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Keywords:

  • anaemia;
  • efficacy;
  • iron deficiency;
  • iron polymaltose;
  • iron sulphate;
  • pregnancy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Abstract.  Khalafallah A, Dennis A, Bates J, Bates G, Robertson IK, Smith L, Ball MJ, Seaton D, Brain T, Rasko JEJ Launceston General Hospital (LGH), Australia; University of Tasmania, Australia; and Centenary Institute, University of Sydney, NSW, Australia) A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. J Intern Med 2010; 268: 286–295.

Background.  Iron deficiency anaemia is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk.

Objectives and design. We conducted a single site, prospective, nonblinded randomized-controlled trial to compare the efficacy, safety, tolerability and compliance of standard oral daily iron versus intravenous iron

Subjects.  We prospectively screened 2654 pregnant women between March 2007 and January 2009 with a full blood count and iron studies, of which 461 (18%) had moderate IDA. Two hundred women matched for haemoglobin concentration and serum ferritin level were recruited.

Interventions.  Patients were randomized to daily oral ferrous sulphate 250 mg (elemental iron 80 mg) with or without a single intravenous iron polymaltose infusion.

Results.  Prior to delivery, the intravenous plus oral iron arm was superior to the oral iron only arm as measured by the increase in haemoglobin level (mean of 19.5 g/L vs. 12 g/L; P < 0.001); the increase in mean serum ferritin level (222 μg/L vs. 18 ug/L; P < 0.001); and the percentage of mothers with ferritin levels below 30 μg/L (4.5% vs. 79%; P < 0.001). A single dose of intravenous iron polymaltose was well tolerated without significant side effects.

Conclusions.  Our data indicate that intravenous iron polymaltose is safe and leads to improved efficacy and iron stores compared to oral iron alone in pregnancy-related IDA.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Nutritional iron deficiency is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk [1–3]. World Health Organization (WHO) data show that iron deficiency anaemia (IDA) in pregnancy is a significant problem throughout the world with a prevalence ranging from 15% of pregnant women in industrialized countries to an average of 56% in developing countries (range 35–75%) [1, 2].

Although iron supplementation during pregnancy is one of the most widely practiced public health measures, there remain many controversial issues with this practice [4–8]. Pregnant women do not always respond adequately to oral iron therapy due to difficulties associated with ingestion of the tablets and their side effects, thereby contributing to reduced rates of compliance [4, 5]. The use of injected iron has been associated with undesirable and sometimes serious side-effects and was previously limited in clinical use [9, 10]. In recent years, type II iron complexes have been developed which are better tolerated and can be used for a rapid reversal of iron deficiency anaemia [9, 10].

This trial was designed to compare the efficacy of two interventions designed to treat IDA in pregnancy: standard oral iron (iron sulphate) and intravenous iron therapy (iron polymaltose) plus identical oral maintenance. Primary endpoints were predelivery haemoglobin and iron stores and secondary endpoints were designed to assess safety, tolerability and compliance for both treatment arms.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Design overview

A prospective nonblinded randomized-controlled trial was conducted between March 2007 and January 2009 at the Launceston General Hospital (LGH), a tertiary referral centre for Northern Tasmania, Australia (Fig. 1). The trial was approved by the Tasmania Human Research Ethics Committee and registered in the ANZCTR website http://www.ANZCTR.org.au/ACTRN12609000177257.aspx. The primary objective of this study was to determine the effectiveness of intravenous (IV) iron plus oral iron maintenance compared to oral iron only therapy in the treatment of IDA in pregnancy. The endpoints were predelivery haemoglobin (Hb) and ferritin levels. Secondary objectives were to assess tolerability, safety and compliance to both treatments, and the effect of iron therapy on birth weight and gestational age at delivery. Cord blood Hb and iron studies data were collected at 37 consecutive deliveries to assess the effects of IV plus oral iron.

image

Figure 1. Trial flow diagram. *Fourteen patients were admitted late in labour, and no blood samples were taken before delivery. The primary hypothesis examined the change in haemoglobin levels between the time of booking and immediately prior to delivery; an ‘intention-to-treat’ analysis was performed according to original randomization group on those patients who had blood samples taken before delivery, whether or not the treatment was completed as per protocol. Twenty one patients withdrew from the trial treatments, but all but one of these patients agreed to continued collection of haematological and other trial data; eight patients gave no reason for withdrawal. §Five patients did not complete the intended treatments, but did not themselves choose to withdraw; three patients in the oral iron group were treated with IV iron when their haemoglobin was judged not to have responded adequately to oral iron, whilst one patient was unable to attend for IV iron treatment.

