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Keywords:

  • Intravenous iron sucrose;
  • oral ferrous sulphate;
  • postpartum anaemia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objective  Postpartum iron deficiency anaemia (IDA) is common in women. Most women are treated with either oral iron supplementation or blood transfusion. Hence, the aim of our study was to compare the effect of treatment with either oral ferrous sulphate or intravenous ferrous sucrose on postpartum IDA.

Design  A single centre, prospective randomised controlled trial.

Setting  Women’s Centre, John Radcliffe Hospital, Oxford, UK.

Population  Forty-four women with haemoglobin (Hb) of <9 g/dl and ferritin of <15 microgram/l at 24–48 hours postdelivery.

Methods  Women were randomised to receive either oral ferrous sulphate 200 mg twice daily for 6 weeks (group O) or intravenous ferrous sucrose 200 mg (Venofer; Vifor International Ltd, St Gallen, Switzerland), two doses given on days 2 and 4 following recruitment (group I). Results were analysed by the Students t-test, chi-square test and analysis of variance.

Main outcome measures  Hb, haematocrit, red cell indices, ferritin and serum iron levels were measured on days 0, 5, 14 and 40.

Results  By day 5, the Hb level in women treated with intravenous iron had risen from 7.3 ± 0.9 to 9.9 ± 0.7 g/dl, while there was no change in those treated with oral iron. Women treated with intravenous iron had significantly higher Hb levels on days 5 and 14 (P < 0.01) than those treated with oral iron; although by day 40, there was no significant difference between the two groups. Throughout the study, ferritin levels rose rapidly in those treated with intravenous iron and remained significantly higher than in those treated with oral iron (P < 0.01).

Conclusions  Intravenous iron sucrose increases the Hb level more rapidly than oral ferrous sulphate in women with postpartum IDA. It also appears to replenish iron stores more rapidly. However, this study was not large enough to address the safety of this strategy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Postpartum haemoglobin (Hb) levels of <10 g/dl are observed in up to 30% of women, with more severe anaemia (Hb < 8 g/dl) seen in 10%.1 Iron deficiency is the principal cause. This is partly attributable to an iron deficit during pregnancy caused by the increased iron demands of the fetoplacental unit and an increased maternal red cell mass.2 Irrespective of mode of delivery, blood loss is a contributing factor, with 5% of deliveries involving loss of more than 1 l.3,4

Iron deficiency anaemia (IDA) is thought to contribute to a variety of morbidities such as lethargy, lactation failure and postpartum depression.5 The standard approach to treatment in the majority of UK institutions is oral iron supplementation, with blood transfusion reserved for more severe or symptomatic cases. However, the transfusion trigger is clinician dependant and a number of studies and audits have shown that the transfusion level varies widely between medical teams and institutions, with a significant proportion of transfusions given inappropriately.6 There are a number of hazards of allogenic blood transfusion including transfusion of the wrong blood, infection, anaphylaxis and lung injury, any of which would be devastating for a young mother. These hazards, together with the national shortage of blood products, mean that transfusion should be viewed as a last resort in otherwise young and healthy women.7

Oral iron supplementation is more commonly used than blood transfusion for postpartum IDA. However, it is unreliable in the treatment of severe anaemia due to its limited absorption and gastrointestinal adverse effects that affect compliance.8,9 Parenteral iron administration with ferrous sucrose is now available and routinely used in a number of European countries. Unlike previous formulations, most notoriously ferrous dextran, which was associated with a significant risk of anaphylactoid reactions, ferrous sucrose has an excellent safety record.10

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

A prospective randomised study was conducted. Ethics committee approval was obtained, and written informed consent from all women was obtained prior to participation in the study.

Participants

The study population consisted of women aged 18 years or more with postpartum IDA (defined as Hb of <9 g/dl and ferritin of <15 microgram/l at 24–48 hours postdelivery). The exclusion criteria were previous iron therapy during pregnancy, intolerance to iron derivatives, peripartum blood transfusion or a history of asthma, thromboembolism, seizures, alcohol or drug abuse. Women with signs of infection or evidence of renal or hepatic dysfunction were excluded from the study.

