Efficacy of Intravenous Iron for Treating Postpartum Anemia in Low-Resource African Countries: A Pilot Study in Malawi

Abstract

Background:

Postpartum hemorrhage may lead to maternal morbidity and mortality, increases risks of transfusion, and incurs costs. We report on the feasibility and efficacy of in-hospital intravenous (IV) iron for treating postoperative anemia at Mtengo wa Nthenga, Malawi.

Patients and methods:

Twenty-eight consecutive women undergoing surgery for complicated pregnancy or complicated childbirth entered the study. Patients with hemoglobin (Hb) <10 g/dL on postoperative day 1 (n = 14) received IV iron sucrose (200 mg/day, 3 consecutive days), and those with Hb ≥10 g/dL (n = 14) received oral iron (ferrous sulfate, 256 mg/day). In-hospital postoperative Hb increase and blood transfusion were recorded.

Results:

Mean changes in Hb from postoperative day 1 to postoperative day 7 were −0.6 ± 1.2 g/dL and 2.1 ± 1.7 g/dL, for the oral and IV iron groups, respectively (p = 0.001). No side effect was seen with IV iron. Only 1 of 4 women receiving allogeneic blood was transfused after the initiation of IV iron treatment.

Conclusions:

Our results suggest that IV iron sucrose is an effective drug for treating puerperal anemia, leading to a rapid recovery of Hb levels. The current availability of generic iron sucrose preparations, with considerably lower acquisition costs, may facilitate in-hospital access to this treatment option in low-resource countries.

Introduction

Worldwide, postpartum hemorrhage is one of the leading causes of maternal mortality and the main component of severe morbidity jeopardizing women's fertility, exposing them to risks of transfusion and intensive care, and incurring costs.^1,2 Therefore, anemia due to heavy bleeding during delivery should be corrected without delay. In addition to initial resuscitation or surgical treatment for control of bleeding, adequate replacement of lost blood is crucial to the survival of these women. In developing countries, however, donor blood is scarce, and blood transfusion facilities are inadequate; with the prevalence of HIV/AIDS in sub-Saharan Africa, safe donor blood transfusion poses a real problem. Thus, implementation of alternatives to donor blood transfusion, such as salvage autotransfusion, has been considered.^3,4

Intravenous (IV) iron administration has been shown to be a useful tool for correcting anemia in a variety of clinical settings.⁵ Once the patient is stabilized, full correction of postpartum anemia may be attained by administration of iron therapy with or without human recombinant erythropoietin.⁵ Recently, several studies reported on the safety and efficacy of in-hospital short-term IV iron sucrose administration (up 200 mg/day for 3 consecutive days) for treating postpartum and early postoperative anemia after gynecological or orthopedic surgery and for reducing the allogeneic blood requirements.^6

–11

Therefore, we decided to implement a similar protocol at Francisco Palau Community Hospital at Mtengo wa Nthenga (Dowa district, Malawi). This is a Mission Hospital administered by the Carmelite Missionaries, which provides maternal and newborn healthcare to a population of 53,600 within a vast rural area. To the best of our knowledge, this is the first study reporting on improvement in postoperative hemoglobin (Hb) in women with postpartum anemia treated with a short-term course of IV iron sucrose in a low-resource African country.

Materials and Methods

Patients

From January to April 2009, consecutive women undergoing surgery for complicated pregnancy or complicated childbirth entered the study. Therefore, there were no specific inclusion criteria. Intolerance to IV iron, history of asthma or allergy, signs of infection, and evidence of severe hepatic dysfunction were exclusion criteria for receiving IV iron. The use of IV iron for treating postoperative anemia was approved by the medical committee of Francisco Palau Community Hospital, and all patients gave informed consent for any necessary medical or surgical procedures during their hospitalization.

Study protocol

Hb level was assessed with a portable hemoglobinometer HemoCue-B Hemoglobin (Hemocue, Ängelholm, Sweeden) before operation and on postoperative days (POD) 1 and 7. HemoCue-B Hemoglobin measures Hb according to the azyde-methemoglobin method (measuring range 0–25.6 g/dL; intraassay and interassay variation coefficients <2%).^12,13 The system complies with the International Committee for Standardization in Hematology (ICSH) standards for Hb measurement, is easy to use, has a low cost, and seems to be of use for diagnosis of anemia in different clinical settings.^12

–15 Patients with Hb <10 g/dL on POD1 received IV iron sucrose (200 mg/day in 200 mL normal saline on 3 consecutive days: Venofer^®, Vifor-Uriach, Barcelona, Spain) (IV iron group). Patients with Hb ≥10 g/dL on POD1 received oral iron (ferrous sulfate, 256 mg/day) (oral iron group). In addition, oral iron was prescribed to all patients on hospital discharge. The main outcome variable was Hb increase from POD1 to POD7. The secondary outcome variable was avoidance of postoperative transfusion.