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Sample size calculations

We calculated the need for 40 completed patients per treatment group based on assumptions: i) a minimum effect size detection of 4.5 g/L increase in Hb in the IV group compared to the oral only group, ii) an untreated change in Hb with SD 7 g/L [11] and, iii) alpha value of 0.05 and power of 80%. The total numbers of patients required to demonstrate this difference would be at least 100.

Participants

We prospectively screened all pregnant women, who presented at the LGH (total 2654) between March 2007 and January 2009 with a full blood count and subsequently iron studies if the Hb level was below 115 g/L. Two hundred caucasian pregnant women aged 18 years or above were identified with moderate IDA, defined as Hb ≤ 115 g/L [reference range (RR) 120–160 g/L] and low iron stores based on a serum ferritin level <30 μg/L (RR 30–440 μg/L). Most of the women (75%) had ferritin levels below 20 μg/L and were equally distributed in both groups. Exclusion criteria included diagnosis of anaemia other than iron deficiency, known malabsorptive syndromes affecting the uptake of oral iron, conditions associated with iron overload, multiple pregnancy, and first Hb check after 28 weeks gestation. Owing to ethical concerns, pregnant women with severe IDA (Hb level < 85 g/L) were offered IV iron without randomization and were excluded from the trial. Moderate iron deficiency anaemia was defined as Hb level < 115 g/L but >85 g/L with serum ferritin level of <30 μg/L.

Measurement of Hb and iron studies

The blood samples were taken from most of participants in the morning without fasting. Only fresh blood samples were analysed at National Association Testing Authority (NATA) accredited laboratory at the LGH at the time of presentation to the antenatal clinic. The blood samples of all participants were processed within 2 h of collection as per turnaround time for the laboratory. All variables were determined consecutively. The serum iron and transferrin were measured on an Abbott Architect c8000 autoanalyzer (Abbott, NYSE, USA), using Iron Liquid reagent (Ferene S, Abbott, NYSE, USA) and Transferrin reagent (immunoturbidimetric, Abbott, NYSE, USA).

The percentage transferrin saturation was calculated using the formula (Iron μmol/L/Transferrin g/L)/26 × 100. The serum ferritin was measured on an Ortho Diagnostics ECi Immunoassay analyser (Ortho Clinical Diagnostics, NJ, USA) using Ortho Diagnostics Ferritin reagent (two-step immunometric). The Hb was measured by NATA-accredited LGH standard reference laboratory using a Beckman Coulter LH-500 (Beckman Coulter, CA, USA). Hb and iron studies were performed at baseline, 4 weeks after treatment as well as predelivery at 38 weeks and Hb was measured at 24–48 h postdelivery.

Randomization and interventions

Informed consent was obtained by a research midwife. Treatment arm was randomized in blocks of 10 and assignment was performed by the LGH Pharmacy Department. The oral only treatment arm comprised iron sulphate 250 mg tablets, elemental iron 80 mg (Abbott, Australasia Pty Ltd, Sydney, Australia) to be taken daily within 2 days after booking until delivery. The IV arm required a single intravenous infusion of iron polymaltose (Ferrosig, Sigma Pharmaceuticals, Sydney, Australia) within 1 week after booking followed by oral iron identical to the other arm. Preenrolment, there were no significant differences in the dietary iron intake or supplement intake between the two groups based on a specially-designed questionnaire addressing these issues. Patients assigned to IV iron polymaltose received a 100 mg test-dose dissolved in 50 mL normal saline infused over 30 min. Clinical observation and vital signs were assessed initially and every 15 min from the start of the infusion. After the test-dose was tolerated, the remainder of iron polymaltose dose was infused. The total dose of IV iron polymaltose was calculated according to the patient’s body weight at their first antenatal visit and entry Hb level according to the product guidelines; iron dose in mg (50 mg per 1 mL) = body weight (maximum 90 kg) in kg × (target Hb (120 g/L) − actual Hb in g/L) × constant factor (0.24) + iron depot (500) [12].

