of participants
Studies based on moderate to severely anaemic Indians irrespective of age groups, gender, ethnicity, educational status, community or setting, other socio-demographic factors, type of anaemia (nutritional deficiencies, such as iron, folate, vitamins B 12 and A; haemoglobinopathies; infectious diseases, such as malaria, tuberculosis, HIV and parasitic infections) were incorporated in this systematic review.Studies done in South-East Asia or at the global level were considered if they provided data separately for the Indian inhabitants.Studies confined to Indians with other comorbidities were excluded from the review.

Types of interventions
Studies in which intravenous ferric carboxymaltose injection was administered to moderately or severely anaemic Indians irrespective of dose, frequency and duration were incorporated in this systematic review.

Types of comparisons
The following comparisons were made in the review: 1. FCM versus placebo 2. FCM versus no treatment 3. FCM versus alternative experimental treatment modality (Iron sucrose or other); 4. FCM in combination with other treatments versus FCM treatment alone.

Types of outcomes
The following outcomes were considered in the review: Primary outcomes: 1. Anaemia 2. Haemoglobin 3. Adverse events: Adverse reaction was considered if the patient experienced any reaction during infusion or after drug administration.It was assessed as a dichotomous outcome with a number of participants who reported adverse events.
Reporting of these outcome measures did not form part of the criteria for including studies in a review.

Search methods for identification of studies
The Cochrane Central Register of Controlled Trials (CENTRAL) (via the Cochrane Library), MEDLINE (via PubMed) Medical subject headings (MeSH) or equivalent and text-word terms were used in order to search bibliographic databases without language restrictions.We preferred studies published in English.Searches were tailored to individual databases.Furthermore, we searched the metaRegister of controlled trials (mRCT),1 clinicaltrials.gov, 2 and the WHO International Clinical Trials Registry Platform (ICTRP) 3 for ongoing trials.Moreover, we examined the reference lists of retrieved articles and conducted hand searches of abstracts from relevant conferences.To uncover additional literature pertinent to the review, we engaged field experts for insights into unpublished and ongoing trials.

Selection of studies
Two reviewers (SU and AA) independently screened the articles retrieved from the searches using the Rayyan online screening tool and determined eligibility by reading the abstract of each study.Subsequently, the review authors eliminated studies that failed to satisfy inclusion criteria and acquired full copies of the remaining studies.Two reviewers (SU and AA) read these studies independently to examine relevant studies, and a third author (MNK) was adjudicated in the event of disagreement.The studies were not anonymised before the assessment.A Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) flow chart was incorporated in the review for a comprehensive overview (23).Notably, the studies included in this review were, irrespective of measured outcome data, reported in a "usable" way.

Data extraction and management
Three review authors (AA, SU and NW) independently extracted data utilizing standardized form, ensuring consistency.Details of the study, participants, intervention and outcomes were extracted and populated in the 'Characteristics of Studies Table ' .The multiple reports of the same study were amalgamated, thus treating each study as the primary unit of focus rather than individual reports.

Assessment of risk of bias in included studies
In each study, two authors (AG and DS) independently assessed the risk of bias, referencing the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions, with any disparities fixed by discussion.We completed a "Risk of Bias" table for each, including using the "Risk of bias 2" (RoB 2) (24) tool for RCTs and ROBINS-I tool (25) for non-RCTs.

