DOI: 10.1111/j.1471-0528.2006.01062.
x
www.blackwellpublishing.com/bjog
Intravenous versus oral iron therapy for
postpartum anaemia
N Bhandal, R Russell
Department of Anaesthesia, Nuffield Department of Anaesthetics, John Radcliffe Hospital, Oxford, UK
Correspondence: Dr N Bhandal, Department of Anaesthesia, Nuffield Department of Anaesthetics, John Radcliffe Hospital,
Oxford OX3 9DU, UK. Email nav1@doctors.org.uk
Accepted 25 July 2006. Published OnlineEarly 28 September 2006.
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.
Please cite this paper as: Bhandal N, Russell R. Intravenous versus oral iron therapy for postpartum anaemia. BJOG 2006;113:1248–1252.
Introduction
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 supplementa-
tion, with blood transfusion reserved for more severe or
symptomatic cases. However, the transfusion trigger is clini-
1248
General obstetrics
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.
Keywords Intravenous iron sucrose, oral ferrous sulphate,
postpartum anaemia.
cian dependant and a number of studies and audits have
shown that the transfusion level varies widely between med-
ical 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 prod-
ucts, 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 unreli-
able 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
ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

European countries. Unlike previous formulations, most
notoriously ferrous dextran, which was associated with a sig-
nificant risk of anaphylactoid reactions, ferrous sucrose has an
excellent safety record.10
Methods
A prospective randomised study was conducted. Ethics com-
mittee 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 preg-
nancy, intolerance to iron derivatives, peripartum blood
transfusion or a history of asthma, thromboembolism, seiz-
ures, 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 fer-
rous 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
ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology
Intravenous versus oral iron therapy for IDA
(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 suc-
rose 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 intra-
venous 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 Win-
dows, 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
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 sec-
tions 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 tech-
nique for the delivery. The fluid management was standar-
dised with a preload of 500 ml Hartmann’s solution during
the administration of the intrathecal injection, and a further
1249
 Bhandal and Russell

Table 1. Baseline data at recruitment into the study Iron status

There was no significant difference in ferritin levels between
Characteristics Group I (n 5 22) Group O (n 5 21) the groups at baseline (Table 1). Figure 2 shows the response
of ferritin levels in the treatment groups. There was a signifi-
Age 29 (3.7) 28 (4.1)
cant increase in ferritin levels in group I by day 5 (P < 0.01),
Hb (before delivery) (g/dl) 11 (1.8) 11.9 (2.1)
Hb (g/dl) 7.5 (0.8) 7.3 (0.9)
and the ferritin levels remained elevated in this group. In
Haematocrit (%) 26.5 (3.1) 27.9 (5.1) comparison, no increase in ferritin levels was seen with oral
Ferritin (microgram/l) 11.0 (4.1) 13.0 (3) iron supplementation. Serum iron levels also increased in
Serum iron (nmol/l) 6.5 (0.3) 7.0 (0.7) both groups, with the levels being significantly higher in
group I at days 14 and 40 (P < 0.01) (Figure 3).
Data are given as mean (SD).
Safety
No serious adverse events was reported. In group I, five
1000–1500 ml Hartmann’s solution was given intraoper- women (23%) complained of a metallic taste during the infu-
atively according to clinical need. Syntocinon
(Alliance, sion of the drug. This was transient in nature and resolved
Wiltshire, UK) was administered postdelivery as a slow intra- immediately after the infusion was complete. Four women
venous bolus injection of 10 iu, followed by a continuous (18%) complained of facial flushing, describing it as a warm
infusion of 40 units in 500 ml 0.9% saline at a rate of 125 tingling sensation; again this was reported as ‘not unpleasant’.
ml/hour. All the women received the above standardised reg- There were no haemodynamic disturbances observed either
imen, with the exception of the woman who had a vaginal during infusion or after infusion.
operative delivery and received intramuscular Syntocinon
In group O, seven women (33%) complained of adverse
only. The range of estimated blood loss was from 550 ml to effects. These were all of a gastrointestinal nature ranging
1.2 l, with a median loss of 750 ml. This was calculated by the from dyspepsia, nausea and constipation. Despite these symp-
theatre staff based on suction volume and swab weights. The toms, 100% compliance was reported and confirmed at the
mean duration to treatment after delivery was 30 ± 5 hours, pill counts.
with no difference between the two groups.