A basic form of counselling was conducted by the research assistant and the midwife. The women received brochures and were educated to take the oral iron at same time of the day with food to avoid side effects and also to take vitamin C to increase the absorption. This information was available to all women included in the study. Furthermore, we offered the iron tablets free of charge to all patients to minimize the cost-effect on the participants through the Pharmacy Department as a monthly script. The LGH-Pharmacy has a record of all women in the study who regularly collected their medication as well as those who did not comply. Patients were asked in a specially designed questionnaire at 2 and 6 weeks after enrolment as well as pre and post delivery regarding their compliance and tolerability of the iron therapy.

Statistical methods

The results were reported on an intention-to-treat basis. Effectiveness of randomisation to the treatment groups was assessed by: (i) general linear modelling for continuous variables, (ii) ordinal logistic regression for number of live births, and (iii) logistic regression for binary variables. The mean levels of Hb and serum ferritin (with standard deviations) and the differences [with 95% confidence intervals (CI) and P-values] between the IV- and the oral iron only groups at trial entry, subsequent intermediate time points, and at delivery were estimated by mixed methods linear regression with correction for repeated measures, and adjustment for maternal age, weight, gestational age and corresponding iron status value at trial entry. The proportion of women with Hb < 116 g/L predelivery was estimated by Poisson regression. P-values were corrected for multiple comparisons by the Holm method [13]. All analyses were performed using Stata/IC 10.1 for Windows (Stata Corp LP, College Station, TX, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

Between March 2007 and January 2009, 2654 women were screened at their first antenatal visit (between 10–16 weeks gestation). We identified 461 women with a Hb level < 115 g/L (RR 120–160 g/L) and low iron stores (17.4%; 95% CI 15.9% to 18.9%). There were 188 women excluded owing to the defined criteria (Fig. 2), 77 declined to participate or were uncontactable. Consequently, 200 women were enrolled in the trial. Amongst these, 98 women were allocated at random to each treatment arm and 4 women declined to participate directly after enrollment and randomization. Twelve women in the oral iron only group and eight women in the IV plus oral iron maintenance group withdrew from treatment following commencement of oral iron therapy because of side effects. Predelivery Hb was not assessable in 13 patients (6 in IV arm and 7 in oral arm) (Fig. 1). Thus, ‘intention-to-treat’ analysis of the effect of treatment on Hb and iron stores at delivery using correctly timed data were performed on 91 women in the oral iron group and 92 women in the IV and oral iron group.

image

Figure 2. Maternal haemoglobin at booking and maternal and cord blood haemoglobin at delivery in the oral iron only versus IV and oral iron treatment groups. Box and whisker plots of haemoglobin, adjusted for maternal age, weight and gestational age at delivery. Plots show 10th, 25th, 50th, 75th and 90th percentiles and individual outlier results.

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Baseline data

Baseline demographic characteristics of age, maternal weight, gestational age at booking and number of previous live births were similar in each treatment arm (Table 1). Initial Hb, ferritin, serum iron, serum transferrin and serum iron saturation were also similar in each treatment arm (Fig. 2). In the IV plus oral iron group, the mean IV iron dose received was 702 mg (SD 143) and 6,900 mg (SD 2,201) of oral iron, whilst in the oral iron only group the mean dose of oral iron received was 7,311 mg (SD 2,969), There was no significant difference in the total iron dose received between the two groups.

Table 1. Description of patients in oral iron only and IV and oral iron treatment groups at baseline
 Oral iron (n = 98)IV plus oral iron (n = 98)Comparison
Mean (SD)Mean (SD)Differencea95% CIP-value
  1. aMean (standard deviation) and comparison of means with 95% confidence intervals and P-values of continuous variables (age, maternal weight, gestational age) in the treatment arms estimated by general linear modelling.

  2. bDistribution of number of live births was compared using ordinal logistic regression.

  3. cNumbers of patients and comparison of categorical variables (current smokers and drinkers, and employed) expressed as odds ratios estimated by logistic regression.