Clinical data

A set of demographic and clinical data was collected for all patients, including age, weight, type of anesthesia, type of surgical procedure and operation time, intraoperative blood loss, crystalloid volume, transfusion volume, perioperative Hb levels, total iron deficiency at postoperative day 1, IV iron administration and IV iron side effects, postoperative complications, and length of hospital stay. Neonates' weight and Apgar test values at 0, 5, and 10 minute after birth also were recorded.

Transfusion protocol

There was not a specific transfusion protocol at the study hospital. Transfusion decisions were made by the attending physician on the basis of clinical judgment (mainly blood loss and signs/symptoms of acute anemia) or Hb values when available. During surgery, estimated blood loss was the main transfusion trigger (taking into account preoperative Hb levels). Whenever a transfusion was indicated, blood donation was requested from a compatible relative. Should a compatible relative not be found, the patient received banked packed red cells if available. In this study, all transfused women received fresh whole blood from directed donations.

Statistics

Differences between independent groups were analyzed using one-way analysis of variance (ANOVA) for mean values and Pearson's chi-square test for proportions. Pairwise comparisons between sampling occasions were evaluated using Student's dependent t test. All analyses were carried out using the statistic package SPSS 17 (Chicago, IL), licensed to the University of Málaga, Spain. A p value <0.05 was considered statistically significant.

Results

During the study period, 28 patients underwent surgery because of complicated pregnancy or complicated childbirth. Of these, 14 had an Hb level <10 g/dL (9 had a Hb level <8.5 g/dL) on POD1 and received postoperative IV iron sucrose. The maternal indications for cesarean section were cephalopelvic disproportion (13, 46.4%), previous cesarean section (2, 7.1%), placenta previa (2, 7.1%), and preeclampsia (2, 7.1%). Fetal distress (6, 21.4%) and breech presentation (2, 7.1%) were the fetal indications (Table 1). In addition, 1 woman underwent surgery for an ectopic pregnancy (3.6%). There were no differences in patient characteristics, anesthesia technique, type and duration of surgery, intraoperative crystalloid volume, postoperative complications, or length of postoperative stay between groups, although intraoperative blood loss was higher in the IV iron group (Table 1). There were also no between-group differences in neonate weight (2878 ± 470 vs. 3042 ± 1007, p = 0.585) or in Apgar test values at 0 (8 ± 2 vs. 6 ± 3, p = 0.152), 5 (9 ± 2 vs. 8 ± 4, p = 0.348), and 10 minutes after birth (10 ± 2 vs. 9 ± 4, p = 0.352).

Table 1.

Demographic and Clinical Characteristics of Patients

	Oral iron group	IV iron group	p
Patients (n)	14	14	–
Age (years)	25 ± 6	26 ± 7	0.747
Weight (kg)	55 ± 8	60 ± 7	0.129
Perioperative hemoglobin (g/dL)
Preoperative	11.9 ± 1.8	9.8 ± 1.3	0.001
Postoperative day 1	10.9 ± 1.0	7.8 ± 1.3	0.000
Postoperative day 7	10.3 ± 0.8	9.9 ± 1.9	0.543
Urgent surgery (n)	10	12	0.225
Regional anesthesia (n)	14	11	0.067
Surgery time (min)	43 ± 12	50 ± 19	0.321
Intraoperative blood loss (mL)	560 ± 130	790 ± 400	0.048
Crystalloids (mL)	3275 ± 1340	2053 ± 520	0.197
Postoperative complications (n)			0.473
Bleeding	0	2
Malaria	1	2
Sepsis	1	0
Other	1	1
Length of hospital stay (days)	7.6 ± 1.5	7.5 ± 1.9	0.957

IV, intravenous.

