Efficacy and safety of ferric carboxymaltose versus ferrous sulfate for iron deficiency anemia during pregnancy: subgroup analysis of Korean women

According to worldwide estimates, 30% of women of reproductive age are anemic and at least half of these cases are attributed to iron deficiency (ID) [1–3]. The prevalence of anemia is 14–52% in women without iron supplementation and 25% even with supplementation, depending on iron dosage [4]. Throughout pregnancy, total iron requirements increase to meet the major hematologic changes of the mother and the increasing demands of the growing fetus [5]. This increased demand for iron puts the mother and offspring at risk of developing iron-deficiency anemia (IDA). IDA during pregnancy is associated with an increased risk of preterm birth, low birthweight, fetal growth restriction, and increased newborn and maternal mortality. Furthermore, ID may predispose a person to postpartum IDA, peripartum blood transfusion, infections, and precipitate heart failure [6].

IDA during pregnancy is often treated with oral iron supplement. However, due to gastrointestinal side effects such as nausea, vomiting, and constipation, compliance is often poor and results in subsequent discontinuation [4, 7]. As such, intravenous iron administration are increasingly being recommended for women who are non-compliant with oral iron, have severe IDA, or those who require rapid intervention [6, 8]. Ferric carboxymaltose (FCM; Ferinject^®) is a dextran-free parenteral iron preparation that allows rapid administration of weekly high single doses of iron and had been approved for the treatment of IDA by the UK Medicines and Healthcare products Regulatory Agency in 2007, US Food and Drug Administration (FDA) in 2013, and Korea FDA in 2010.

In the FER-ASAP (FERrric carboxymaltose-Assessment of SAfety and efficacy in Pregnancy) study, pregnant women (gestational weeks 16–33) with IDA were randomized in a 1:1 ratio to FCM or ferrous sulfate (FS) for 12 weeks [9]. Hemoglobin (Hb) levels improved at comparable rates in both treatments; however, significantly higher number of women achieved anemia correction within a shorter time frame with FCM (84%) than with FS (70%; P = 0.031). FCM treatment significantly improved the quality of life (QoL) from baseline up to delivery, and there were markedly fewer gastrointestinal treatment-related adverse events (AEs) with FCM (11%) than with FS (15%).

Geographic variations in anemia prevalence are attributed to differences in iron nutrition and socioeconomic status; however, variations in the tolerability profile of FCM between populations (according to race) have not been investigated. Approximately 40% of the women randomized and treated in the FER-ASAP study were from Korea, where the prevalence of IDA during pregnancy is reported as 15–25% [10]. Notably, total fertility rate of Korea has continued to decrease, and is now one of the lowest in the world (1.05 in 2017). With the dramatically decreasing number of pregnant women in Korea, improving the health status of pregnant women is an ever-more important issue in terms of nation-wide investment in health, and the necessity to evaluate the various anemia treatment methods.

Therefore, we performed a post –hoc subgroup analysis of the efficacy and safety of FCM in pregnant Korean women who participated in the FER-ASAP study.

Results from this FER-ASAP subgroup analysis of pregnant Korean women with IDA during late stage pregnancy showed that Hb increases were greater after FCM treatment compared with FS treatment, although the difference was not statistically significant at week 3. Secondary iron parameter measurements including serum ferritin, TSAT, and serum transferrin receptor levels were significantly better in FCM, and more women were likely to achieve anemia correction with FCM as well. In terms of QoL, FCM treatment led to significant and clinically relevant improvements compared to FS in all three SF-36 components prior to delivery.

The FER-ASAP study was the largest prospective randomized study conducted in pregnant women with IDA, and its results showed that intravenous FCM was effective and well tolerated during late-stage pregnancy [9]. In our subgroup analysis, efficacy outcomes of FCM in Korean women were generally consistent with those observed in the overall study population. However, a few major differences were observed. For example, in the overall FER-ASAP population, significantly more women achieved anemia correction within a shorter timeframe with FCM treatment (P = 0.031); such difference in timeframe was not statistically significant in pregnant Korean subgroup (P = 0.304), which is probably due to the lack of sufficient statistical power. Both oral and intravenous iron were more efficacious for correcting IDA in pregnant Korean women (89.7%) than in non-pregnant Korean women (69.6%; P < 0.001), despite the mean treatment duration being similar (FCM, Korean 78.4 days vs non-Korean 79.8 days; FS, Korean 71.2 days vs non-Korean 74.7 days). One possible explanation for this phenomenon is that the pregnant Korean women enrolled in this study tended to have lower pre-pregnancy and baseline weight (mean 54 kg and 60 kg, respectively) than those of the non-Korean population (mean 60 kg and 68 kg, respectively), which may also explain the higher response rate in pregnant Korean women with similar treatment duration. In this study, FCM was administered at a conservative dose, with each single dose not exceeding 15 mg iron per kg of body weight, which is lower than the current recommended dose (20 mg iron per kg of body weight). The use of the lower FCM dose in our study may have impacted the outcomes and it should be considered that use of a higher dose in accordance with the current label may lead to greater efficacy [9].

