|Ahead of print publication
Randomized controlled trial to compare injection ferric carboxymaltose and oral iron in reducing postpartum anemia: A multicenter, pilot study
Sushil Chawla, Manoj Kumar Tangri, Ajai K Srivastava, Davinder Bhardwaj, Indu, Rajesh Mishra
Department of Obstetrics & Gynaecology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||24-Oct-2020|
|Date of Decision||20-Dec-2020|
|Date of Acceptance||26-Dec-2020|
|Date of Web Publication||28-Oct-2021|
MS, DNB, FICOG, Professor, Obs & Gynae, INHS Kalyani, Visakhapatnam
Source of Support: None, Conflict of Interest: None
Introduction: Iron-deficiency anemia (IDA) in pregnancy is common due to the increase demand for iron during pregnancy and is aggravated by blood loss associated with delivery. Intravenous iron formulations offer an alternative approach in the presence of moderate and severe anemia, due to intolerance of or nonadherence to oral iron and malabsorption status, to correct and prevent IDA. Ferric carboxymaltose (FCM) is a newer dextran-free iron formulation which allows for single and higher dose (up to 1000 mg) of IV iron infusion, making it a potentially ideal candidate for the treatment of postpartum anemia (PPA). Materials and Methods: A randomized control trial was conducted at two tertiary care centers involving 800 women (400 women in oral iron group and 400 women in the injection FCM group) to compare the efficacy of each in protecting the women from anemia in the postpartum period. Results: The compliance was 100% in the FCM group as the injection was given before the patient was sent on discharge after delivery. The mean rise in the hemoglobin levels in the FCM group and oral iron group was 3.76 g% and 2.476 g%, respectively. The mean rise in the serum ferritin levels in the FCM group was 214.265 mg% as noted at the end of 6 weeks. Conclusion : Injection FCM in the dose of 1000 mg given in a single dose before discharge in postpartum women helps in reducing PPA without any significant adverse effects.
Keywords: Ferric carboxymaltose, ferrous sulfate, postpartum anemia
|How to cite this URL:|
Chawla S, Tangri MK, Srivastava AK, Bhardwaj D, Indu, Mishra R. Randomized controlled trial to compare injection ferric carboxymaltose and oral iron in reducing postpartum anemia: A multicenter, pilot study. J Mar Med Soc [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=329472
| Introduction|| |
Anemia is a major global public health problem affecting the women worldwide with major consequences on health and socioeconomic development of the society. The iron-deficiency anemia (IDA) is the most common nutritional anemia seen during the pregnancy and postpartum period.,,, The approximate requirement for a singleton gestation is around 1000 mg during the pregnancy and postpartum period. Iron is required for the growth of the fetus, placenta, and also for the physiological changes in the mother causing the expansion of blood volume, red blood cells (RBCs), hemoglobin (Hb), growth of the uterus, and other organs.,,
The anemia in the postpartum period leads to maternal tiredness, increased depression episodes, reduced physical as well as cognitive performance, and cardiovascular problems. These women also have been seen to show poor mother-infant interaction This results in a longer average length of hospital stay and thereby higher hospitalization cost.,,,
Postpartum anemia (PPA) is defined as Hb <11 g% at 1 week postpartum and < 12 g% at 8 weeks postpartum. In consecutive series of European women, the prevalence of anemia 48 h after delivery is approximately 50%. In developing countries, the prevalence of PPA is in the range of 50%–80%.,
IDA is preventable and treatable. The oral iron preparations have been traditionally used to prevent and treat the anemia in both the prophylactic and therapeutic doses and if required they were supplemented by the blood. The gastrointestinal side effects in the form of constipation, gastritis, nausea, pain abdomen, and diarrhea are a common occurrence with these oral iron preparations and result in the poor compliance of the patients. The conventional discharge policy for the hospitals is to discharge the uncomplicated postpartum women to take one single tablet of iron preparations for a period of 6 weeks and reassessed when she comes back for the review for postpartum and newborn review.
Injectable iron preparations for the intramuscular or intravenous use have been available to the patients with poor compliance and with malabsorption status. The commonly use iron preparations in form of iron dextran and iron sucrose are associated with multiple dosing schedules, long infusion time thus needing multiple and longer stay at the health-care facility. They are also associated with risk of anaphylaxis, arthralgia, myalgia, and fever.,
Ferric carboxymaltose (FCM) is a new iron preparation which has more bioavailability than the injectable iron preparations available earlier due to its near neutral pH. The absence of dextran molecule in the FCM further reduces the incidence of adverse events with the preparation. FCM also allows for dosage up to 1000 mg to be infused over a period of 15 min thus reducing the number of hospital visits by the postpartum women and also shorter stay in the hospital.,
This study was conducted as a randomized controlled trial to compare the use of injection FCM with oral iron tablets of ferrous sulfate in postpartum women in reducing the incidence of PPA.
| Materials and Methods|| |
This was a multicenter, randomized controlled trial (RCT) carried as a pilot study for a period of 1 year in the department of obstetrics and gynecology in two tertiary care centers. The present study was approved by the Institutional Ethical Committee.
