Efficacy and safety of ferric carboxymaltose for the management of iron deficiency anemia in women

INTRODUCTION

Iron deficiency remains the most common nutritional deficiency across the world with about 1 in four people suffering from anemia.¹ Globally, 1.5 billion people worldwide, and 52% of pregnant women in developing countries are anemic.² The 2019–2021 National Family Health Survey-5 data from India reported that 57.0% of reproductive-age women, and 52.2% of pregnant women in India were anemic.¹ Almost 50% of the burden of anemia is contributed by iron deficiency anemia.¹ The World Health Organization (WHO) defines iron deficiency anemia (IDA) as hemoglobin <12.0 g/dl in women who are not pregnant and <11.0 g/dl in women who are pregnant (WHO; IDA presents as hemoglobin concentration (Hb≥8 and <12 g/dl), serum ferritin (<30 µg/l), transferrin saturation <20%, red blood cell (RBC) mean corpuscular volume (MCV<80 fl), and RBC mean corpuscular hemoglobin (MCH<27 pg).³

The causes of iron deficiency anemia in Indian women include poor nutrition, pregnancy, menstruation, dysfunctional uterine bleeding, malaria, infestations and chronic infections.

Iron deficiency anemia spans across the life of a female. In the neonatal period, if the mother is anemic, the neonate would also be anemic.⁴ In adolescence and reproductive age group, menstruation and nutritional deficits contribute to IDA. About 20% of women suffer excessive menstrual blood loss.⁵ In pregnancy, multiparity which is common in India leads to IDA.⁴

Several reasons have been cited for IDA in Indian women such as nutritional deficiency, poor intake of iron rich food stuff, worm infestations, repeated pregnancies in a short interval of time, absence of replenishing of the iron stores lost due to menstrual loss.⁶

Data from Indian Council of Medical Research (ICMR), National Nutrition Monitoring Bureau (NNMB) and District Level Household Survey (DLHS) have shown that prevalence of anemia is extremely high (ranging between 80% and 90%) in adolescent girls, preschool children, pregnant and lactating women.⁴ Postpartum anemia reportedly affects up to 27% of women.⁷

Consequences of IDA

Iron deficiency (ID) and IDA may lead to adverse pregnancy and fetal outcomes.¹ Iron deficiency is associated with fatigue, restless legs syndrome (RLS), reduced work productivity, impaired quality of life, impaired cognitive function, and infertility.³ Frequent infections, preterm labor, fetal growth restriction (FGR), post-partum hemorrhage, cardiac failure and puerperal sepsis have been found frequently in women who were anemic during antenatal period.⁴

Consequences of IDA during pregnancy

Pregnancy is associated with an increased demand for iron throughout pregnancy. Iron requirement during pregnancy is about 4–6 mg/day. ID and IDA are linked to increased risks of thyroid dysfunction, preterm labor, placental abruption, pre‐eclampsia, eclampsia, cesarean delivery, postpartum anemia and need for blood transfusion, postpartum depression and fatigue.⁸ A significant prolongation of total hospital stays and ICU stay have also been observed in pregnant women with IDA.

The adverse fetal outcomes include stillbirths, low birth weights, and small-for-gestational-age (SGA) babies. The adverse outcomes in children include increased rates of stunting; impairment in both short-term and long- term brain development (brain growth, myelination, neurotransmitters, and brain programming), including significant (likely non-reversible) motor and neurocognitive changes; anxiety and depression; and an increased risk of autism spectrum disorder.^1,9

Objectives

The objective of this study was to assess the efficacy of the IV iron formulations, ferric carboxymaltose for the management of IDA in women, especially during pregnancy in the real-world setting.

METHODS

This systematic review was performed using the PRISMA method using PubMed, Web of science, google scholar databases and WHO and CDC recommendations. 362 records were screened and 226 records were retrieved. 106 records were excluded due to no access to full text of the papers. The search words included iron deficiency anemia, women, pregnancy, dysfunctional uterine bleeding, oral iron, parenteral iron, ferric carboxymaltose, iron sucrose and iron dextran. Case report and non-randomized studies were excluded.

Management of IDA

Iron therapy for IDA has been shown to reduce morbidity by improving physical activity and reducing fatigue and cognitive deficits.^3,7,10 Iron therapy can be administered orally or parenterally.^3,5,11 Globally, oral iron has been the first line of treatment and standard of care to address the prevention and treatment of anemia in pregnancy.^3,5,11

Oral iron therapy and parenteral iron therapy

Healthy females absorb 5.6% of iron in diet. The maximum rate of absorption of 100 mg of oral iron is 20% to 25% and is reached only in the late stage of iron deficiency. In latent iron deficiency and iron deficiency anemia, the mean absorption rates of iron are 10% and 13%, respectively.³

Oral iron is readily available, inexpensive, and convenient, making it a commonly used treatment option.³ However, the use of oral iron must be limited to patients with mild anemia (Hb 11.0-11.9 g/dl in non-pregnant women) because repletion occurs slowly.³ The Hb level should increase by 2 g/dl within 4 to 8 weeks. Depending on the severity of the deficiency and underlying cause, normalization of the Hb level may take up to 3 months, and it may take longer to replace iron stores (ferritin >100 µg/l).³

Oral iron can often lead to gastrointestinal side effects, such as nausea, diarrhea or vomiting, that can adversely impact patient adherence to treatment and, ultimately, the efficacy of the iron treatment.

