Ferric Carboxymaltose in the Management of Iron Deficiency Anemia in Pregnancy: A Subgroup Analysis of a Multicenter Real-World Study Involving 1191 Pregnant Women

Background Real-world evidence of the efficacy and safety of ferric carboxymaltose (FCM) infusion in Indian pregnant women with iron deficiency anemia (IDA) is lacking. Objective To assess the efficacy and safety of intravenous (IV) FCM in Indian pregnant women with IDA in 4 weeks in a real-life scenario. Methods This is a subgroup analysis of our previously conducted retrospective, multicenter, observational, real-world PROMISE study. Data on demographic and hematological parameters, patient-reported adverse events, and physicians' clinical impressions of efficacy and safety were analysed at 4 ± 1 week. Results This subgroup analysis included 1191 pregnant women in whom IV FCM resulted in a significant increase in hemoglobin (Hb) by 2.8 g/dL and serum ferritin by 30.03 μg/L at 4 weeks (P < 0.001 for both). In 103 pregnant women with severe IDA, there was a significant increase in Hb by 3.6 g/dL (P < 0.001), and serum ferritin by 16.96 μg/L (P=0.12). In 978 pregnant women with moderate IDA, significant improvement in Hb by 2.74 g/dL and serum ferritin by 33 μg/L (P < 0.001 for both) was noted. Similarly, there was a significant increase in red blood cell count, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin (P < 0.001 for all). In pregnant women with mild IDA (n = 26), Hb increased significantly by 1.99 g/dL (P < 0.001). Adverse effects were reported in 8.6% of pregnant women. No new safety signals or serious adverse effects were observed. Based on physicians' global assessment, good to very good efficacy and safety of IV FCM was noted in 99.2% and 98.6% of pregnant women, respectively. Conclusions IV FCM rapidly corrected anemia in a short period of 4 weeks with favorable safety in the second and third trimester of pregnancy with all severities of IDA (severe, moderate, and mild). The physicians' favorable global assessment of FCM's efficacy and safety in pregnant women with IDA supports its use in daily clinical practice. This trial is registered with CTRI/2021/12/039065.


Introduction
Anemia is a serious global health concern that commonly afects pregnant women [1]. Te World Health Organization (WHO) reported globally that 40% of pregnant women have anemia [1]. According to the World Bank data, 48% of pregnant women in South Asia and 50% of pregnant women in India had anemia in 2019 [2]. Te National Family Health Survey (NFHS-5; 2019-2020) data reported that 52.2% of Indian pregnant women have anemia [3]. Two recent studies from India reported anemia in 81.8% (91% had moderately severe anemia) [4] and 90% (60.5% had moderately severe anemia) [5] of pregnant women. Despite the availability of treatments and guidelines [6,7], minimal improvement is witnessed in the anemia status of pregnant women in India.
Iron defciency anemia (IDA) accounts for 75% of anemia cases in pregnancy [8]. Te iron defciency is more severe in pregnancy because of the increased iron demand [4,7]. Further, maternal iron demand increases in the second and third trimester of pregnancy as the majority of iron transfer to the fetus occurs during this period [7]. Maternal anemia also results in adverse maternal and neonatal outcomes, which are proportional to the increasing severity of anemia [9]. Anemia in pregnancy accounts for 20% of maternal and 18% of perinatal mortality in South Asian countries including India [10]. Terefore, prompt correction of anemia in pregnancy is needed, and this limits the use of oral iron preparations, especially in moderate to severe anemia [11].
Ferric carboxymaltose (FCM) is a third-generation parenteral iron formulation used for correcting IDA. Tere are many Indian [12][13][14][15][16][17][18][19][20] and international [21][22][23][24] clinical studies supporting the efcacy and safety of FCM in treating IDA in pregnancy. However, there is limited real-world evidence (RWE) [25][26][27][28][29] reporting the efcacy and safety of FCM in pregnancy and particularly in India. Many of these Indian studies are of small sample size and reported from a single center. RWEs are important because they substantiate the clinical trial evidence in real-world scenarios [30]. Te previously reported PROMISE study is a retrospective, observational, real-world study of 1800 patients with IDA that assessed the efcacy and safety of intravenous (IV) FCM in adolescents and adults with IDA [31]. Herewith, we represent the efcacy and safety of IV FCM for correcting anemia in a subgroup of 1191 pregnant Indian women with IDA.

Study Design, Subject, and Treatment Characteristics.
Tis is a subgroup analysis of a multi-center, retrospective, observational, data collection study (PROMISE) across 269 centers in India in a real-world scenario [31]. Pregnant women with IDA (hemoglobin (Hb) level between 4 and <12 g/dL), who provided informed consent for future use of their medical records for research and received IV FCM were included in the PROMISE study. Te following subjects were excluded from the PROMISE: anemia other than IDA; severe iron defciency with Hb < 4 g/dL; frst trimester pregnancy; known hypersensitivity to FCM or its excipients, or other IV iron products; malignancy; iron overload conditions (e.g. hemochromatosis/hemosiderosis); participant considered unsuitable by the investigator.
Te subgroup analysis was performed with data of pregnant women who received Injection FCM 500/1000 mg infusion (Orofer FCM, Emcure Pharmaceuticals Ltd., Pune, India; not exceeding 1000 mg iron per infusion) between January 1, 2021 and December 31, 2021 in real-life clinical practice. Te cumulative FCM dose for iron repletion was determined based on the subject's body weight and Hb level and is detailed in Table 1.

