Clinical effectiveness of ferric carboxymaltose (iv) versus iron sucrose (iv) in treatment of iron deficiency anaemia in pregnancy: A systematic review and meta-analysis

Anaemia is a global public health problem. The World Health Assembly (WHA) has endorsed the global nutrition target of a 50 per cent reduction of anaemia in women of reproductive age by 20251. In 2019, anaemia in women of reproductive age was estimated to be 29.9 percent and it was 36.5 per cent in pregnant women2. Iron deficiency is the leading cause of anaemia in pregnancy, with a global prevalence of 40 per cent. Haemoglobin (Hb) <11 g/dl of blood is defined as anaemia in pregnancy, and <7 g/dl is considered severe anaemia, according to the World Health Organization3. Serum ferritin <15 µg/L is associated with iron deficiency anaemia (IDA) in pregnancy. However, evidence shows that iron-deficient erythropoiesis is present at even higher levels of serum ferritin (25 µg/L) in non-pregnant women4. Absent marrow haemosiderin, considered the gold standard for iron deficiency diagnosis, is found in non-pregnant women with serum ferritin levels up to 37 µg/L5.

Anaemia in the first trimester is treated with oral iron. For women who cannot tolerate/non-responsive to oral iron and for moderate-to-severe anaemia in the second and third trimesters, parenteral iron is given6. The most commonly used iron formulation for anaemia in pregnancy is iron sucrose complex (ISC). ISC is a sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose, administered intravenously (iv). The administration of iv ISC necessitates multiple visits, thereby leading to additional costs.

Intravenous ferric carboxymaltose (FCM), a ferric hydroxide carbohydrate complex, is administered as a single dose. Evidence shows that FCM is associated with a significantly higher rise in Hb levels as compared to oral ferrous sulphate and ISC78, and more improvement in fatigue scores and lesser number of hospital visits as compared to ISC7. Even in countries with high anaemia burden like India, FCM is recommended as part of national guidelines for the treatment of IDA in pregnancy6.

Existing systematic reviews on the usage of iv FCM in pregnant women with IDA take into account majorly the studies assessing the efficacy and safety of iv FCM and not maternal and neonatal outcomes and cost-effectiveness910. These reviews are not comprehensive and do not include many studies.

Anaemia Mukt Bharat recommends the use of iv iron sucrose (IS) or FCM in the treatment of IDA in pregnant women when parenteral iron treatment is indicated. Since FCM, unlike ISC, does not require multiple sittings for dose completion, there is a high possibility of reduced OOPE (out of pocket expenditure) burden on the affected individuals.

This review aims to study the clinical effectiveness of change in haematological parameters and maternal and neonatal outcomes on using iv FCM as a treatment option in moderate and severe IDA in pregnant women compared to iv ISC.

Material & Methods

The protocol of this systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022306092, https://www.crd.york.ac.uk/prospero /display_record.php?RecordID=306092). Studies that were published in English language and met the inclusion criteria as mentioned below were included in the review. The population of interest was pregnant women of reproductive age (15-49 yr) in their second and third trimesters, diagnosed with moderate-to-severe IDA (Hb <9 g/dl) and not responding to oral iron therapy. The population exclusion criteria were pregnant women diagnosed with anaemia other than IDA and anaemic pregnant women who underwent medical termination of pregnancy or had a spontaneous abortion.

The intervention in this review was iv FCM. The comparator was iv ISC or no comparator. Studies published until November 30, 2022 were included. Randomized control trials (RCTs) and non-randomized trials (Non-RCTs), comparing the clinical effectiveness and safety of iv FCM and iv ISC were included along with observational studies (cross-sectional, cohort studies and case-control) on iv FCM in the treatment of IDA in pregnancy. The outcomes of the review included maternal clinical outcomes such as a change in haematological parameters, the incidence of adverse events at the time of drug administration and after the time of administration, indication for blood transfusion during pregnancy, delivery and postpartum period and neonatal outcomes.

