Effect of treatment with single total-dose intravenous iron versus daily oral iron(Iii)-hydroxide polymaltose on moderate puerperal iron-deficiency anemia

Background: Iron-deficiency anemia is the most common nutritional cause of anemia in pregnancy and is often responsible for puerperal anemia. Puerperal anemia can impair postpartum maternal and neonatal well-being. Objective: To determine the effect of treatment of moderate puerperal iron-deficiency anemia using a single intravenous total-dose iron dextran versus daily single dose oral iron(III)-hydroxide polymaltose. Methodology: A randomized controlled study in which postpartum women with moderate iron-deficiency anemia were randomized into treatment with either a single total-dose intrave¬nous iron dextran or with daily single doses of oral iron(III)-hydroxide polymaltose tablets for 6 weeks. Effects on hemoglobin concentration using either method were compared at 6 weeks postpartum. Analysis was per protocol using SPSS version 17 for windows. P-values ≤0.05 were considered significant. Results: Two hundred eighty-four women were recruited for the study: 142 women received single total dose intravenous infusion of iron dextran while 142 received daily oral iron(III)- hydroxide polymaltose tablets. Approximately 84.0% (237/282) completed the study and were analyzed including 81% (115/142) of those randomized to injectable iron therapy compared to 85.9% (122/142) of those randomized to oral treatment. The proportions of women who had attained hemoglobin concentration of at least 10 g/dL by the 6 weeks postpartum visit did not differ significantly between cases and controls (95.7% vs 94.3%; P=0.73). Similarly, the mean increases in hemoglobin following either therapeutic route were comparable (1.03±0.56 g/dL for intravenous iron and 0.97±0.46 g/dL for the oral group; P=0.42). Conclusion: Single total-dose intravenous iron for treatment of puerperal iron-deficiency anemia was as effective as daily single doses of ferric iron tablets. For puerperal patients with iron-deficiency anemia in whom compliance with and tolerability of oral iron are not certain, a single total-dose intravenous iron can be safely offered. The study was carried out in the two tertiary health care institutions in Enugu namely University of Nigeria Teaching Hospital, Ituku Ozalla and Enugu State University Teaching Hospital, Parklane, Enugu. Both centers offer both primary maternity care and tertiary health services. The annual delivery rate in each of these two centers ranges between 1,500 and 2,000. The study population included all women who had singleton vaginal deliveries in the study centers during the study period from April 2013 to October 2015. This was a randomized controlled study. Cases were defined as women who had postpartum hemoglobin concentration of 6–7.9 g/dL associated with red blood cell features of iron deficiency at 48 hours or later following vaginal delivery of a singleton pregnancy and who were treated with single total-dose intravenous infusion of iron dextran (intervention). Controls were defined as women who had hemoglobin concentration of 6–7.9 g/dL associated with red blood cell features of iron deficiency at 48 hours or later following vaginal delivery of a singleton pregnancy and who were treated with single daily oral doses of iron(III)-hydroxide polymaltose tablet (standard treatment). The minimum sample size (n) for this study was derived by the formula for sample size calculation for two independent samples in an equivalence trial with a categorical variable as main outcome measure: where n is the size per group; p is the response rate of standard treatment group; p0 is the response rate of new drug treatment group; zx is the standard normal deviate for a one- or two-sided x; d is the real difference between two treatment effect; and δ0 is a clinically acceptable effect size. Assuming P=50% since we had no previous study on the use of single dose oral therapy for treatment; Z1–α/2=1.96, Zβ=0.845, δ0=18% and substituting in the equation; n=121; assuming a loss to follow-up of 18%, and adding to this, n=142.8 For convenience we chose 142 as sample size for each arm of the study. All the women who had vaginal delivery during the period of the study were counseled and screened for postpartum anemia by determining hemoglobin concentration and also examining blood film for red cell morphology. For the purpose of the study, hemoglobin level <10 g/dL was considered as anemia in line with the definition of anemia in Nigerian hospitals.28 Postpartum period was defined as the period between delivery of the baby and 6 weeks after. Moderate anemia was defined as hemoglobin concentration of 6–7.9 g/dL. Iron-deficiency anemia was defined as the presence of hemoglobin level <10 g/dL associated with blood film features of red cell hypochromia and microcytosis with or without anisocytosis and poikilocytosis. The inclusion criteria for the study included vaginal delivery of singletons occurring within 48 hours, moderate anemia with