Age (years)28.2 (5.7)27.5 (5.9)−0.6(−2.3 to 1.0)0.44
Maternal weight (kg)74.6 (20.4)73.2 (18.6)1.4(−7.0 to 4.2)0.62
Gestational age at randomization (weeks)25.1 (5.4)25.6 (4.7)0.4(−1.0 to 1.8)0.59
Iron status
 Haemoglobin (g/L)109.3 (4.8)107.4 (5.4)−1.9(−4.3 to 0.6)0.28
 Serum ferritin (μg/L)17.7 (17.7)18.1 (16.3)0.5(−20.4 to 21.3)0.62
 Serum iron (mmol/L)12.3 (5.8)12.6 (5.7)0.3(−1.8 to 2.4)0.62
 Serum transferrin (μg/L)3.72 (0.49)3.61 (0.67)−0.11(−0.27 to 0.05)0.63
 Iron saturation (%)13.5 (7.6)14.0 (7.2)0.5(−2.1 to 3.1)0.29
   ORb95% CIP-value
Number of live births1.41 (1.42)1.12 (1.3)0.69(0.41 to 1.16)0.16
 NNORc95% CIP-value
Current smokers28270.92(0.49 to 1.73)0.80
Current drinkers17191.12(0.54 to 2.31)0.76
Employed46491.18(0.67 to 2.08)0.57

Primary outcome measurements

Mean Hb levels in women in the oral iron group increased from 109.3 g/L (SD 4.8) at booking to 121.8 (SD 8.7) predelivery, whilst those women in the IV plus oral iron group increased from 107.4 g/L (SD 5.4) at booking to 126.6 (SD 9.7) at delivery (Fig. 3). Thus, the single IV iron therapy in addition to oral iron maintenance improved predelivery Hb by an additional 6.6 g/L (95% CI 3.4–9.8; P < 0.001) compared to oral iron alone. The proportion of women with mild-to-moderate anaemia with Hb < 116 g/L predelivery was lower in the IV plus oral iron group (16%) than the oral iron only group (29%); incidence rate ratio 0.55 (95% CI 0.31–0.98; P = 0.043).

image

Figure 3. Difference in measured values of iron status between IV plus oral iron and oral iron groups at different times following trial entry: intention-to-treat analysis. Graphs show mean difference (95% Cl);*P < 0.05, **P < 0.01, ***P<0.001. Analysis performed on all patients from whom blood was sampled, including those who withdrew or did not receive treatment as per protocol. Differences estimated by mixed methods linear regression, corrected for repeated measures, and adjusted for maternal age, weight and gestational at trial entry age. The corresponding iron status value difference after trial entry was adjusted for the initial difference at trial entry. P-values corrected for multiple comparisons by the Holm method. Interpretation of graphs: Difference is IV plus oral group mean minus oral group mean (e.g. predelivery Hb is 6.6 g/L (95% CI 3.4–9.8) higher in the IV plus oral group compared to the oral group when adjusted for initial Hb levels. Thus, IV plus oral iron raises Hb, ferritin and to a lesser extent iron saturation, lowers transferrin, and leaves serum iron unchanged.

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Following delivery, mean Hb levels fell to 111.6 g/L (SD 14.2) and 115.5 g/L (SD 10.8) in the oral iron and IV plus oral iron groups respectively, with a beneficial effect of IV plus oral iron therapy of 5.8 g/L (95% CI 2.5–9.1; P = 0.004) persisting despite the blood loss of delivery. Substitution of missing delivery Hb test results with the latest values prior to labour showed minimal change from the estimates reported above (mean Hb benefit at time of delivery of IV plus oral iron versus oral iron only was 6.2 g/L; P < 0.001).