Randomisation

The women were randomised to one of the two groups using a computer-generated randomisation schedule. Opaque, sealed envelopes containing the treatment allocation were prepared and marked with a sequential numerical code by an independent person. After obtaining consent, the next consecutive envelope was opened by the recruiter and the woman was prescribed the appropriate treatment.

Treatments

Treatment was started at 24–48 hours after delivery. Women were randomised either to group I, where they received two doses of intravenous ferrous sucrose 200 mg (Venofer; Vifor International Ltd, St Gallen, Switzerland) given on days 2 and 4 following recruitment or to group O, where they received oral ferrous sulphate 200 mg twice daily for 6 weeks.

In group I, the dose of intravenous ferrous sucrose used was based on pooled data from four different randomised studies using cumulative doses of 100–800 mg.10 The ferrous sucrose was administered as an infusion in 250 ml of 0.9% sodium chloride for more than 30 minutes. This group received no further iron supplementation. They were asked, however, to note any symptoms or adverse effects of treatment.

In group O, the women were advised to take 200 mg ferrous sulphate twice daily together with meals for 6 weeks from the day of recruitment. They were given a date on which to stop oral iron supplementation. Women were required to document treatment compliance and symptoms on a diary chart provided for that purpose. Compliance was further emphasised by regular contact with one of the investigators (N.B.), community midwives and health visitors. A pill count was carried out on days 14 and 40.

Laboratory procedures

Blood samples were taken at recruitment into the study (day 0) and at days 5, 14 and 40 after the start of the treatment. These time-points were chosen based on previous studies10 and to minimise any inconvenience to the women, as they would normally have had contact with either community midwives or health visitors on these days. The time-points were also chosen to detect any differences in the speed of restoration of Hb and iron stores. Hb, haematocrit, red cell indices, mean corpuscular volume and mean corpuscular Hb levels were measured. Iron status markers measured included serum ferritin and serum iron. The C-reactive protein level was also measured at each time-point to exclude artificial elevation of ferritin levels due to an acute inflammatory response.

The incidence and severity of adverse events were recorded. In accordance with recommendations, the intravenous sucrose was administered in areas where there were facilities for monitoring and resuscitation. Vital signs (pulse, noninvasive blood pressure and oxygen saturation) were monitored during and for 30 minutes after infusion.

Statistical analysis

From previous studies, it was found that treatment with intravenous iron sucrose increase the Hb concentration by 25% by day 5. To detect this increase with 90% power at the 5% significance level, we calculated that 20 women needed to be recruited to each group. Hb data at each of the three postbaseline assessment times were analysed by analysis of covariance. All analyses were conducted using SPSS for Windows, version 10.0 (SPSS Inc, Chicago, IL, USA). The effect of iron supplementation on maternal iron status was analysed by Student’s t-test.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Forty-four women entered the study, but data were available from only 43. All the women were haemodynamically stable at the time of inclusion into the study. A single exclusion from the study occurred when a woman in group O suffered a secondary postpartum haemorrhage at home and was re-admitted for blood transfusion. The groups did not differ at baseline in characteristics or laboratory data (Table 1). Forty-two women had elective lower segment caesarean sections and one had a vaginal operative delivery. All the women in the study received 0.5% hyperbaric bupivacaine 2.5–2.7 ml and fentanyl 15 micrograms intrathecally using a spinal technique for the delivery. The fluid management was standardised with a preload of 500 ml Hartmann’s solution during the administration of the intrathecal injection, and a further 1000–1500 ml Hartmann’s solution was given intraoperatively according to clinical need. Syntocinon® (Alliance, Wiltshire, UK) was administered postdelivery as a slow intravenous bolus injection of 10 iu, followed by a continuous infusion of 40 units in 500 ml 0.9% saline at a rate of 125 ml/hour. All the women received the above standardised regimen, with the exception of the woman who had a vaginal operative delivery and received intramuscular Syntocinon® only. The range of estimated blood loss was from 550 ml to 1.2 l, with a median loss of 750 ml. This was calculated by the theatre staff based on suction volume and swab weights. The mean duration to treatment after delivery was 30 ± 5 hours, with no difference between the two groups.