Search strategy: A preliminary search of relevant studies was conducted and compiled by Medical Subject Headings and free text search words. The electronic databases searched were MEDLINE through PubMed, Cochrane Library, EMBASE and Scopus.

We developed the search strategy using appropriate Boolean terms, as per the specifications of each electronic database (Supplementary Table I) Two researchers independently conducted the search. Title and abstract screening were done using Rayyan – Intelligent Systematic Review software. Studies meeting the inclusion criteria were selected after excluding duplicates. Conflicts regarding the inclusion of the studies were settled consultatively by a third researcher.

Data collection: The search was documented as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines11. A structured data extraction tool was used to extract the relevant data. Participant characteristics, interventions, comparator methods and outcomes were documented in a spreadsheet. We assessed the quality of the studies considered for data extraction. Two independent reviewers critically assessed the quality of the included studies in terms of methodology.

Quality assessment strategy: Cochrane risk-of-bias tool (RoB 2.0)12 was used for RCTs; the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) assessment tool13 was used to appraise non-RCTs, Appraisal tool for Cross-Sectional Studies (AXIS)14 and Critical Appraisal Skills Programme (CASP) tools15 were used for case control, cross-sectional, and cohort studies.

The CASP checklist has 11 items but does not have a scoring system, so we appraised the case–control and cohort studies as follows: up to two negative attributes (no/can’t say) indicated ‘good quality’; three to five negative attributes indicated ‘fair quality’ and six or more negative attributes were marked as ‘poor quality’. As the AXIS tool for cross-sectional studies had no scoring system, the following scoring method was desired: of the 20 items on the tool; if up to three had negative attributes, it was marked as ‘good quality’; four to eight was marked as ‘fair quality’ and nine or more was marked as ‘poor quality’. A GRADE (Grading of Recommendations, Assessment, Development and Evaluations) assessment of the studies included in the meta-analysis was conducted (results in Supplementary Table II).

Data analysis: A qualitative synthesis of the included studies was undertaken and summarized. The analysis compares the study designs and the key results of the included studies. RCTs, Non-RCTs and observational studies were included in the systematic review to provide a comprehensive evidence on the clinical effectiveness and safety of iv FCM. However, the meta-analysis included only the data obtained from the comparative studies.

Clinical effectiveness was reported in terms of a rise in Hb levels and serum ferritin levels at different time points during pregnancy. Side effects were reported as the number of events and percentage. The studies reporting these outcomes were considered for meta-analysis. The post-infusion Hb and ferritin were the end-line values recorded after administration of the drugs at different points of follow up, as reported in the included studies. Further, the mean rise in Hb and ferritin was the difference between the baseline and end-line values of the Hb and ferritin.

Meta-analyses and heterogeneity analyses were conducted using RevMan 5 software version 5 (revman.cochrane.org). For ease of analysis, the units of measurement of Hb and serum ferritin were standardized to g/dl and µg/L, respectively. Standard deviations were estimated and used as a measure of dispersion. The summary measure in this meta-analysis was the mean difference for Hb and serum ferritin (continuous variables) and odds ratio for adverse events (dichotomous variable), respectively. The mean differences in haematological parameters were pooled based on the follow up period (up to four weeks and above four weeks after iv iron infusion). The odds ratio of adverse events was pooled from the studies reporting their incidence. The analysis was conducted using a random effects model with 95 per cent confidence interval. I² indicates heterogeneity and P value indicates significance. Forest plot identified the dispersion of effect sizes within the studies. The outcomes from the observational studies measuring the clinical effectiveness and safety of iv FCM in the treatment of IDA in pregnancy, with no comparator group, were analyzed separately.

Results

The summary of the search results is given in the PRISMA flow diagram (Fig. 1). A total of 18 articles that addressed one or more of the outcomes were included of which seven studies compared iv FCM and iv ISC (five RCTs716171819 and two retrospective audits)2021 and 11 were observational studies2223242526272829303132 on safety and effectiveness of iv FCM.

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Fig. 1

PRISMA flow diagram.