Mean serum ferritin levels at booking were similar and low in both groups: 17.8 μg/L (SD 20.0) in the oral iron group and 17.3 μg/L (SD 16.4) in the IV plus oral iron group. There was a modest rise in the oral iron group, half of which could be attributed to a very large rise in serum ferritin in the three women who were judged not to have responded to oral iron and crossed over to the IV plus oral iron arm as part of the protocol. These three crossover women were retained in the oral iron only group based on intention-to-treat (ITT)-analysis. However, the serum ferritin of those in the IV plus oral iron group increased markedly within 4 weeks of the IV therapy (increase 222 μg/L; 95% CI 194–249; P < 0.001), and a substantial improvement persisted until delivery (increase 108 μg/L; 95% CI 43–209; P < 0.001). Prior to delivery 53 (79%) of 67 women (with analyzable iron status measurements) who received oral iron only had ferritin levels below 30 μg/L, whereas only 3 (4.5%) of the analyzable 66 women treated with IV iron plus oral iron maintenance had ferritin levels below 30 μg/L. There was a reduction in serum transferrin in the IV plus oral iron group at the time of delivery (change −0.46 μg/L; 95% CI −0.62 to −0.31; P < 0.001) and an increase in iron saturation (5.7%; 95%CI 2.0–9.5; P = 0.013), whilst change in serum iron (2.3 μg/L; 95% CI −0.7–5.4; P = 0.54) was similar in the two treatment arms.

The analyses of the above primary outcomes were performed unadjusted for potential confounding variables. The randomization process appeared to be successful in distributing potential confounding variables equally between the treatment groups. Repeating the analyses with adjustment for potentially confounding variables resulted in no significant alteration in the estimated effects of the treatments on Hb or iron status measurements. In the analyses adjusted for age, parity, socio-economic index (using Australian Bureau of Statistics 2006 census collector district SEI as proxy), maternal weight and gestational age at booking, there was a small but significant association between Hb and gestational age (P < 0.001), and a small but significant negative association between serum iron and iron saturation and maternal weight (P < 0.001). There were no other significant associations (Table 1).

Exploratory analysis found no difference in the improvement in Hb with IV plus oral iron compared to oral iron in women with initial serum ferritin levels below 12 μg/L compared to women with ferritin above that level (P = 0.69). There was also no greater benefit in women with lower initial Hb levels at booking (Hb < 100 g/L) compared to higher initial levels. Repeating the primary analysis excluding patients who failed to complete the study treatment according to their randomization protocol (22 oral iron patients and 18 IV plus oral iron patients) resulted in trivial changes in estimates of benefits of IV plus oral iron treatment: haemoglobin improvement 6.8 g/L (P < 0.001) predelivery and 6.1 g/L (P = 0.003) postdelivery, ferritin improvement 235 μg/L (P < 0.001) at 4 weeks posttreatment and 109 μg/L (P < 0.001) predelivery. Although there was a small tendency for improvement in Hb in the IV plus oral iron group compared to the oral iron group to be greater in women with initial Hb levels below 109 compared to women above 109 (difference 2.3; 95% CI −4.5–9.2; P = 0.50) the trend was weak and irregular. Subgroup analysis could not be more precise due to a lack of power of statistics in patients with Hb < 109 g/L.

Newborn weight, Hb and Ferritin

The birth weights of the babies in the two arms were the same (3.42 kg in the oral iron only versus 3.44 kg in the IV plus oral iron maintenance; difference 0.03 kg; P = 0.77). Gestational age at delivery (oral iron only mean age 39.1 weeks versus IV plus oral iron 38.9 weeks (difference 0.2 weeks; P = 0.74) was similar in the two treatment groups. There were no significant differences in placental cord Hb or iron status between the two treatment groups in the subset analysed. Mean cord Hb was 165 g/L (SD 9.6) in the oral iron group and 157 g/L (SD 14.1) in the IV and oral iron group (difference −7; 95% CI −18–3; P = 0.17), whilst ferritin was 142 μg/L (SD 86) and 185 (SD 101) respectively, (difference 43; 95% CI −59–145; P = 0.41).