A total of 800 women delivering had to be studied and formed the study group. The sample was divided in two groups, i.e., 400 women in the FCM group and 400 women. Both the centers had 200 women in the FCM group and 200 women in the oral iron group. During the course of our study, we could study more number of participants with PPA.
The inclusion criteria were to include all women delivering at term (37–42 weeks) of gestation and who were diagnosed with anemia after delivery, i.e., Hb < 11 g%, low serum ferritin, and peripheral blood smear findings of IDA. The remaining patients with no evidence of IDA were worked up to find out the other causes of PPA.
The exclusion criteria were as follows: Hb >11 g% or serum ferritin levels (15 mcg/L or more), Hb <7 g%, history of oral iron intolerance during pregnancy, history of injectable iron therapy during the pregnancy, history of allergic reactions, postpartum hemorrhage requiring blood component therapy, history of anemia other than IDA, current treatment with myelosuppressive drugs or recent blood transfusion, and erythropoietin within 3 months before delivery.
Written and informed consent was obtained and blood samples were obtained, 24–48 h after the delivery for Hb, RBC indices, and serum ferritin levels. The details regarding the patient's age, weight, parity, mode of delivery, history of postpartum hemorrhage, comorbidities, and history of blood transfusion were collected.
Based on the computer randomization, the patients were put in two groups – Group A was given tab ferrous sulfate (200 mg), one tablet daily for a period of 6 weeks. She was told to take the tablet before meals and was advised to avoid tea, coffee, or milk products for at least 1 h before and after the ingestion of the tablets. Group B was given FCM 1000 mg IV stat in 250 ml of normal saline over 15 min. These patients were told to bring back the unused tablets to assess the adherence to the treatment, and an enquiry was made regarding the intake of the tablets after 6 weeks at review. The samples were taken for the Hb levels and serum ferritin levels. The treatment efficacy was assessed by change in Hb and ferritin levels from baseline, at 6 week after treatment and the safety was assessed from adverse events reported within 1 week post FCM administration.
The primary outcomes studied were Hb levels 6 weeks after the delivery and serum ferritin levels 6 weeks after the delivery. The secondary outcomes measured were primarily for the compliance and the occurrence of the side effects in terms of allergic reactions, gastrointestinal side effects, musculoskeletal side effects, and compliance.
Data collected were thereafter statistically analyzed by Microsoft Excel using Levene's test and two-tailed t-test with 95% confidence interval of difference.
| Results|| |
A total of 996 patients were recruited at both the centers, as shown in [Figure 1].
The analysis shows that the mean Hb and ferritin levels in both the groups were comparable in the postpartum period at the time of the recruitment [Table 1]. The oral iron group when asked about the intake of tablets gave the history of missing at least 1–3 tablets per week. The common reasons given for missing the tablets were forgetfulness, busy in the house hold activities, and side effects such as nausea, vomiting, constipation, and pain abdomen. These patients were issued a total of 17,136 tablets, and the compliance was about 74% as patients brought back 6100 tablets when they came back for the review after 6 weeks. The compliance was 100% in the FCM group.
The mean rise in the Hb levels in the FCM group and oral FS group was 3.76 g% and 2.476 g%, respectively, at the end of 6 weeks. The difference was significant as seen in the table. The mean rise in the serum ferritin levels in the FCM group was 214,265 mg%, and the same has shown a rise of 124,967 mg% in the oral iron group at the end of 6 weeks. The difference was statistically significant [Table 2]. Women in both the groups showed rise in the Hb levels, but the 86 women in the oral iron group still had the Hb levels between 10 and 10.9 g% (below 11 g%) at 6 weeks review. All women in the FCM group had Hb levels >11 g%.
[Table 3] shows that the adverse events were uncommon in the FCM group and in the women taking oral iron the common side effects observed were associated with gastrointestinal symptoms.
| Discussion|| |
Anemia in the postpartum period renders a lady, weak, and delays her recovery to a normal condition. It also causes her the inability to concentrate, general apathy, and irritability; all of which seriously impact a new mother's quality of life.
