Anemia, defined as a low blood hemoglobin concentration is one of the major public health problem[1]. According to WHO, 32.4 million pregnant women suffer from anemia worldwide. WHO defines anemia in pregnancy as hemoglobin concentration less than 11g/dL[2]. According to ICMR, anemia is categorized as mild (hemoglobin 10 - 10.9 g/dL), moderate (hemoglobin 7 - 9.9 g/dL), severe (hemoglobin 4 - 6.9 g/dL) and very severe (hemoglobin < 4 g/dL)[3].

Iron deficiency anemia during pregnancy is associated with an increased risk of low birth weight, preterm birth, maternal and perinatal mortality and poor Apgar score[4,5]. Furthermore, iron deficiency anemia in pregnancy may predispose to postpartum iron deficiency anemia[6].

Intravenous ferric carboxymaltose (FCM) is a parenteral dextran free iron. FCM comprises a macromolecular iron hydroxide complex of polynuclear iron (III) hydroxide in a carbohydrate shell. FCM has a molecular weight of around 150,000 daltons. In FCM, iron hydroxide is tightly bound within a carbohydrate shell which causes gradual release of iron in the body, thus avoiding acute toxicity and allowing large amounts of iron to be delivered. This results in a wider therapeutic window. Whereas incase of less stable complexes, there is rapid release of iron which causes high level of transferrin saturation and increase in non-transferrin bound iron (NTBI) which is toxic to the body[7]. 

FCM has better safety and tolerability compared to other parenteral iron. This is because FCM does not cross react with dextran antibodies and does not provoke oxidative stress reactions⁷. FCM does not cross placental barrier in an in vitro dual perfusion model[8]. The highest non-lethal dose of FCM was at least 5 times higher than that for iron sucrose. 1000 mg dose of FCM can be administered safely over 15 minutes.

The present study was aimed to evaluate the efficacy and safety of ferric carboxymaltose in treatment of iron deficiency anemia in pregnancy.

AIMS AND OBJECTIVES:

To assess the efficacy and safety of intravenous ferric carboxymaltose in the treatment of iron deficiency anemia in pregnancy.

This study was carried out in the Department of Obstetrics and Gynecology, Kamla Nehru State Hospital for Mother and Child, Indira Gandhi Medical College, after approval from hospital ethical committee, from 1^st June 2019 to 31^st May 2020 for a period of one year.

Study Design: Prospective study.

Study Population: The study included 43 antenatal women with iron deficiency anemia.

Inclusion Criteria:

Gestational age 12 to 36 weeks 

Hemoglobin 7 – 9.9 g/dl 

Microcytic hypochromic anemia on peripheral blood smear 

Exclusion Criteria:

Gestational age < 12 weeks or > 36 weeks

Prior history of blood transfusion

Anemia not caused by iron deficiency 

History of disease associated with iron overload (thalassemia, hemochromatosis).

Known hypersensitivity to parenteral iron

Chronic renal / hepatic or cardiovascular disease

Not consenting

This was a hospital based prospective study. Enrolled women after fulfilling the inclusion and exclusion criteria were given intravenous FCM in single dose of 1000 mg intravenous FCM. 1000 mg FCM was diluted in 250 ml of normal saline and was transfused over a period of 30 minutes.

Demographic data like age, educational qualification, socioeconomic status were recorded. Detailed menstrual, obstetrics and dietary history was taken from all the subjects. 

Parameters used for the diagnosis of iron deficiency anemia were:

• Complete blood count ­­-

  • Hemoglobin 

  • Packed cell volume 

• Peripheral blood smear with reticulocyte count

• Serum iron 

• Serum ferritin 

• Total iron binding capacity

These investigations were done prior to infusion and at 2 and 4 weeks post infusion.

All the subjects included in the study were administered antihelminthic therapy with tablet albendazole 400mg first dose followed by repeat dose after 14 days.

The general condition of the patient, blood pressure and pulse rate was examined every 5 minutes during transfusion and fetal heart rate was checked before and after transfusion. Patients were observed for adverse reactions for 4 hours post infusion.

Outcomes were assessed by measuring complete blood count including hemoglobin and packed cell volume, peripheral blood smear along with reticulocyte count, serum iron, serum ferritin and total iron binding capacity values 2 and 4 weeks post infusion.

The rise in these parameters were assessed at 2 and 4 weeks post infusion. These outcome parameters were also compared at 4 weeks with respect to the baseline estimates.

Complete blood count measurements were done by an automated blood analyser machine, model MS^TM 39S.

For performing peripheral smear, blood slides were stained with Giemsa stain. The stock solution of giemsa stain was prepared by mixing 0.15g of giemsa powder in 12.5ml of glycerine and 12.5 ml of methyl alcohol. Before use one volume of stock solution was dissolved in nine volume of buffered water (1:9). The blood smears were fixed with methanol for 2-5 minutes. The fixed films were then transferred to jars containing giemsa stain and allowed to stand for 7-15 minutes after which the slides were washed and air dried and examined under oil emersion lens of microscope.