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Out of the five RCTs, four were conducted in India7161719 and one in Pakistan18. One retrospective audit each from Switzerland20 and Australia21 were included. Among the 11 observational studies, four25272832 were from India, two2324 from Australia and one each from Bangladesh26, UAE22, Spain31, Turkey30 and The Netherlands29.

The included studies diagnosed IDA in pregnant women based on their Hb and serum ferritin levels before enrolment. Serum iron studies were not done to confirm iron deficiency in any of the studies comparing iv FCM and iv ISC. Two studies719 measured Hb and serum ferritin levels for diagnosis of IDA. After the enrolment of participants, serum iron levels were done as part of the baseline investigations. However, the participants were not excluded from the studies on the basis of serum iron levels. Among the observational studies, serum iron studies were done to confirm iron deficiency only in one study28.

In the included studies, the iron requirement was calculated using the Ganzoni formula33 [2.4 × Body weight (kg) × (Target Hb - Actual Hb (g/dl)) + iron storage depot (mg)] and the iv iron treatment was given accordingly, after calculating the required dose of iv FCM/ISC as per allotment.

For IS, a slow iv infusion of upto 200 mg of elemental iron diluted in 200 ml of 0.9% normal saline was given over 30 minutes. Until the required dose was administered, the injection was repeated on alternate days. For FCM, a single intravenous dose of up to 1000 mg of elemental iron diluted in 250 ml of 0.9% normal saline was given over 15 minutes.

All the RCTs reported a rise in Hb and serum ferritin levels with an average follow up period of six and a half weeks (one week to 20 wk). Four RCTs7161719 reported the incidence of adverse events that happened during iv iron treatment. One study7 reported pregnancy and neonatal outcomes such as preterm birth, spontaneous abortion and the birth weight of the newborn. Both retrospective audits reported post-infusion Hb levels, incidence of adverse events and pregnancy and neonatal outcomes. One study21 reported a rise in serum ferritin and mean corpuscular volume levels. The inferences on the haematological and safety parameters are presented in Table I. The studies721 showed no significant difference between the groups in pregnancy and neonatal outcomes.

All the observational studies discussed the improvement in Hb levels after iv FCM therapy. A rise in serum ferritin levels was reported by three prospective observational studies232728 and three retrospective studies243132. Incidence of adverse events was reported by all studies except two3031. Among the observational studies, pregnancy and neonatal outcomes were reported by six232425293031. The inferences from the observational studies are reported in Table II. The summary of findings from all the studies is given in the

The adverse events reported by the included studies were minor local and systemic reactions. None of the included studies reported adverse events that occurred after the completion of iv iron administration.

The data regarding blood transfusion requirement due to IDA are given in only one study21 comparing iv FCM and iv ISC. One study16 has excluded pregnant women with a history of blood transfusion in the past and those with anticipated need for blood transfusion. Other studies do not mention any data on blood transfusion. Hence, this outcome was not taken for analysis. All the included studies have declared no conflict of interest.

Risk of bias and critical appraisal of studies reviewed: The risk of bias of the included RCTs, retrospective audits and observational studies is presented in tables in the Supplementary material. Two RCTs1718 had a moderate risk of bias due to some concerns in selective reporting. The other three RCTs71619 had a low overall risk of bias. Both the retrospective audits had moderate bias based on the ROBINS-I tool due to non-randomization. One study20 had a moderate risk of bias due to missing data. Based on the AXIS tool, the quality of all the cross-sectional studies was fair. The case control and cohort studies were found to have evidence of fair quality, based on assessment using appropriate CASP tools.

Results of meta-analyses: Meta-analysis was conducted to measure the changes in haematological parameters and the incidence of adverse events. The included studies measured the haematological outcomes at different points of follow up. Hence, the data were analyzed under three categories such as: (i) up to four weeks, (ii) at five to six weeks and (iii) at 12 wk, as applicable. The mean difference between the groups in post-infusion Hb levels up to four weeks after iv iron therapy was 0.38 (0.01, 0.75) g/dl (P=0.05, I²=82%) (

The mean difference between the groups in mean rise in Hb levels up to four weeks after iv iron therapy was 0.57 (0.24, 0.9) g/dl (P=0.0008, I²=75%) (Fig. 2A) and at 12 wk after iv iron therapy was 0.78 (−0.13, 1.69) g/dl (P=0.09, I²=98%) (Fig. 2B). The mean rise in Hb levels was significantly better in the FCM group up to four weeks. The mean rise in Hb levels at five to six weeks could not be analyzed due to a lack of data.