Table 1.  Baseline data at recruitment into the study
CharacteristicsGroup I (n= 22)Group O (n= 21)
  1. Data are given as mean (SD).

Age29 (3.7)28 (4.1)
Hb (before delivery) (g/dl)11 (1.8)11.9 (2.1)
Hb (g/dl)7.5 (0.8)7.3 (0.9)
Haematocrit (%)26.5 (3.1)27.9 (5.1)
Ferritin (microgram/l)11.0 (4.1)13.0 (3)
Serum iron (nmol/l)6.5 (0.3)7.0 (0.7)

Hb response

Hb levels increased from baseline in both treatment groups at days 5, 14 and 40 (Figure 1), with higher levels in those in the intravenous group at days 5 and 14 (P < 0.01). The mean increase in Hb level from baseline at day 5 was 2.5 g/dl in group I and 0.7 g/dl in group O. However, by day 40, there was no significant difference between the treatment groups (Table 2).

image

Figure 1. Response of Hb to intravenous and oral iron therapies.

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Table 2.  Laboratory data after treatment with iron
 Group OGroup I
  • Data are given as mean (SD).

  • *

    P < 0.01.

  • **

    P < 0.05.

Hb (g/dl)
Day 07.5 (0.8)7.3 (0.9)
Day 57.9 (0.6)9.9 (0.7)*
Day 149.0 (0.4)11.1 (0.6)*
Day 4011.2 (1.2)11.5 (1.3)
Ferritin (microgram/l)
Day 011.0 (4)13.0 (3)
Day 512.0 (2)48.0 (6)*
Day 1416.0 (4)37.9 (5)*
Day 4015.0 (3)42.2 (7)**

Iron status

There was no significant difference in ferritin levels between the groups at baseline (Table 1). Figure 2 shows the response of ferritin levels in the treatment groups. There was a significant increase in ferritin levels in group I by day 5 (P < 0.01), and the ferritin levels remained elevated in this group. In comparison, no increase in ferritin levels was seen with oral iron supplementation. Serum iron levels also increased in both groups, with the levels being significantly higher in group I at days 14 and 40 (P < 0.01) (Figure 3).

image

Figure 2. Response of ferritin to intravenous and oral iron therapies.

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image

Figure 3. Response of serum iron to intravenous and oral iron therapies.

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Safety

No serious adverse events was reported. In group I, five women (23%) complained of a metallic taste during the infusion of the drug. This was transient in nature and resolved immediately after the infusion was complete. Four women (18%) complained of facial flushing, describing it as a warm tingling sensation; again this was reported as ‘not unpleasant’. There were no haemodynamic disturbances observed either during infusion or after infusion.

In group O, seven women (33%) complained of adverse effects. These were all of a gastrointestinal nature ranging from dyspepsia, nausea and constipation. Despite these symptoms, 100% compliance was reported and confirmed at the pill counts.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The study was performed to ascertain whether administering intravenous ferrous sucrose to women with postpartum anaemia results in higher Hb concentrations and improved iron stores than using standard treatment with oral iron.

In our study, ferritin and serum iron were used as indicators of iron storage. Although ferritin levels are low in pregnancy due to plasma dilution, ferritin remains a reliable indicator of iron deficiency, where a cutoff level of <15 microgram/l is used.11,12 A spontaneous restoration of ferritin levels due to physiological changes and fluid shifts postpartum is know to occur, but it had little effect in this study as there was minimal change in the ferritin levels in those treated with oral iron.

We have shown that two 200 mg doses of intravenous ferrous sucrose significantly increases Hb levels and rapidly replenish iron stores within 5 days, with a mean increase from baseline of 2.5 g/dl. Although Hb levels were similar in both groups by day 40, only intravenous ferrous sucrose appeared to restore iron reserves, with a statistical difference throughout the treatment period.