Measures of treatment effect
We employed fixed-effect and random-effects models that gage the comprehensive effect's direction, size, and consistency.Risk ratios (RR) along with 95% confidence intervals (CI) were calculated for dichotomous variables, while mean differences (MD) with 95% CI were used for continuous data when measurements were consistent across studies.Standardized mean differences (SMD) were applied for conceptually similar results with varied measurement scales.Comprehensive records of means and standard deviations were noted.Imputation was performed in cases lacking sufficient information for calculating standard deviations of changes.
When published data were missing, incomplete or inconsistent with RCT protocols, we pursued additional information from the original authors/manufacturers.We emailed authors to solicit the necessary details for studies presenting data discrepancies.
The clinical heterogeneity was assessed using the Chi2 test (p value <0.1 for statistical significance) and quantified with the I 2 statistic.Heterogeneity was considered considerable if I2 exceeded 75%, substantial between 50 and 90%, moderate between 30 and 60%, and mild if below 40%.In cases of statistical heterogeneity (I 2 ≥ 50%), we conducted prespecified subgroup analysis and employed a randomeffects model to explore potential causes.Subgroup analyzes were performed based on ferric carboxymaltose administration duration.
In the case of 10 or more included studies, we intended to perform the funnel plot test to detect reporting bias.We also investigated potential and feasible sources of asymmetry in the funnel plot (Supplementary material).
We used the statistical package RevMan 5.4 for analysis, conducting a meta-analysis only when participants, interventions, comparisons, and outcomes were identical, ensuring a clinically meaningful and relevant answer.
As recommended by 'The Cochrane Handbook' , chapter 4.6.6., and the 'GRADE Handbook for grading the quality of evidence and strength of recommendations' (26), we included a 'Summary of findings' (SoF) table.SoF tables were presented for comparisons of Hemoglobin, serum ferritin, and adverse events between FCM and alternative experimental treatments (ISC, iron sucrose, ferrous ascorbate).Utilizing the GRADE gdt system, two review authors assessed the overall evidence quality for each outcome and presented findings in the SoF tables.Decisions to downgrade study quality were substantiated through footnotes.

High quality
We are very confident that the true effect lies close to that of the estimate of the effect.

Moderate quality
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low quality
Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.

Very low quality
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect (26).

Results
A total 255 records were retrieved from electronic sources.After removing the duplicates, the search yielded 213 records.We discarded 171 records in initial screening based on title and abstracts.We assessed full text of the remaining 42 articles for eligibility and excluded 28 articles based on wrong population (n = 23), wrong intervention (n = 2), and wrong design and outcome (n = 3).Finally, we included the remaining 14 studies in qualitative synthesis and ten in the meta-analysis.We presented the selection process as a PRISMA Flow diagram in Figure 1.
All the studies included adults, with the mean age of the study participants ranging from 18 to 40 years.All the studies recruited people with moderate to severe anemia.Eight studies were conducted on pregnant women (8, 14-16, 18-21), five on post-partum women Frontiers in Medicine 06 frontiersin.org(17,19,(28)(29)(30), two on females with menorrhagia (19,27), and two studies on women of reproductive age groups (19,31).None of the studies were conducted on men.All studies except two that failed to specify the type of anemia (16,17) included participants with IDA.
Hemoglobin was assessed in all the included studies.Except for the two included studies (27,31), all other studies assessed the serum ferritin levels.Most of the studies except four studies (15,17,19,27) reported adverse events.The outcomes assessed ranged between 2 weeks to 12 weeks.We have presented characteristics of included studies in Table 1.

Details of ongoing studies
Details of four ongoing studies can be found in Supplementary Table S1.