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Fig. 2

(A) Rise in Hb levels up to 4 weeks (g/dL). (B) Rise in Hb levels at 12 weeks (g/dL).

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The mean difference between the groups in post-infusion serum ferritin levels up to four weeks after iv iron therapy was 34.65 (29.66, 39.64) µg/L (P<0.0001, I²=0%) (Fig. 3), at five to six weeks after iv iron therapy was 94.83 (−6.37, 196.04) µg/L (P=0.07, I²=88%) (

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Fig. 3

Post infusion serum ferritin levels upto 4 weels (mcg/L).

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The mean difference in the rise in serum ferritin levels at four to five weeks after iv iron therapy was 106 (−44.35, 256.36) µg/L (P=0.17 and I²=90%) in favour of FCM (

The pooled odds ratio of incidence of adverse events was 0.5 (0.32, 0.79) with I²=0 per cent, P=0.003 (Fig. 4). The results were in favour of FCM, showing fewer adverse events with iv FCM than in iv ISC treatment. Publication bias could not be derived upon rom the funnel plots due to less number of studies.

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Fig. 4

Incidence of treatment related adverse events.

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Results of analysis of observational studies: The outcomes from the observational studies were separately analyzed, measuring the clinical effectiveness and safety of iv FCM in the treatment of IDA in pregnancy. The mean rise in Hb levels up to three weeks and above three weeks after iv FCM therapy was 1.98±0.42 g/dl and 2.28±0.97 g/dl, respectively. The mean rise in serum ferritin levels up to three weeks and above three weeks after iv FCM therapy was 205.94±55.09 µg/L and 106.88±67.48 µg/L, respectively. The average incidence of adverse events following iv FCM therapy in pregnant women was 13.38 per cent. The mean birth weight of the newborns of the participants was 3394±163.36 g. The mean APGAR score at one minute and five minutes of life was 8.75±0.5 and 9±0.7, respectively. The included studies showed that iv FCM is clinically effective in improving the anaemia status of the participants.

Discussion

This systematic review and meta-analysis assessed the clinical effectiveness of iv FCM, as compared to iv ISC, for the treatment of moderate-to-severe IDA in pregnancy. Among the 18 studies included in the systematic review, nearly two-thirds (11/18) were from low- and middle-income countries.

We found that iv FCM was effective in improving end-line Hb levels than ISC at four weeks, five to six weeks and 12 wk post iv iron treatment. The mean rise in Hb levels was significantly better in the FCM group at four weeks. FCM group showed significantly higher post-infusion serum ferritin levels at four weeks post-iv iron treatment, compared to ISC. The overall rise in serum ferritin levels was higher with FCM, but the results were insignificant. These findings show that in moderate and severe anaemia in pregnant women, FCM is more effective in improving Hb and serum ferritin levels in the short term, potentially reducing the need for blood transfusion. However, definitive inference could not be made due to a lack of data on blood transfusion requirement post iv iron therapy.

These haematological parameters guide the direction of the diagnosis and treatment of IDA during pregnancy. Close follow up of the Hb and serum ferritin levels of the anaemic pregnant women on iron treatment will enable early diagnosis of failure of treatment and development of severe anaemia. In clinical practice, this will help the practitioners identify pregnant women with indications for blood transfusion when the iv iron treatment proves to be insufficient.