Ferrous sucrose appears to be effective because it is rapidly removed from the plasma and used for erythropoiesis. After a bolus dose of saccharated iron, plasma levels peak at 10 minutes. Twenty-four hours after administration, the plasma level is negligible, indicating rapid incorporation. This has been shown by positron emission tomography studies, which show immediate incorporation into the bone marrow while the plasma levels fall.13 These studies, mostly investigating renal patients with severe IDA, have shown that 70–97% of the iron is used for erythropoiesis, with only 4–6% elimination.

Other intravenous iron preparations have been used previously, particularly ferrous dextran, but due to their high anaphylactoid risk, there is now considerable reluctance to administer them. In our study, intravenous ferrous sucrose was well tolerated and not associated with any serious adverse effects. This finding is supported by previous larger studies that have investigated the safety profile of intravenous ferrous sucrose both during pregnancy and in the postpartum period.14–16 Perewunsnyk et al.10 studied 400 women who received a total of 2000 ampoules of ferrous sucrose. Minor general adverse effects including a metallic taste, flushing of the face and burning at the injection site occurred in 0.5%, with doses up to 200 mg. The high tolerance of the drug has been partly attributed to slow release of iron from the complex and also due to the low allergenicity of sucrose.

The dose of oral ferrous sulphate used in our study was based on standard practice in our hospital. This dose is also widely used in the majority of institutions in the UK. Higher doses appear to increase reported adverse effects without a significant effect on haematological parameters.8

In our study, compliance with oral treatment was surprisingly good and was reinforced with regular visits and verbal contact by the investigator. This contrasts with compliance findings described in other studies. Gastrointestinal adverse effects are thought to be dose related and occur more frequently at higher doses.8 al-Momen et al.17 described gastrointestinal adverse effects with a frequency of up to 30% in women treated with oral iron. In our study, adverse effects occurred in 33% of women but were not severe enough to affect compliance. It has to be noted that this group of women was highly motivated and therefore may have persisted with oral iron for longer than the general postpartum population. If this is true, then the benefits of intravenous iron over oral iron may be greater in clinical practice than in this study setting.

The general health effects of iron deficiency in the obstetric population have been identified as an area of research priority.18 It is well known that women with anaemia suffer from increased cardiovascular strain, reduced exercise performance and various symptoms including a feeling of reduced wellbeing, headaches, tiredness and dizziness. All these symptoms can be debilitating, especially when caring for a newborn. Women suffering from early postpartum anaemia may also have an increased risk of developing postpartum depression.19 Our study did not examine the effects of improving the haematological parameters on the symptom profile. Due to the relatively small number of women in our study, there would have been numerous confounding factors that would have made results difficult to interpret, and it was therefore decided to concentrate on more objective data. However, a larger study matching for such external factors would be useful to assess the effects of rapidly improving anaemia on symptomatic relief.

UK blood services remain under considerable pressure to provide safe and sufficient allogenic blood components for clinical use. Improved safety when considering the risks of transmission of HIV and hepatitis is well documented,20 but newer fears have emerged, especially regarding the transmission of variant Creutzfeldt-Jakob disease.21 This has led to a further reduction in blood supplies as a government decision to exclude donors who themselves have received a blood donation since 1980. With such demands placed on the blood services, one of the main strategies must be to use alternative methods and therefore avoid the need for a transfusion. If used appropriately, intravenous ferrous sucrose may help reduce the incidence of allogenic blood transfusions during the postnatal period, with transfusion being reserved for women with haemodynamic instability and continuing bleeding.

In our study, intravenous ferrous sucrose appeared to provide a rapid resolution of both iron stores and Hb for women with postpartum IDA. However, a larger study is needed to examine the risks of the infusion and the accompanying clinical benefits this may provide.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
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    Al-Momen AK, Al-Meshari A, Al-Nuaim L, Saddique A, Abotalib Z, Khashogji T, et al. Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. Eur J Obstet Gynecol Reprod Biol 1996;69:1214.
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