Outcome Measures and Statistical Analyses.
Available data on hematological parameters (Hb, serum ferritin, and so on) at baseline and/or at minimum of 4 ± 1 week (henceforth reported as 4 weeks) were anonymously captured from the subjects' medical records. Demographic and hematological parameters were analysed using descriptive statistical methods. Data were synthesized for the entire study population and by the severity of anemia. Quantitative data were described as the mean ± standard deviation (SD). Categorical data were represented as frequencies and percentages. A paired T-test was carried out to compare the hematological parameters at baseline and 4 weeks after FCM infusion.
Hb values ≥11 g/dL were considered normal as per WHO Hb cut-of values for anemia in pregnancy [32]. Anemia was categorized as mild, moderate, and severe based on the WHO's Hb cut-of values [32]: severe anemia (Hb < 7 g/dL); moderate anemia (Hb 7 to 9.9 g/dL); and mild anemia (Hb 10-10.9 g/dL).
Efcacy was assessed based on the hematological improvement seen and safety was assessed based on the occurrence of adverse events throughout the study duration. Physicians' global assessment of the efcacy and safety of FCM in their subjects were graded as very good, good, average, or poor.

Baseline Characteristics.
Data of 1191 pregnant women was included in this subanalysis; the mean age was 30.33 years (range 19 to 48 years); with a mean Hb of 8.03 g/ dL and a mean serum ferritin at 40.06 μg/L. Other demographic and hematological parameters at baseline are shown in (Table 2). Te mean weeks of gestation were 28.3 weeks. Te mean cumulative FCM dose was 1027 mg, and the average FCM infusion time was 18.10 minutes. Hypertension, diabetes, hookworm infestation, and kidney disease were seen in a small percentage of the study population (Table 2).

Obstetrics and Gynecology International
In pregnant women with severe IDA (n � 103), a signifcant increase in Hb by 3.6 g/dL at 4 weeks was noted (P < 0.001). Te serum ferritin increased by 16.96 μg/L (P � 0.12). A signifcant increase in RBC count and MCH at 4 weeks (P < 0.001 for both) was also noted. MCHC MCV, and hematocrit improved at 4 weeks as compared to baseline (MCHC: P � 0.47, MCV: P � 0.086, and hematocrit: P � 0.735) ( Table 4).
A signifcant rise in Hb by 2.74 g/dL and serum ferritin by 33 μg/L was noted in pregnant women with moderate IDA (n � 978), (P < 0.001 for both) (Table 4); similarly, there was a signifcant increase in RBC count, hematocrit, MCV, and MCH (P < 0.001 for all). Te improvement in MCHC at 4 weeks was noted (P � 0.179).

Physician Reported
Outcomes. Good to very good efcacy of FCM was noted in 99.2% of pregnant women. Poor response was noted in none of pregnant women (Figure 1). Good to very good safety was reported in 98.6% of pregnant women. None of the pregnant women reported poor tolerability (Figure 1).