For measuring reticulocyte count, staining was done with brilliant cresyl blue followed by examination under 100X magnification of objective lens.

Measurement of serum iron was done by TPTZ-NO DEPROTEINIZATION method.

Measurement of serum ferritin was done by Chemiluminescent Microarticle Immunoassay (CMIA).

Statistical Analysis:

Data was entered in Microsoft Excel spreadsheet and analysed using Epi Info Software version 7.2.2 Descriptive statistics were presented as proportions and their 95% confidence interval for qualitative variables whereas for quantitative variables means and their standard deviation were calculated. Sudent’s T- test was used for comparison of change in variables. A two sided p value <0.005 was considered statistically significant.

A prospective study to evaluate the efficacy and safety of ferric carboxymaltose in the treatment of iron deficiency anemia in pregnancy was conducted in the Department Of Obstetrics and Gynaecology, Kamla Nehru State Hospital For Mother And Child (KNSH for M&C), Shimla, Himachal Pradesh with effect from (w.e.f.). 1^st June 2019 to 31^st May 2020.

In our study 43 antenatal women fulfilling the inclusion criteria were taken and given single dose of intravenous ferric carboxymaltose.

Table 1: Distribution according to Age and Socio Economic Status

In our study, there were 2 participants in 18 - 20 years of age group, 21 participants in 21 - 25 age group, 15 participants in 26 - 30 age group and 5 participants in 31 - 35 age group.It was observed that maximum subjects were in the age group of 21-25 years. 

According to distribution of subjects according to socioeconomic status calculated by modified Kuppuswamy scale 2019, in our study, only 1 participant belonged to class I, 3 participants belonged to class II, 32 participants belonged to class III, 6 participants belonged to class IV while 1 participant belonged to class V. It was observed that maximum subjects belonged to class III (lower middle class) according to modified Kuppuswamy scale (74.4%).

Table 2: Distribution according to POG, Parity and BMI

In our study, 9 participants were in the period of gestation between 21 to 25+6 weeks, 18 participants between 26 to 30+6 weeks and 16 participants between 31 to 36 weeks. So, maximum 41.9% of the subjects were between the period of gestation 26 to 30+6 weeks. In our study, 65.1% belonged to multigravida and 34.9% belonged to primigravida. All the subjects in our study were having normal BMI (between 18.5 - 24.9 kg/ m²). 

Table-3 shows that all the subjects received a single dose of 1000 mg FCM.

Table 3: Dose of FCM

The mean value of baseline hemoglobin, reticulocyte count, packed cell volume, serum iron, serum ferritin and total iron binding capacity was found to be 8.33 g/dL, 0.77 %, 25.6 %, 35.94 ug/dL, 10.298 ng/mL, and 491.85 ug/mL respectively. The mean value of hemoglobin, reticulocyte count, packed cell volume, serum iron, serum ferritin and total iron binding capacity at two weeks post infusion was found to be 10.48 g/dL , 2.88%, 33.64%, 114.67 ug/dL, 135.3 ng/dL and 387.48 ug/dL respectively. The mean value of hemoglobin, reticulocyte count, packed cell volume, serum iron, serum ferritin and total iron binding capacity at four weeks was found to be 11.428 g/dL, 2.965%, 45.128%, 137.95 ug/dL, 107.072 ng/dL and 335.88 ug/dL respectively.

Table 4: Comparison of variables at baseline, 2 weeks and 4 weeks

These variables were compared at four weeks with respect to the baseline estimates. There was a very strong evidence against null hypothesis and there was significant difference in all the parameters at four weeks (p<0.001).

Table 5: Difference in the variables from baseline to 4 weeks

Out of 43 subjects, only 2 subjects (4.7%) developed local adverse effects in the form of pain at injection site. There were no systemic adverse effects observed among patients. 

Table 6: Distribution of Side Effects

Iron deficiency is the most common cause of anemia in pregnancy. Iron requirement during pregnancy is increased due to increased demands of growing fetus and expansion of maternal blood volume. Iron deficiency anemia is associated with significant risk of maternal and fetal morbidity. Intravenous iron preparations provide a rapid response with lesser side effects as compared to oral iron. Intravenous ferric carboxymaltose is dextran free iron preparation commonly used for the treatment of iron deficiency anemia in pregnancy and postpartum iron deficiency anemia.

The present study was conducted with the objective of evaluating ferric carboxymaltose in regards to their efficacy and safety in pregnancy. 