Risk of bias in included studies
The Risk of Bias (ROB 2) assessment was conducted for several studies, and the results are summarized below and depicted in Figures 2, 3.
In the study by Jose et al. (15) several outcomes such as hemoglobin, serum ferritin, serum iron, transferrin saturation, and TIBC had some concerns overall.
In Rathod et al. (28) iron sucrose group, both hemoglobin and serum ferritin had high risk of bias overall due to deviations from intended intervention and missing outcome data.Adverse events also had a high risk of bias overall due to the outcome's measurement, deviations from the intended intervention, and missing outcome data.
Naqash et al. (19) study had a high risk of bias in all outcomes, namely hemoglobin, serum ferritin, serum iron, transferrin saturation, and TIBC, due to deviations from intended interventions.TIBC also had some concerns due to randomization process.
In Damineni et al. (31) there was a high risk of bias in hemoglobin and adverse events outcomes due to the high risk of deviations from intended interventions and some concerns due to the randomization process and selection of reported results in the group where oral ferrous ascorbate was the comparator.
In Mahey et al. ( 27) there was a high risk of bias in hemoglobin, serum iron, and adverse events due to the high risk of deviations from intended interventions and some concerns due to the randomization process and selection of reported outcome.
In Patel et al. ( 8) hemoglobin, serum ferritin, and adverse events had an overall high risk of bias due to the high risk of deviations from intended interventions and some concerns due to the randomization process and selection of reported results.Adverse events also had a high risk in measuring the reported outcome.
Dakhale et al. ( 29) had an overall high risk of bias in hemoglobin, serum ferritin, and adverse events due to the high risk of deviations from intended interventions and some concerns due to the randomization process and selection of reported outcome.
Parikh and Agarwal et al. ( 20) also had an overall high risk of bias due to the high risk of deviations from intended interventions and some concerns due to the randomization process and selection of reported results.Adverse events also had a high risk in the measurement of reported results.
In Agrawal and Masand et al. (14) there was an overall high risk of bias in hemoglobin, serum ferritin, and adverse events outcomes due to deviations from intended intervention and missing outcome data along with some concerns in the selection of reported results.Hemoglobin also had some concerns in the randomization process, serum ferritin had a high risk in the randomization process, and adverse events had a high risk in the measurement of outcomes.
In Patil and Tehalia et al. (21) iron sucrose comparator group, both hemoglobin and serum ferritin had an overall high risk of bias due to deviations from intended interventions, some concerns due to the randomization process, and selection of reported results.Adverse events outcomes also had high risk in the measurement of the outcome.In the ISC group of Patil et al., hemoglobin had a high risk of bias due to the high risk of deviations from intended interventions and some concern in the randomization process and selection of reported results.In the oral iron group of Patil et al., both adverse events and serum ferritin had a high risk of bias due to the high risk of deviations from intended interventions and some concern in the randomization process and selection of reported outcomes.
In the ROBINS-I assessment, Kaur et al. (17) had only some concerns about the hemoglobin and serum ferritin outcomes due to some concerns of bias due to missing data.Kant et al. had a low risk of bias in both the hemoglobin and serum ferritin outcomes.Sharma et al. (30) had an overall high risk of bias in the hemoglobin, serum ferritin, and adverse events outcomes due to a high risk of bias in selecting participants for the study and bias in the classification of interventions.
To summarize, the studies reviewed in the ROB 2 tool had various levels of risk of bias in different outcomes, with some studies having a high risk of bias in multiple outcomes and others having only some concerns in one or two outcomes.The ROBINS-I tool assessed the risk of bias differently, with some studies having a low risk of bias in certain outcomes and others having a high risk of bias overall.Both tools provided a systematic approach to evaluating the risk of bias in studies, which was crucial for accurately evaluating their outcome.(15), at 4 weeks.Subgroup analysis was undertaken according to the different time points.All the included studies demonstrates that the serum iron levels in the FCM group were lower than in the ISC group in two studies at 3 weeks and at 4 weeks ( 19) but not at 6 and 12 weeks (15).As the heterogeneity amongst the studies was substantial (I 2 = 99.2%), and as one study (15) reported serum ferritin levels at different time points, we did not pool the findings of the studies (Supplementary Figure S5).Risk of Bias (RoB 2 tool) assessments in included randomized controlled trials.

Hemoglobin
Only one study (21) compared FCM with intramuscular injection of iron sorbitol on hemoglobin levels in anemic participants as post-scores and two studies as change-scores.The outcomes were assessed at 2 and 6 weeks.The study showed significant improvements in Hb levels at postscores as well as change-scores (Figure 7; Supplementary Figure S6).

Adverse events
Only one study (21) assessed the adverse events of FCM and iron sorbitol when administered to anemic participants.The study showed fewer adverse events with FCM as compared to iron sorbitol.The pooled analysis shows that the risk of adverse events in FCM group was 78% less than that in iron sorbitol (RR 0.22, 95% CI 0.11 to 0.45; participants = 100; studies = 1).

Serum ferritin
Only one study (21) detailed the data on serum ferritin levels at baseline and at the end of the treatment and changed scores at baseline level and at 2 weeks, and 6 weeks.Subgroup analysis was undertaken according to the different time points.The study demonstrates that the serum ferritin levels in the FCM group were significantly higher as compared to iron sorbitol.The serum ferritin levels were higher at 6 weeks as compared to 2 weeks (Figure 8; Supplementary Figure S7).

TIBC
None of the included studies reported this outcome.

Anemia
None of the included studies reported this outcome.

Hemoglobin
Only two studies (28, 31) compared FCM with oral iron (ferrous ascorbate) on hemoglobin levels in anemic participants as post-scores as well as change-scores.In one study (31) outcomes were assessed at 1 week and 4 weeks, and in the other study (28), the outcomes was assessed at 2 weeks and 6 weeks.Both the studies showed significant improvements in Hb levels at post-scores as well as change-scores in FCM group as compared to oral iron (Figure 9; Supplementary Figure S8).