Discussion
Te NFHS-5 (2019-2020) data showed that anemia is prevalent in more than half (52.2%) of all Indian pregnant women [3]. IDA accounts for 75% of anemia cases in pregnancy [8]. Tus, anemia is a signifcant health concern in pregnancy in India. Further, maternal iron demand increases in the second and third trimester of pregnancy as the majority of iron transfer to the fetus occurs during this period [7]. Tus, the average daily iron requirement of a pregnant woman increases from 0.8 mg/day in the frst trimester to 7.5 mg/day in the third trimester [33]. Tus, the iron defciency becomes more severe in pregnancy because of the increased iron demand [4,7].
Te present subgroup analysis showed that pregnant women (n � 1191; 62.2%) comprised a signifcant proportion of IV FCM-treated PROMISE study subjects with IDA (N � 1800). Additionally, moderate (59.3% to 91%), moderate-to-severe (60.5%), and severe anemia (8.8% to 13.1%) are common in Indian pregnant women [4,5,20,33]. In line with this previously reported data from India, our study also showed that 82.1% of the included pregnant women had moderate anemia and 8.6% had severe anemia. Terefore, it can be inferred that moderate to severe anemia continues to be a signifcant health concern during the second and third trimester in pregnant women in India.
If not corrected promptly, maternal anemia signifcantly impacts perinatal, neonatal and maternal outcomes, conferring a signifcantly higher risk of perinatal mortality, preterm birth, low birth weight, neonatal, and maternal morbidity and mortality compared to pregnant women without anemia [10,34]. Tus, timely diagnosis and management of anemia in pregnancy are crucial for preventing adverse outcomes [11]. However, a major problem noted in India is that women often present for their frst antenatal visit in the second or third trimester [5]. Tus, anemia is diagnosed late, thereby increasing the risk of adverse maternal and neonatal outcomes. Hence, there is an urgent need to restore iron stores and correct the anemia quickly to prevent these adverse maternal and neonatal outcomes. Tis need can be adequately fulflled with parenteral iron therapy and the parenteral iron used in pregnancy should be fastacting, must not cross the placenta, and have the properties  .05, non-signifcant diference. %-percentage; μg/L-micrograms per liter; fL-femtoliters; g/ dL-grams per deciliter; MCH-mean corpuscular hemoglobin; MCHC-mean corpuscular hemoglobin concentration; MCV-mean corpuscular volume; mn/ mm3-million per millimeter cube; N-number of participants; pg-picograms; RBC-red blood cell; SD-standard deviation. Note: 4 weeks is 4 ± 1 week. 0.05 ± 4.88 NS * P value <0.001, statistically signifcant diference; NS-P value >0.05, nonsignifcant diference. %-percentage; μg/L-micrograms per liter; fL-femtoliters; g/ dL-grams per deciliter; MCH-mean corpuscular hemoglobin; MCHC-mean corpuscular hemoglobin concentration; MCV-mean corpuscular volume; mn/ mm3-million per millimeter cube; N-number of participants; pg-pictograms; RBC-red blood cell; SD-standard deviation. Note: 4 weeks is 4 ± 1 week. that allow large doses to be administered safely in the second and third trimester of pregnancy [7,11]. FCM matches all these properties of ideal parenteral iron, and therefore is a good therapeutic option for rapid correction of anemia during pregnancy [11].
In this context, a diferent recently published real-world study involving pregnant women from India reported that IV FCM signifcantly and rapidly improved Hb levels by 4.23 g/dL in severe IDA at 4 weeks (P < 0.001) [25]. Te signifcant increase in Hb was seen as early as day 20 after IV FCM (P < 0.001). Also, IV FCM resulted in a signifcant improvement in Hb in pregnant women who received FCM after 34 weeks of gestation (P � 0.002) [25]. Similarly, the present study highlighted that within a short span of 4 weeks, IV FCM signifcantly increased Hb by 3.6 g/dL in pregnant women with severe anemia and a signifcant rise in Hb by 2.74 g/dL and serum ferritin by 33 μg/L in pregnant women with moderate IDA (P < 0.001 for all).
Despite a good clinical profle in pregnancy, there are very limited RWE studies [25][26][27][28][29] substantiating the efcacy and safety of FCM for managing IDA during pregnancy. Te REGAIN retrospective study (N � 1001) showed that the there was a direct relationship between the FCM dose and increase in Hb levels [26]. Te majority of study participants (70.3%) received 1000 mg of FCM, and this resulted in an increase of Hb by ≥2 g/dL in 39.2% of pregnant women on this dose [26]. Te present subgroup analysis of the PROMISE study showed that large doses of FCM (1000 mg) administered as a single infusion resulted in rapid improvement in Hb, iron stores, and other hematological parameters within 4 weeks of FCM infusion.
Compared to other parenteral iron preparations, FCM has an excellent safety profle in pregnancy [25], with no [14] or minimal mild adverse efects reported by fewer patients [12,15,16,23,24]. Te most common adverse efects reported, usually after ≥2 FCM doses are headache, mild local reaction, nausea, dizziness, abdominal pain, constipation, and fever and chills [12,15,16,23,24]. Te present subgroup analysis also reported minimal adverse efects in 8.6% of study population which is in line with the published data. No new safety signals were noted, and no SAEs were reported in this study. Tus, the present analysis demonstrated that FCM is a safe treatment option for correcting IDA in pregnant women in real-life setting in resource-limited settings.
Te study is limited by its retrospective design, missing data, and the fact that few subjects received two FCM 500 mg infusions instead of a single 1000 mg infusion. However, to the best of our knowledge, this is the largest real-world study (N � 1191) in pregnant women with IDA demonstrating the efcacy and safety of FCM in real-life management scenarios. Also, though health-related quality of life improvement after FCM administration is often reported [23,24], literature on physicians' assessment of the efcacy and safety of FCM is lacking. Te present study highlights the excellent efcacy and safety of FCM based on physicians' reported global assessment. Good to very good efcacy and safety were noted in 99.2% and 98.6% of pregnant women, respectively.

Conclusions
Te present large real-world evidence supports clinical place of IV FCM in management of IDA in pregnant women. Rapid and signifcant improvement in hematological parameters with favorable tolerability was noted in a large cohort of 1191 pregnant women with IDA. In a resourcelimited setting, single-dose administration, a rapid improvement of hematological parameters with favorable tolerability makes FCM as the best-suited option for the management of moderate-to-severe IDA during pregnancy [35].

Data Availability
It will be provided on request.

Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Tis PROMISE study was approved by the Ripon Independent Ethics Committee and registered with the Clinical Trial Registry of India (CTRI) (registration number: https://clinicaltrials.gov/ct2/show/ CTRI/2021/12/039065).

Conflicts of Interest
Dr. Ajinkya Rodge and Dr. Onkar C Swami are full time employees of Emcure Pharmaceuticals Ltd, which actively markets Ferric Carboxymaltose.