This systematic review shows that iv FCM is associated with the incidence of fewer adverse events compared to iv ISC. None of the studies included in the systematic review showed the incidence of hypophosphataemia as an adverse effect of using FCM to treat anaemia during pregnancy. Unlike ISC, FCM has the advantage of being given as a single large dose with a lower risk of adverse events. This renders FCM an option worth considering as a programmatic intervention. The findings of this review could further help in evidence-based decision-making and alleviate apprehensions around the use of this compound from second trimester of pregnancy. This, in turn, has programmatic translation potential to benefit pregnant women.

Two systematic reviews were done before the present study on a similar topic. The systematic review of 20189 included RCTs and observational studies, involving the administration of iv iron, regardless of the comparator, to manage antenatal IDA. Here, only two RCTs appeared, that compared iv FCM to iv ISC. The IPM (iron polymaltose) group observed highest improvement in Hb levels. Several studies on iv FCM got published after 2016. Hence, in the present review, the five RCTs published after 2016 that compared FCM with ISC were included additionally. Our analysis also revealed that FCM showed better improvement in Hb levels up to four weeks after infusion and fewer adverse drug reactions than iv ISC. The 2018 review9 also showed no significant results on pregnancy and neonatal outcomes. In this review, serum ferritin levels were analyzed across individual studies and the results segregated into different time points based on the follow up period and the meta-analysis undertaken.

The 2021 review10 included two RCTs that compared iv FCM to iv ISC. Unlike the 2021 review10, our search was not limited to specific study designs, and so yielded more studies that met the inclusion criteria. Intravenous FCM was found to improve Hb levels in the 2021 systematic review10 and network meta-analysis. This review10 measured only effect of oral and parental iron preparations on haematological indices. The present review focussed on FCM in particular, and has measured the incidence of adverse events, pregnancy and neonatal outcomes and improvements in haematological indices.

Unlike the previous reviews910, our review focuses on FCM and ISC, in terms of clinical effectiveness, safety, pregnancy and neonatal outcomes, in the background of IDA in pregnancy. Quality of the included studies was assessed with design-specific tools. The studies were grouped based on follow up period for meta-analysis. Direction of change in outcomes was measured with mean difference and odd ratio. Among the included studies, four RCTs and nine observational studies have not appeared in the previous reviews. All these studies had a low–moderate risk of bias and contributed to comprehensive meta-analyses.

Even though we have tried to conduct this review comprehensively using the robust methodology, some limitations were identified. Due to the availability of fewer RCTs and more observational studies, the review has high heterogeneity in terms of the study design. We tried to overcome this by measuring the results after grouping studies with similar follow up periods, to reduce heterogeneity that is expected in systematic reviews. Since trimester-wise data are not available in the included studies, the suggested second-trimester versus third-trimester subgroup analysis could not be performed. Pregnancy and neonatal outcomes could not be incorporated in the meta-analysis due to insufficient data. Publication bias could not be concluded upon from the funnel plots due to less number of studies34.

We considered ferric derisomaltose, another formulation that allows the total dose infusion of intravenous iron with fewer incidents of hypophosphataemia, as an intervention in this review. Due to a lack of studies at the start of this review, it was not included. On reviewing the literature after the completion of our review, we found only two studies3536 meeting our inclusion criteria for anaemia in pregnancy published after the completion of our review. The study done by Hansen et al35 in 2023 had oral iron as the comparator. One woman (1%) in the iv iron group and three women (3.1%) in the oral iron group had hypophosphataemia at any time after baseline (P=0.62). No cases of severe hypophosphataemia were observed. The study done by Aggarwal et al36, was an observational study on ferric derisomaltose, with 50 pregnant women. In this study, 20 per cent of the participants experienced mild adverse drug reactions at the end of day 27.

Future trials should assess the blood transfusion requirement, pregnancy and neonatal outcomes in pregnant women treated with iv FCM to understand the clinical relevance of the improvement in haematological parameters. Further, a cost-effectiveness analysis of treatment using the iv FCM versus iv ISC, including the costs other than the price of the drug, will give a comprehensive insight. Studies assessing the cost-effectiveness of FCM are essential in understanding the role of FCM in policies addressing IDA in pregnancy. Hence, in the Indian context the findings of this review will contribute to the evidence base to support the national programme.