The efficacy of oral iron is diminished when uptake through the gut is impaired or when iron losses are large and/or continuous (e.g., menorrhagia, gastrointestinal bleeding, or post-surgery). Dose-dependent gastrointestinal side effects hinder compliance and result in poor patient compliance in up to 50% of patients.³

Parenteral iron therapy

For patients who are diagnosed with IDA during 2nd or 3rd trimesters, intravenous iron replacement therapy (IRT) is recommended.⁸ Compared to oral iron, pregnant women treated with IV iron have consistently shown a more rapid and robust response in raising and maintaining hemoglobin concentrations and ferritin during pregnancy and after delivery. Parenteral iron administration is also preferred for patients who are unable to tolerate oral iron therapy, or are unresponsive to oral iron treatment and for patients who are unable to absorb sufficient iron in the gastrointestinal tract or for whom blood transfusions should be avoided.^3,11 Four to six weeks after IRT initiation, testing for serum ferritin is recommended.⁸

The commonly used parenteral iron formulations include ferric carboxymaltose (FCM), iron sucrose and iron dextran.³

Ferric carboxy maltose

FCM is a type I polynuclear iron (III)-hydroxide carbohydrate complex. It produces a slow and controlled delivery of the complexed iron to endogenous iron binding sites.^12,13

Iron supplied as FCM is quickly distributed to different tissues, such as the bone marrow, liver, and spleen, the volume of distribution being approximately 3 l. Following the administration of an i.v. dose of FCM, the level of total serum iron is reduced between 24 hours and 72 hours. Serum ferritin increases in a dose dependent manner within 48–120 hours post FCM dose, with maximum levels of a 23–210-fold increase above baseline level.¹³

In randomized trials in pregnant women with IDA, postpartum women with anemia and women with heavy menstrual bleeding, treatment with FCM significantly improved hemoglobin levels compared with oral iron treatment (Tables 2-4).^14,15

Special features of FCM observed in clinical trials

In the study by Breymann et al, 252 pregnant women (gestational weeks 16–33) with IDA were randomized 1:1 to FCM (1000–1500 mg iron) or FS (200 mg iron/day) for 12 weeks.19 Pregnant women treated with FCM were twice as likely to achieve anemia correction (Hb≥11.0 g/dl) than those treated with FS (84% versus 70%) and the median time to achieving this correction was shorter with FCM treatment (3.4 versus 4.3 weeks) (Figure 2).

Significantly greater increase in serum ferritin levels with FCM treatment compared with FS were observed (Figure 3). During late-stage pregnancy, FCM may be a more appropriate option than first-line oral iron for rapid and effective anaemia correction (Table 5).¹⁹

FCM had a dramatically reduced burden of treatment: comparable improvements in Hb levels were achieved with a 12-fold lower total dose and a 12-fold lower duration of exposure to FCM compared with FS. This improved patient compliance to treatment.¹⁹

FCM has been compared with other Parenteral iron formulations and has been found to have better efficacy and tolerability features (Tables 6 and 7).

DISCUSSION

Oral iron is readily available, inexpensive, and convenient treatment option to treat iron deficiency anemia. The limitations of oral iron formulations when used to treat iron deficiency anemia include slow rise of hemoglobin and gastrointestinal adverse effects which can adversely affect patient adherence to treatment.³ In women who are diagnosed with IDA during 2nd or 3rd trimester, intravenous IRT is recommended.⁸ FCM is a parenteral iron formulation that produces a slow and controlled delivery of the complexed iron to endogenous iron binding sites.^12,13 FCM is an i.v. iron formulation which can be used at high doses and allows rapid administration (up to 1000 mg in a single dose infused in 15 min). Since FCM is a dextran-free, it does not react with dextran antibodies, thus resulting in a lower risk for hypersensitivity reactions.³⁶ Clinical trials have proven the efficacy of FCM in significantly improving hemoglobin levels compared with oral iron treatment.^14,15 FCM provides better improvement in quality of life as compared to Iron sucrose.²⁸ Compliance is better with FCM as compared to IS because of lesser number of total doses hence less number of needle pricks and reduced number of visits to hospital translating to better patient compliance to treatment.³¹

Limitations

This a review paper based on published studies.

CONCLUSION

IDA has been proved to be associated with increased morbidity and mortality in pregnancy and post-partum period. Over the past few decades’ oral iron supplementation has been utilized as the standard of care in treating and preventing ID and IDA. But the results of oral iron supplementation in pregnant women with moderate to severe iron deficiency are often suboptimal due to limited intestinal absorption and poor patient adherence to treatment. Parenteral iron supplements are associated with faster normalization of iron in pregnant women and also overcomes the drawbacks of oral iron supplements. Amongst the IV iron formulations, FCM is associated with robust and rapid increase in iron and improved outcomes of pregnancy in women with IDA. Another important benefit of FCM is the better tolerability profile as compared to other parenteral iron formulations. FCM is an i.v. iron formulation which can be used at high doses and allows rapid administration (up to 1000 mg in a single dose infused in 15 min). Since FCM is a dextran-free, it does not react with dextran antibodies, thus resulting in a lower risk for hypersensitivity reactions. The novel iron formulation FCM has a better potential for restoring the iron stores. It reduces the dosage frequency which is the chief drawback of parenteral preparations and there is minimal drug related adverse effects. Hence, FCM can be the drug of choice for the management of iron deficiency anemia in women, especially during pregnancy when rapid and robust increase in iron is required.

ACKNOWLEDGEMENTS

The authors thank Clinical Medicine Informatics India, for providing medical writing and editorial assistance. The views expressed and discussed in the meetings and stated in this article are the independent views of the authors and not of Abbott India Ltd.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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