IDA is still the most common cause for PPA in the world and various oral and injectable iron preparations are being used to prevent it. This was a multicenter study involving large population (>800 women) which compared a new compound injection FCM to oral iron (tablet ferrous sulfate). Thus, making it one of the largest study involving FCM and comparing it to oral iron. The outcome measures taken in the study were Hb and serum ferritin levels before and after the treatment, and the studies in literature have taken these measures besides using various other methods such as transferrin saturation, transferring receptor levels to diagnose the cases of anemia, and monitor the response to iron therapy., The trials by Breymann et al., Bhandal and Russell, and Westad et al. compared the use of oral iron to iron sucrose in postpartum women (enrolled within 10 days of the delivery), encompassing a total of 230 women in their studies. They analyzed the changes in the Hb levels, ferritin levels, transferrin levels, and the quality of life. They concluded that injectable iron sucrose is better to oral ferrous sulfate to build iron stores and prevent PPA in women. These three trials measured the parameters multiple times during the study and thus concluded that the rise in Hb levels was not significant at the end of the trial, but women in the injectable group showed an early rise in Hb, whereas the ferritin levels rise was significant in the injectable iron group.,, Our study has shown that the rise in the Hb and ferritin levels is significantly higher in the injectable iron group as compared to the oral iron group, but both the values were measured only once after the treatment period of 6 weeks. Westad et al. have reported a compliance of 50% in the oral iron group and have implicated poor compliance as the reason for the poor results with the oral iron group, while in our study, the compliance rate was 74% in the oral iron group and 100% in the FCM group.
Breymann et al. in their multicenter RCT involving 349 postpartum women (enrolled within 7 days of the delivery) at 12 centers in Eastern Europe compared the efficacy of FCM to oral iron. They measured the parameters at 1, 2, 4, and 12 weeks and reported compliance of 90% in the oral group. Hb levels of the FCM group showed a more rapid rise by end of 1st week, but there was no significant difference in the mean rise in Hb in two groups at the end of 3 months. Ferritin levels of the FCM group were significantly elevated. Our study, in which samples were taken only once after the treatment period finished after the oral iron therapy also proves a rise in the ferritin levels on similar lines in the FCM group, but it also shows a significant rise in the Hb levels among the FCM group.
Van Wyck et al. enrolled 361 postpartum anemic women with Hb 10.0 g% or less and compared FCM to oral iron. They had a compliance rate of 98% and 84% in the FCM group and the oral group, respectively. They said that the rise in the Hb was directly proportional to severity of anemia, and the two groups showed no difference in the number of patients who achieved a rise in Hb 2.0 g% or more within 42 days. This is contrary to the results of our study. The serum ferritin levels showed a prompt increase in the FCM group, while the oral group showed minimal increase, which is similar to our study.
Seid et al. evaluated the efficacy, safety, and tolerability of FCM to oral iron in 291 postpartum anemic women in a multicenter trial. The Hb rise in the FCM group when compared to oral iron group (91.4% vs. 66.7%, P < 0.0001) was more significant. This is similar to the findings of our study.
Seid et al. while evaluating the safety of FCM in 996 women in a study involving 2045 women reported adverse events in < 1% of patients and that also were not related to the drug. The FCM group had infusion site reactions and oral iron group had more of gastrointestinal side effects. They concluded similar to our study that FCM was well tolerated and effectively increased mean Hb levels in postpartum women.
Rathod et al. studied 366 postpartum women in three groups to receive either oral iron or IV FCM or iron sucrose. An increase in Hb and serum ferritin level was observed in all three groups, but the increase in FCM group was significantly higher (P < 0.0001) than conventional iron sucrose and oral iron group, similar to our study. Adverse drug reactions were significantly less (P < 0.001) in FCM group when compared with other two groups, as in our study. Adverse drug reactions were seen in 51% of patients on oral iron, whereas in our study, GI side effects were seen in 38% of patients. This led to poor adherence to oral iron in these patients.
Barish et al. concluded that the most common treatment emergent events include nausea, headache, diarrhea, and fatigue in the FCM group, whereas in our study, headache and thrombophlebitis were seen commonly. They also found postinjection episodes of transient hypotension in FCM group which was not seen in our study.
Mulder et al. while comparing the FCM with another injectable iron preparation of iron isomaltoside in >1200 patients from different departments concluded that only 2% patients in the FCM group had any adverse reaction and of that also 1.5% had mild hypersensitivity reaction in form of skin rash.
| Conclusion|| |
This randomized controlled trial showed that injection FCM helps in reducing PPA and is better alternative to oral iron preparations. The compound in the dose of 1000 mg can be given as a single dose before discharge in postpartum women. The injection FCM provide this advantage over the oral iron preparations without any significant adverse effects.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]