Adverse events
Only two studies (28,31) assessed the adverse events of FCM and oral iron (ferrous ascorbate) when administered in anemic participants.The study showed fewer adverse events with FCM as compared to oral iron.The pooled analysis shows that the risk of adverse events in FCM group was 98% less than in oral iron (RR 0.02, 95% CI 0.01 to 0.12; participants = 246; studies = 2) (Figure 10).

Serum ferritin
Only one study (28) reported data on serum ferritin levels at baseline and at the end of the treatment at 2 weeks, and 6 weeks.The study demonstrates that the serum ferritin levels in the FCM group were significantly higher as compared to oral iron.The serum ferritin levels were lesser at 6 weeks as compared to 2 weeks (Supplementary Figure S9).

TIBC
None of the included studies reported this outcome.

Comparison 4: ferric carboxymaltose in combination with other treatments versus ferric carboxymaltose treatment alone
None of the included studies assessed this comparison.

GRADE assessments for FCM compared to ISC for anemia in Indians
The assessment of hemoglobin quality using Tables 3, 4 revealed 'low quality' at 2, 4, and 6 weeks, "moderate quality" at 3 weeks, and "very low quality" at 12 weeks.This was attributed to a high risk of bias and limited participant numbers in the analysis.The quality of evidence for serum ferritin was "low quality" at 2, 4, and 12 weeks, and "very low quality" at 6 weeks due to factors like high risk of bias, presence of heterogeneity, and a few number of participants in the analysis.The quality of evidence for adverse events was assessed as 'moderate quality' due to the presence of high risk of bias.
When using the "RoB 2" tool, we found that all included studies had high risk of bias in at least one of the six domains.Most of the included studies did not describe the method of randomization and allocation concealment that may pose a serious selection bias (D1: Randomization process).The majority of the studies were open-label, and it was uncertain if blinding was successful in blinded studies, raising the potential of performance bias (D2: Deviation from intended intervention).Clinical outcome measures, such as hemoglobin, serum ferritin not affected by the subjectivity of the participants, were highly  The inconsistency was only high for two outcomes (Hemoglobin and serum ferritin, Comparison 1 and 2) owing to a considerable level of heterogeneity, which was addressed through subgroup analyzes.The evidence in this review did not have issues regarding indirectness.Forest plot of comparison: FCM verses alternative experimental treatment modality, outcome: hemoglobin (change-scores).
Imprecision was an issue owing to small sample sizes, which lowered our confidence in the effects by one level.Except for two studies (15,19), we did not find the protocol available.Hence, the risk of reporting bias had some concern.There were insufficient trials included in the metaanalyzes to utilize a funnel plot and assess the possible risk of publication bias.

Discussion
Our findings indicate that FCM can serve as a viable option for women with IDA, addressing not only the correction of hemoglobin deficiency but also the replenishment of iron stores.Other treatment of IDA, such as Iron sucrose complex, Iron sorbitol, or ferrous ascorbate, showed an increase in the hemoglobin level; however, the increment was significantly higher in the participants treated with FCM as compared to ISC infusion or iron sorbitol infusion, or oral iron.Serum ferritin level was also increased in the other treatment modalities but was higher in participants treated with FCM.FCM was well tolerated in patients with IDA, and most drug-related adverse events considered mild to moderate in severity.
The convenient dosing with a lesser total number of required doses decreased the reduces the frequency of hospital visits and, in turn, resulted in satisfactory compliance (18), higher patient satisfaction (28), higher acceptability, better general well-being (28), better HRQOL (19), minimum requirement of hospital resources and increase in acceptability as compared to patients treated with other treatment modalities (19).

Overall completeness and applicability of evidence
Evidence regarding FCM for anemia in India is limited, with data available only from small sample-sized RCTs that limits us from reaching reliable conclusions regarding the effects of FCM.These studies are also limited in their generalisability, as all the studies included women between 18 to 40 years of age.
The results of this systematic review can only be interpreted in consideration of the following factors.
• None of the studies assessed the comparison between FCM in combination with other treatments versus FCM alone.