In addition to improvements in hematological parameters, FCM provided a number of QoL benefits compared with FS. Mental, physical, and vitality components of the SF-36 questionnaire showed clinically significant improvements prior to delivery in the FCM group, which is expected to provide benefits in physical stress management during pregnancy and childbirth [9]. More QoL benefits were seen in the Korean subgroup compared with the overall FER-ASAP population—the overall FER-ASAP population only showed significant improvements in vitality components (P = 0.025), and not in mental and physical components. These improvements in QoL parameters are generally consistent with previous studies suggesting FCM use in patients with anemia [11, 12] and may be due to the dramatically reduced burden of FCM treatment (i.e., a 12-fold lower total dose and a 10-fold shorter duration of exposure compared with FS). This is important as a higher treatment burden could lead to a decrease in compliance and adherence and lead to subsequent worsening of disease and increased healthcare costs [13].

FCM was well tolerated in Korean women during late-stage pregnancy and the incidents of TEAEs for FCM and FS treatment were generally consistent with the safety profiles observed in the primary FER-ASAP trial [9]. However, compared with non-Korean population, the incidence rates of TEAEs were significantly higher in the Korean subgroup (61.8% in Korean group vs. 34.8% in non-Korean group, P < 0.001) although TRAEs were similar between Korean and non-Korean groups and the frequency of AEs leading to permanent discontinuation was lower in the Korean subgroup (2.2%) than in the non-Korean subgroup (3.8%). Higher incidence of TEAEs and not TRAEs could be due to the older mean age of Korean subjects. In line with previous reports, treatment with FCM led to fewer gastrointestinal AEs than with FS [11, 14, 15]: 8 out of 44 (18.2%) pregnant Korean women using FS experienced gastrointestinal disorders, whereas TRAEs of this clinical category occurred in only 2.2% of the FCM group (P = 0.01). Furthermore, gastrointestinal side effects caused permanent discontinuation in two Korean women treated with oral FS. This considerable decrease in stress related to gastrointestinal disorders may be valuable for increasing the overall QoL in the latter stages of pregnancy [13].

ID and IDA during pregnancy can be further aggravated by blood loss during delivery and subsequently lead to increased risk of peripartum blood transfusion and chronic IDA [6]. In Korea, the primary mode of treatment for IDA during pregnancy has been oral iron administration and red blood cell (RBC) transfusions. Oral iron is commonly used because it is inexpensive and moderately effective. However, as many previously published studies and our Korean subgroup analysis revealed, oral iron intake was associated with a considerable amount of gastrointestinal side effects [11, 14].

Blood transfusion is a substantial alternative; however, blood transfusion is also associated with substantial risks such as transfusion-related acute lung injury, microbial contamination, possibility of incorrect transfusions, acute hemolytic allergic transfusion, and febrile non-hemolytic transfusion reactions [16]. There are special considerations for blood transfusion in Korea: first, transfusion guidelines and patient blood management programs are not commonly implemented in Korea. Second, there are growing concerns in Korea over the potential decrease in blood donations and possible blood shortages due to reduced fertility rates and increased aging population. Lastly, under the current Korean healthcare system, blood product transfusion therapy is provided at a low cost—considering per capita gross domestic product and purchasing power parity, the RBC prices in Korea were estimated to be 30–40% of those of other countries [17]. Therefore, the optimal costing model must be ensured to decrease blood component transfusion and to find the alternative treatment modality with higher cost-effectiveness.

Intravenous iron supplementation may be a preferable alternative. To date, thousands of patients have been treated with FCM in various clinical trials and recovery of iron stores has been consistently reported [11, 14, 18–20]. In patients with more severe or prolonged IDA, anemia correction using FCM consistently resulted in clinically significant increases of Hb values. In addition to the correction of hematological parameters, intravenous FCM therapy led to significant improvements of QoL and functional status. Previous studies have also suggested that FCM is associated with cost savings in various chronic IDA conditions [21–23]. For example, iron repletion with FCM for IDA in chronic heart failure patients was shown to be cost-effective when compared with placebo in Korea [24]. Further evaluation regarding the cost-effectiveness of FCM during pregnancy may be required.

Interpretation of this study is subject to some limitations. First, this was an inherent open-label study, which may introduce bias especially in terms of self-reporting QoL parameters and AEs. However, previous randomized trials have also shown that FCM showed benefits such as decreasing AEs and improving QoL [9, 11, 20]. Second, this was not a pre-specified post-hoc subgroup analysis of the FER-ASAP trial and thus could be prone to selection bias. Third, the fact that this was a Korean subgroup analysis involving 40% of the primary FER-ASAP study population would also indicate insufficient power to draw definitive conclusions. Nonetheless, the demographics and characteristics of the Korean population were generally consistent with those of the overall FER-ASAP population and the outcomes observed in the Korean population were similar to those of the overall study population. Importantly, as 40% of the total FER-ASAP populations included were Korean women and considering the special circumstances in Korea, clinical experience will be essential for providing the safety profile between intravenous and oral iron supplement in pregnant Korean women.

FCM offered an efficacious and time-efficient correction of IDA in Korean women during late stages of pregnancy. Furthermore, clinically significant improvements in QoL and significantly decreased gastrointestinal side effects were observed in the Korean subgroup. In patients who are unable to tolerate oral iron or only have very short time period prior to delivery (and identification or non-correction of IDA), FCM could be an alternative solution for anemia correction with a similar safety profile to oral iron.