Tolerability and compliance

This aspect was measured via questionnaire at booking as well as phone surveys at 2 and 6 weeks, predelivery and postdelivery. Two patients developed urticarial reactions soon after commencement of IV iron infusion, therefore treatment was discontinued and they improved without any further intervention. Seven patients in the oral iron only and two patients in the IV plus oral iron group were unable to tolerate the oral iron tablets. Furthermore, about 28% of women on oral iron experienced a mild degree of self-limiting gastro-intestinal upset in form of diarrhoea or constipation or abdominal discomfort. Noncompliance in the oral iron arm occurred in 12.5% of patients, and varied from missing a few tablets (self-reported) to neglecting to pick up repeat prescriptions. Two patients did not attend their appointment for IV iron infusion after randomization. Two patients decided against IV iron once randomized. Two patients desired a different oral iron dose, therefore withdrew from the trial after randomization. One patient had premature rupture of membrane at 28 weeks before the planned IV treatment was commenced. In the oral iron group, 1 patient had a stillbirth at 30 weeks and three patients declined continued participation because of the side effects of oral iron.

Cost effectiveness

The cost of one iron sulphate tablet (250 mg) is USD 0.5, so the average cost throughout one pregnancy is calculated to be USD 165. The cost of one ampoule of iron polymaltose containing 100 mg is USD 3, so the average treatment cost for average weight (60–80 kg) is USD 30–40. In Australia the cost of the outpatient hospital visit and nursing time for the IV iron, adds approximately USD 60 to the cost.

Quality of life assessment

Questionnaires designed to assess participants’ perception of their quality of life were performed at 2 and 6 weeks post initiation of treatment and at 28 and 34 weeks gestation as well as post delivery. The questionnaires incorporated categories, which assessed energy levels, activity, tolerance and symptoms and side effects of treatment as well as impact of anaemia and treatment on wellbeing, social and psychological welfare. Quality of life and wellbeing were measured regularly via functional and physical assessment as well as global health score. There was a benefit in the IV plus oral iron group in terms of amelioration of symptoms attributed to anaemia (energy level, wellbeing and physical activity) within a shorter period of time, in most cases between 1 and 2 weeks, from commencement of IV iron (P = 0.039) compared to no significant difference in quality of life after 4 weeks as measured in the oral iron only group. Overall, we found a trend towards an increase in levels of perceived wellbeing over the course of the trial in both groups. Perception of increased quality of life was scored from 1 (no improvement) to 5 (maximum improvement) with a mean score of 3.2 for the oral only arm of treatment and 3.4 for IV plus oral iron treatment at the end of the trial.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

This study examined the effect of the use of IV plus oral iron versus oral iron only in the context of a particular population and its health service. However, it is worth emphasizing that different populations may respond to each management strategy in different ways. We observed a 17.4% prevalence of moderate IDA during pregnancy at the time of the first antenatal visit. In our series, treatment with oral iron only resulted in a modest improvement of Hb at the time of delivery. The addition of a single dose of IV iron polymaltose led to a superior rise in Hb, which was statistically significant (P < 0.001) with a significant large additional ferritin increase at the time of delivery (P < 0.001). At delivery, subnormal ferritin levels were reduced from 79% with oral iron to less than 5% with IV plus oral iron. Consistent with this, prior to delivery 29% of women remained moderately anaemic with Hb < 116 g/L in the oral iron group versus 16% in the IV plus oral iron group (P = 0.04). It is worth noting that the mean ferritin level in the oral only iron group was largely attributed to the high ferritin level of three women who subsequently crossed over to receive IV iron therapy as part of the protocol. Birth weight and gestational age at delivery as well as cord blood Hb and ferritin levels were similar on the alternate treatment regimens. Thus, out-patient IV iron therapy in addition to oral iron in pregnant women with IDA appeared to be safe, effective and practical in a tertiary referral centre in a developed-country health service.

Although there are different recommendations for iron supplementation, mainly in the oral form during pregnancy, it remains a challenge to restore the depleted iron and correct the anaemia efficiently. A meta-analysis of 17 different randomized trials studying the effect of different iron therapies on IDA during pregnancy showed that there are significant gastro- intestinal adverse effects with oral iron compared with other routes of iron administration [14]. The same review and other reports suggested that intramuscular iron was associated with higher rates of local and systemic reactions compared to IV iron [10, 14–16].

Four studies have examined the effects of IV iron (in different preparations) and oral iron only: two randomized controlled trials utilized IV iron sucrose (a total of only 69 women) [12, 17] and two nonrandomized controlled trials utilized IV iron dextran and iron polymaltose (220 women) [9, 18], all conducted in major city teaching hospitals. Most showed the improved effectiveness of IV iron only or in combination with oral iron compared to oral iron only on Hb levels at delivery.