Hb levels were higher in patients from the oral iron group than in those from the IV iron group, both preoperatively and at POD1 but not at POD7 (Table 1). Mean changes in Hb level were −0.6 ± 1.2 g/dL and 2.1 ± 1.7 g/dL for oral and IV iron groups, respectively (p = 0.001). After excluding 1 patient who was transfused after the initiation of IV iron therapy, mean Hb increase from POD1 to POD7 was 2.3 ± 1.7 g/dL. Interestingly, Hb levels decreased in 8 of 14 patients in the oral iron group from POD1 to POD7, whereas they increased in 13 of 14 patients in the IV iron group during the same postoperative period. In addition, within the IV iron group, this increase was higher in patients with Hb <8.5 g/dL on POD1 (2.4 ± 1.8 g/dL, n = 9) than in those with Hb between 8.5 g/dL and 10 g/dL (2.0 ± 1.6 g/dL, n = 4), although the difference was not statistically significant (p = 0.760). For a target Hb level of 12 g/dL, the amount of iron sucrose administered was enough to replenish 50% of total iron deficiency (1100 ± 190 mg) and 88% of Hb deficiency (600 ± 190 mg). No side effect attributable to IV iron administration was witnessed during the hospital stay.

No patient from the oral iron group was transfused, whereas 4 women from the IV iron group received fresh allogeneic whole blood transfusion from directed donations (28.6%). Of these, only 1 received one blood unit after the initiation of IV iron therapy. Thus, the transfusion rate between POD1 and POD7 in this group was 7.1%. Patient 1 experienced abdominal pain and hypotension, was diagnosed with an ectopic pregnancy by echography, and underwent urgent surgery. She received 450 mL of fresh whole blood intraoperatively, according to clinical criteria. There were no postoperative complications, and she was discharged 8 days later.

Patient 6 had a previous cesarean section and at labor had cephalopelvic disproportion. She underwent a cesarean section again. During surgery, a uterine rupture was observed that caused a blood loss of 1500 mL. The patient received 450 mL of fresh whole blood shortly after surgery. There were no other postoperative adverse events, and she was discharged on POD10.

Patient 13 had suspected fetal distress and underwent cesarean section, with an intraoperative blood loss of 500 mL. There was a postoperative intraperitoneal hemorrhage (1000 mL) requiring new surgery. The patient received 450 mL of fresh whole blood intraoperatively and another 450 mL on the following day. Her Hb level at POD7 was lower than at POD1 (7.8 g/dL vs. 8.2 g/dL, respectively), but she was uneventfully discharged on POD12.

Patient 18 had a previous cesarean section, and a vacuum extraction was unsuccessful. She underwent an urgent cesarean section under general anesthesia. Blood loss volume was approximately 1500 mL, and she received 450 mL of fresh whole blood in the immediate postoperative hours (Hb = 6.3 g/dL). The patient was discharged on POD5; on POD7, she attended the hospital for skin suture removal, and her Hb was 8.9 g/dL.

Discussion

The primary objective of the study was to assess the changes in Hb levels between POD1 and POD7 after surgery for complicated pregnancy or complicated childbirth in women with postpartum Hb <10 g/dL receiving a short course of IV iron sucrose (600 mg) compared with those observed in women with postpartum Hb ≥10 g/dL receiving oral iron. Hb levels in women with postpartum anemia were lower at admission and at POD1, but not at POD7 (Table 1). Moreover, more women from the IV iron group showed an increase in Hb levels during the study period, and there were no significant differences in Hb increase between those with Hb <8.5 and those with Hb between 8.5 g/dL and 10 g/dL at POD1. These results are in agreement with those reported in previous studies, although those studies first evaluated the effect of IV iron after 5–28 days.^7,9,11,16,17 Others, however, have not found differences between oral and IV iron.¹⁸ Overall, data from this study strongly suggest that although a similar Hb response can be expected in the midterm (4–6 weeks), the initial response is faster and greater with IV iron than with oral iron. In addition, Westad et al.¹¹ also reported that women who received 600 mg IV iron sucrose followed by standard oral iron after 4 weeks replenished their iron stores more rapidly and had a more favorable fatigue score, indicating improved quality of life, compared with those receiving only oral iron. In our pilot study, neither an extended follow-up of laboratory parameters nor a quality of life assessment was possible because of limited resources and population characteristics; this might be considered to be a study limitation.

Only 1 woman, who sustained a severe postoperative hemorrhagic complication, received an allogeneic blood transfusion (7%) after initiation of IV iron therapy. Again, this transfusion rate is in agreement with those previously reported in patients with severe postpartum anemia in European countries.^7,9 In this regard, it is worth noting that in a retrospective study from a large obstetrical department, the number of blood transfusions for postpartum anemia was reduced to about one third after introduction of IV iron sucrose.¹⁹