features of iron deficiency, hemodynamic stability and written consent to participate in the study. The exclusion criteria included severe anemia, that is, Hb<6 g/dL; mild anemia, that is, Hb 8–9.9 g/dL; secondary postpartum hemorrhage; vaginal delivery of multiple pregnancy; cesarean delivery, genotype SS; HIV infection; comorbidities, such as hypertensive disorders, renal pathology and refusal of consent. Consenting women were then recruited into the study and were randomized into receiving intravenous iron (cases) and receiving oral iron (controls). Based on sample size of 284, numbers 1 to 284 were randomly split into two equal groups using computer generated random numbers. The numbers in each group were written on identical square cards with the letter “i” for cases and “o” for controls. The cards were then placed each in a small opaque envelop and sealed. The sealed envelopes containing all the numbers were put in a nontransparent bag. Each study subject to be recruited was asked to dip her hand in the bag and pick one of the envelopes. She was assigned the number which appeared on the card enclosed in the envelop and this number was used to allocate her to either case or control according to the earlier randomization. The ratio of cases to controls was 1:1. Cases and controls were matched by age (within 2 years), parity (nulliparity, multiparity and grandmultiparity) and marital status. The protocol for the administration of intravenous iron was as follows: A vial of iron dextran (Imferon MD®, Shreya Life Sciences Pvt Ltd, Mumbai, India) contained 5 mL of parenteral iron equivalent to 250 mg elemental iron. The dose of intravenous iron administered was determined from the deficit in hemoglobin concentration calculated as the difference between the expected hemoglobin (of 10 g/dL) and the patient’s hemoglobin concentration at 48 hours postpartum. It was assumed that 250 mg of parenteral iron would increase hemoglobin concentration by 1 g/dL per week.29 Therefore, the required dose in milligram was obtained by multiplying each participant’s deficit in hemoglobin concentration by 250 to get the amount of iron dextran in milligrams to be administered. Fifty percent of this value was also added to replenish the iron stores. The cases received, in addition, 0.4 mg of folic acid tablets daily. The calculated amount was added into and mixed with an infusion of 0.9% Normal saline to a maximum of six vials of iron dextran (ie, 1,500 mg) in 1 L of saline. Then, intravenous access was secured and a premedication consisting of chlorpheniramine 10 mg was administered intramuscularly. Thirty minutes after, a test dose was first administered by giving the iron dextran infusion at a slow rate of 10 drops per minute >30 minutes while the patient was monitored for hypersensitivity reaction. Subsequently, if there was no reaction, the infusion was allowed to run at 30 drops per minute till the end of the infusion. If any degree of adverse/allergic reaction was noticed either during the test dose or afterwards while the infusion was running, the patient was given some rescue medications that include intravenous hydrocortisone 200 mg statim and promethazine 50 mg statim and the iron infusion was discontinued. For oral iron, each tablet of Fegem® (Torrent Pharmaceuticals Ltd, Gujarat, India) contained iron(III)-hydroxide polymaltose complex equivalent to 100 mg elemental iron and also 350 µg of folic acid. The drug came in chewable form to encourage. To enhance compliance with oral therapy among the control group, an individualized drug administration card containing every day of the 6 weeks postpartum was issued to patients where they ticked each day’s dose taken. Besides, participants were sent weekly SMS reminders to facilitate compliance. Participants were instructed to bring the drug administration card along while coming for the 6 weeks follow-up appointment. Blood samples were taken for hemoglobin estimation at the 6 weeks visit. The data collected were analyzed using the statistical package for social sciences (SPSS) computer software version 17.0 for windows (SPSS Inc., Chicago, IL, USA). Data analysis were done per protocol (patients who did not complete the study were excluded). The target hemoglobin concentration was 10 g/dL for both cases and controls for the reason that this was the threshold level for definition of anemia in Nigeria.28 The main outcome measure was the proportion of women who had attained a hemoglobin concentration of at least 10 g/dL by the 6 weeks postpartum visit among cases and controls. Categorical variables for the groups were compared using chi-square. Comparison of means of hemoglobin levels was done with Student’s t-test. P-value ≤0.05 was considered significant. Ethical clearance for the study was obtained from the Research Ethics Committee of the University of Nigeria Teaching Hospital, Enugu. All the hematinics were given to participants free of charge and any extra day stayed in the hospital for the purpose of the study was not surcharged.