In the present study maximum subjects were in age group 21 - 25 years. Similar distribution of age was reported [9,10] 

In the present study 65.1% women were multigravida. [11,12] also showed that iron deficiency anemia is more common in multigravida. Less inter pregnancy interval leading to depleted iron stores, poor nutrition due to economical burden can be factors contributing to higher prevalence of iron deficiency anemia among multigravida.

In our study maximum subjects belonged to lower middle class according to modified Kuppuswamy scale. Our study is consistent with the study done [11,13] observed higher prevalence of iron deficiency anemia in lower socioeconomic class. Therefore our study also suggests that lower socioeconomic status is a predisposing factor for the development of iron deficiency anemia.

Antenatal women with moderate anemia were included in our study. The baseline hemoglobin was 8.33 g/dL in subjects. [14] also included subjects with moderate anemia and the baseline hemoglobin was 8.7 g/dL. [15] included subjects with severe anemia and the mean value of baseline hemoglobin was 7.8 g/dL.

In the present study the subjects after treatment with intravenous ferric carboxymaltose were followed up at 2 and 4 weeks. At 2 weeks post infusion the mean hemoglobin was 10.48 g/dL. Mean hemoglobin at 4 weeks was 11.42 g/dL. The change in hemoglobin at 2 and 4 weeks was statistically significant (p value < 0.001). In study conducted [11] the subjects when followed up at 2 weeks showed statistically significant increase in hemoglobin. Similar observations were made at 4 weeks of follow up in hemoglobin which was higher and was found to be statistically significant (p value <0.001). [16] also reported a significant rise in hemoglobin at 2 and 4 weeks of treatment with ferric carboxymaltose. Whereas [15] followed up patients at 4 weeks only and found a significant rise in hemoglobin levels in subjects treated with ferric carboxymaltose.

The earliest response to treatment incase of iron deficiency anemia is reticulocytosis. [17] observed a rise in reticulocyte count by fifth day post intravenous iron transfusion. In our study patients also had reticulocytosis on treatment follow up.

In the stage of iron deficient erythropoiesis, there is fall in hemoglobin levels with low serum iron and serum ferritin but at this stage packed cell volume remains unchanged. The stage of iron deficiency anemia is associated with a fall in packed cell volume.

All the subjects in our study had decreased levels of packed cell volume (25.6 %) . The rise in PCV at 4 weeks from the baseline was 11.4%. Similar observations were made [18] who showed rise in packed cell volume . [19]  also reported a significant rise in PCV While in comparison to these studies, our study observed a higher rise in packed cell volume in subjects treated with ferric carboxymaltose (11.4% in the present study versus 6.57% [18,19]

Over 90% of iron deficiency anemia is associated with depleted iron stores. Insufficient supply of iron causes inability to sustain a normal hemoglobin concentration, therefore iron deficiency anemia develops. In our study all the subjects had low serum iron before the start of treatment and baseline value of serum iron was 35.9 ug/dL. The rise in serum iron at 4 weeks was 102.01 ug/dL. Whereas [15] followed up patients at 4 weeks only and documented a significant rise in serum iron in subjects treated with ferric carboxymaltose. 

Body iron stores are determined by serum ferritin levels. Serum ferritin levels < 12 ng/mL is diagnostic of iron deficiency anemia. In the present study baseline value of serum ferritin was 10.2 ng/mL. The rise in serum ferritin at 4 weeks was 96.7 ng/mL. [12] observed a significant rise in serum ferritin. [11] also reported a significant rise in serum ferritin. However [20] followed up patients up to 12 weeks post infusion and found that ferric carboxymaltose produced similar replenishment of iron stores. Our study also showed that ferric carboxymaltose provides better replenishment of iron stores.

Iron deficiency anemia is characterized by increase in total iron binding capacity. In the present study, on follow up at 4 weeks the fall in TIBC was 155.97 ug/dL. [15] reported a statistically significant fall in TIBC in subjects treated with ferric carboxymaltose. Whereas [20] followed up patients at 3 weeks post infusion and found non-significant fall in TIBC.

Safety of iron preparation was assessed by observation of local and systemic adverse effects following infusion. In the present study out of 43 subjects, 4.7% developed local adverse reactions and none of the subjects developed systemic reactions. [9] reported no adverse effects in FCM group. [13] reported local adverse reactions in 6% of patients in FCM group but there were no systemic adverse reactions. Similarly [21] reported similar safety profile in FCM group. 

Parenteral iron preparations like ferric carboxymaltose is preferred in subjects who experience side effects after oral iron treatment, are non-compliant to oral iron or due to malabsorption .Single dose of ferric carboxymaltose offers considerable benefits in terms of safety and replenishment of iron stores in a short duration of time. The present study concluded that intravenous ferric carboxymaltose is efficacious in replenishment of iron storesss and improvement of hemoglobin levels and has better safety profile.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Kamla Nehru Hospital, IGMC, Shimla, (H. P.), India

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