Our study has other limitations. A real control group of women with postpartum anemia receiving oral iron or no iron is lacking. It is well known that high-quality scientific evidence derives from large, well-conducted, randomized, double-blind, placebo-controlled trials, which also require considerable economic support. This is not our case, as we did not have financial support to perform the study. As a result, only a limited number of IV iron sucrose ampules (120 ampules containing 100 mg each) were available. In a previous study, Gredilla et al.⁹ reported on the safety and efficacy of in-hospital short-term IV iron sucrose administration (200 mg/day for 3 consecutive days) for treating anemia (Hb <10 g/dL) after vaginal delivery or cesarean section. They evaluated the effect of IV iron 15 day after the last dose and found that Hb levels increased by 3.2 g/dL, and only 3 of 245 patients (1.2%) were transfused. On the other hand, the availability (mostly directed blood donations) and safety of allogeneic blood transfusion in Malawi are in no way comparable to the situation in developed countries. Therefore, although oral iron formerly was the standard of care at the study hospital, we decided to give IV iron to women with POD1 Hb <10 g/dL, as we considered that they were more at risk for transfusion than those with POD1 Hb ≥10 g/dL.

As expected, Hb levels at POD7 were not increased with respect to POD1 levels, thus reflecting the lack of efficacy of oral iron, although the patients were not at risk for transfusion during their hospitalization. The lack of efficacy of oral iron may be attributed to the effects of the inflammatory status that follows surgery and blood loss on iron homeostasis (decreased intestinal iron absorption and impaired iron recirculation from macrophages); thus, iron is not available for erythropoiesis, and there are low levels of circulating erythropoietin (EPO) because of inflammation and relatively high Hb levels.^5,20 Nevertheless, oral iron was prescribed to all women on hospital discharge. Out-hospital adherence to treatment could not be assessed, however, as most of the women did not attend the follow-up visits (because of, e.g., the long distance to the hospital they have to cover on foot or by expensive public transport, childcare, low opinion of the importance of medical care).

In this study, we compare an anemic collective to a nonanemic collective, which biases the results, as anemia before therapy might have induced high reactive EPO levels that stimulate erythropoiesis more strongly than in the oral iron group.²⁰ We were aware of this possibility because in a previous work, we observed that in anemic women scheduled for abdominal hysterectomy, the lower the baseline Hb level, the higher was the response to IV iron.²¹ Thus, we gave IV iron to anemic patients in an attempt to rapidly increase Hb levels and to decrease the risk for blood transfusion in women who usually have to resume daily activities shortly after hospital discharge.

Another limitation is that we administered only 600 mg of IV iron, which is the maximum weekly dose recommended for iron sucrose, and the mean length of postoperative stay was 7 days. According to Ganzon's formula, mean total iron deficiency (TID) at POD1 (mean Hb = 8 g/dL) for a target Hb of 12 g/dL and 500 mg of iron depot was 1100 mg (TID =[12 − Hb_{postoperative day 1}] × weight × 2.4 + 500). Thus, 600 mg is a modest dose compared to the amount of iron required for correcting postpartum anemia and restoring iron depots. Because of the absence of ferritin level measurement to evaluate the iron depot and the limited availability of iron sucrose at the study hospital, however, this dose seems to be prudent, as it provides the iron needed for attaining an Hb level of 12 g/dL in 85% of patients. Iron depots could be later repleted by oral iron. As expected from its safety profile (absolute rates of life-threatening adverse drug events and mortality of iron sucrose are 0.6 and 0.11 per 10⁶ doses, respectively),²² no clinically relevant immediate side effect of IV iron sucrose was observed. Again, the sample size has insufficient power to detect some potential negative effects (e.g., on sepsis or on clinical malaria).

Conclusions

Despite the noted limitations, our results suggest that IV iron sucrose may be an effective drug for treating puerperal anemia, leading to a rapid recovery of Hb levels. The high cost of IV iron therapy may be an important hurdle for its wider use in low-resource countries, but the availability of generic iron sucrose preparations, with considerably lower acquisition costs, and the possibility of administration of IV iron sucrose as a 2-minute push,²³ may facilitate access to this treatment option during the hospital stay.

Footnotes

Acknowledgments

We gratefully acknowledge the donation of IV iron medication (Venofer) by Vifor-Uriach (Barcelona, Spain) and HaemoCue B Hemoglobin photometer and measuring cuvettes by Izasa (Barcelona, Spain), the collaboration of the anesthesia staff at Francisco Palau Community Hospital (Malawi), and the manuscript review by John Huge Palmer, M.D. (Clínica Santa Elena, Torremolinos, Spain),

Disclosure Statement

E.B. has received honoraria for lectures and consultancy from Vifor-Uriach, Spain. M.M. has received honoraria for lectures and consultancy from Vifor-Pharma, Switzerland, Vifor-Uriach, Spain, Renapharm, Sweden, and PharmaCosmos, Denmark.

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