A single IV iron sucrose dose has been reported to produce an increased incidence of thrombosis (9/41; 22%) [14]. In contrast, six small doses of IV iron sucrose were administered over a three-week period without infusion-associated thrombosis in the 24 pregnant women studied [17]. In a subsequent randomized trial, IV iron sucrose was administered in five daily doses to 45 pregnant women, which was also well tolerated [12]. However, both trials administered IV iron sucrose in pregnancy at the expense of a vastly greater effort from the women as well as extra demands on hospital resources [12, 17]. In the first study, there was no significant difference between IV iron sucrose versus oral iron sulphate in the Hb levels at any time as measured at days 8, 15, 21, 30 and at delivery [17], whilst in the second trial, there was a significant difference in Hb levels in favour of the IV iron sucrose group as measured at 2 and 4 weeks after administration of IV iron and at delivery [12].

In our study, a single dose of IV iron polymaltose was well tolerated without serious adverse events and produced a significant rise in the Hb and ferritin levels at 4 weeks and at delivery compared to the oral iron only group. None of the studied patients received blood transfusion for correction of anaemia during pregnancy. Two patients (0.9%) in the oral iron only group received a blood transfusion secondary to obstetrical postpartum haemorrhage. The side effects of oral iron supplementation create an evident obstacle as our study showed that up to 30% of women experienced significant gastrointestinal symptoms whilst taking oral iron. The effect this can have on compliance was again well demonstrated in this trial; up to 12.5% of patients who received oral iron missed taking the tablets or obtaining further supplies. In addition, there are difficulties with absorption of oral iron in its most commercially available salt, iron sulphate, despite the prescription of vitamin C to enhance iron absorption. Furthermore, concerns have been raised recently regarding the inadequacy of the daily recommended iron intake in women with low iron stores [19]. Moreover, it is well known that absorption of oral iron is irregular and immeasurable routinely, and can be low due to various factors. Therefore, the purpose of the alternative method of iron administration (IV iron plus oral versus oral iron) is to deliver, theoretically, a higher total iron load to improve the toleration of high iron access to the body.

It is worth noting that it was not possible to evaluate the potential effect of a concurrent illness or infection on serum ferritin levels at the time of the assay. Nevertheless, due to the fact that low ferritin levels were observed in the absence of clinically detected illness in all participants, this confounder is unlikely to have occurred.

In conclusion, IDA appears to be a common finding during pregnancy in industrialized countries, which is commonly ignored and undertreated. A single dose of IV iron polymaltose appeared to be a safe and well tolerated form of iron supplementation in this cohort of patients. The IV plus oral iron arm of the study led to superior outcomes in terms of correction of anaemia and iron stores. Further studies are warranted to confirm these findings in different populations and to improve the estimates of the magnitude of the benefits. Examination of the effects of IV plus oral iron on postpartum psychological welfare of the mother, the quality of the bonding to her baby and the rate of developmental progress of the baby would also be worth determining in future studies. Furthermore, the current guidelines for the management of iron deficiency anaemia should incorporate intravenous iron polymaltose as effective and safe treatment not only in the pregnant population but also in other cohorts of patients with iron deficiency anaemia.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

All authors declare no financial conflicts of interest in relation to this research.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References

This research received a grant from the Clifford Craig Medical Research Trust, Launceston, Tasmania, Australia. The authors acknowledge the generous assistance of the Pharmacy Department at the Launceston General Hospital.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure
  8. Acknowledgements
  9. References
  • 1
    World Health Organization [WHO], Division of Family Health, Maternal Health and Safe Motherhood Programme, Division of Health Protection and Promotion, Nutrition Programme; WHO. The Prevalence of Anaemia in Women: A Tabulation of Available Information, 2nd edn. Geneva, Switzerland: World Health Organization, 1992.
  • 2
    ACC/SCN (United Nations Administrative Committee on Coordination/Standing Committee on Nutrition). 2004. Fifth report on the world nutrition situation: Nutrition for improved development outcomes. Geneva, 2004, Available at http://www.unscn.org/en/publications/rwns.
  • 3
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