Potential biases in the review process
Our review followed the principles outlined in Cochrane's Handbook of Systematic Reviews (32).We executed a thorough search and searched data sources (including multiple databases, and clinical trial registries) that necessitate the inclusion of all published studies concerning FCM formulations.Although language limitations were taken into account, our focus remained on studies published in languages we anticipated.The evaluation of each study's relevance was carried out meticulously, with the screening process executed by independent reviewers in duplicate.For robustness, data extraction, encompassing assessments of risk of bias (RoB) as well as GRADE assessments, were undertaken in duplicate by two independent reviewers.This dual approach served to guarantee the precision and accuracy of data extraction and reporting.
The present study was based on comprehensive bibliographical search that encompassed the inclusion of all published clinical trials addressing various intravenous formulations.
Due to a lack of details in the methodology and results section of the included studies, we had to pool some incompatible data.Some data were provided graphically in the published reports.The absence of crucial information like standard deviations hindered the execution of specific analyzes.

Agreements and disagreements with other studies or reviews
The findings of this systematic review confirm the results from already published systematic reviews on studies from other countries.In all the available systematic reviews (Table 5), among the different   *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and therelative effect of the intervention (and its 95% CI).

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.iron formulations available for the treatment of IDA, FCM was found to be superior when compared with other iron regimens in terms of improving hemoglobin levels and serum ferritin levels in different populations with iron deficiency anemia and indicated a high safety profile.

Conclusion
The evidence from this SR does not support a robust clinical efficacy conclusion.In summary, this review indicates that a gradual single 1 g FCM infusion is both safe and effective for treating IDA in women.FCM demonstrates superior elevation of hemoglobin levels and restoration of iron stores compared to other interventions (ISC, Iron sucrose, and ferrous ascorbate), with minimal adverse events.However, the evidence is of 'low' to 'very low' quality, primarily based on ten studies with a high risk of bias and insufficient participant numbers for conclusive results.Further research is likely to influence these findings.FCM consistently shows fewer adverse events than other interventions, with evidence ranging from 'moderate' to 'very low' quality.The outcomes indicate FCM's well-tolerated, safe, and effective role as an alternative to other interventions for IDA in women.
FCM offers the advantage of swiftly addressing IDA in some patients within just 2 weeks, requiring a single dose without the need for repeated administrations-thus offering a more convenient treatment approach.This approach also offers benefits such as administering a substantial dose per session, minimizing the number of required doses, reducing hospital visits, lowering transportation costs, needing less infusion-related equipment, and alleviating patient discomfort linked to multiple needle insertions.
However, despite these advantages, the body of evidence in this SR falls short of supporting a definitive conclusion regarding clinical efficacy.

Implications for research
Information from adequately powered, multicentric, methodologically rigorous RCTs to compare the efficacy and safety of FCM over other alternative treatment modalities for the treatment of anemia are necessitated.Cost-effectiveness analyzes are also necessitated.

FIGURE 3
FIGURE 3Risk of Bias assessments (ROBINS-I) in included non-randomized controlled trials and single-arm studies.

FIGURE 8 Forest
FIGURE 8 Forest plot of comparison: FCM verses alternative experimental treatment modality, outcome: serum ferritin (change scores).

FIGURE 10 Forest
FIGURE 10Forest plot of comparison: FCM verses alternative experimental treatment modality, outcome: adverse events.

Explanationsa.
Downgraded by one for limitation in study design (high RoB) b.Downgraded by one as sample size not optimal c.Downgraded by one for limitation in study design (high RoB in D2 domain of RoB 2) d.Downgraded by one for limitation in study design (high RoB) in three out of four studies e. Downgraded by one for limitation in study design (high RoB) in two out of three studies f.Downgraded by one for inconsistency (heterogeneity) I 2 =84% g.Downgraded by one for limitation in study design (high RoB) in all studies h.Downgraded by one for inconsistency (heterogeneity) I 2 =92% 10.3389/fmed.

TABLE 1
Characteristics of all included studies.

TABLE 2
Adverse events.

TABLE 3
GRADE assessments for ferric carboxymaltose compared to iron sucrose complex (ISC) for anemia in Indians.

TABLE 5
Findings of other systematic reviews for all countries on effect of FCM for treatment of anemia.