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).
Discussion
The study was performed to ascertain whether administering
intravenous ferrous sucrose to women with postpartum anae-
mia 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 indi-
cators of iron storage. Although ferritin levels are low in
pregnancy due to plasma dilution, ferritin remains a reliable

14
Table 2. Laboratory data after treatment with iron

Group O Group I
12
*
Haemoglobin (g/dl)

Hb (g/dl)
* Day 0 7.5 (0.8) 7.3 (0.9)
10 Day 5 7.9 (0.6) 9.9 (0.7)*
Day 14 9.0 (0.4) 11.1 (0.6)*
Day 40 11.2 (1.2) 11.5 (1.3)
8 Ferritin (microgram/l)
Day 0 11.0 (4) 13.0 (3)
Oral Iron
IV Iron Day 5 12.0 (2) 48.0 (6)*
6 Day 14 16.0 (4) 37.9 (5)*
*p<0.01 Day 40 15.0 (3) 42.2 (7)**

Prepartum 0 5 14 40
Data are given as mean (SD).
Days *P , 0.01.
**P , 0.05.
Figure 1. Response of Hb to intravenous and oral iron therapies.

1250 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

 Intravenous versus oral iron therapy for IDA

* minutes. Twenty-four hours after administration, the plasma

50 * level is negligible, indicating rapid incorporation. This
has been shown by positron emission tomography studies,
* which show immediate incorporation into the bone marrow
40
while the plasma levels fall.13 These studies, mostly investi-
gating renal patients with severe IDA, have shown that
Ferritin (µg/l)

30 70–97% of the iron is used for erythropoiesis, with only

20
10
0 effects. This finding is supported by previous larger studies
0 5 14
Days
Figure 2. Response of ferritin to intravenous and oral iron therapies.
indicator of iron deficiency, where a cutoff level of <15 micro-
gram/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 through-
out 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
35
30 * was highly motivated and therefore may have persisted with
Serum Iron (nmol/L)
*p<0.01 4–6% elimination.
Other intravenous iron preparations have been used pre-
viously, particularly ferrous dextran, but due to their high
anaphylactoid risk, there is now considerable reluctance to
Oral iron administer them. In our study, intravenous ferrous sucrose
IV iron
was well tolerated and not associated with any serious adverse
40
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 com-
plex 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 sig-
nificant effect on haematological parameters.8
In our study, compliance with oral treatment was surpris-
ingly 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 fre-
quently at higher doses.8 al-Momen et al.17 described gastro-
intestinal 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
oral iron for longer than the general postpartum population.

25 If this is true, then the benefits of intravenous iron over oral

iron may be greater in clinical practice than in this study
20
setting.
15
The general health effects of iron deficiency in the obstetric
population have been identified as an area of research prior-
10 *p<0.01 ity.18 It is well known that women with anaemia suffer from
increased cardiovascular strain, reduced exercise performance
5 oral iron and various symptoms including a feeling of reduced well-
IV iron
being, headaches, tiredness and dizziness. All these symptoms
0
can be debilitating, especially when caring for a newborn.
0 5 14 40
Women suffering from early postpartum anaemia may also
Days
have an increased risk of developing postpartum depression.19
Figure 3. Response of serum iron to intravenous and oral iron therapies. Our study did not examine the effects of improving the

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 1251

 Bhandal and Russell
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 transmis-
sion 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 dona-
tion 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 post-
natal period, with transfusion being reserved for women
with haemodynamic instability and continuing bleeding.
In our study, intravenous ferrous sucrose appeared to pro-
vide 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 clin-
ical benefits this may provide. j
References
1 Aggett P. Iron and women in the reproductive years. In: The British
Nutrition Foundation’s Task Force, editors. Iron: Nutritional and Phy-
siological Significance, 1st edn. London: Chapman and Hall; 1995.
p. 110–8.
2 Baker W. Iron deficiency in pregnancy, obstetrics and gynecology.
Hematol Oncol Clin North Am 2000;14:1061–77.
3 Gulmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L,
et al. WHO multicentre randomised trial of misoprostol in the manage-
ment of the third stage of labour. Lancet 2001;358:689–95.
4 Kotto-Kome AC, Calhoun DA, Montenegro R, Sosa R, Maldonado L,
Christensen MD. Effect of administering recombinant erythropoietin to
women with postpartum anemia: a meta-analysis. J Perinatol 2004;
24:11–15.
1252
5 Atkinson LA, Baxley EG. Postpartum fatigue. Am Fam Physician 1994;
50:113–18.
6 Silverman JA, Barrett J, Callum JL. The appropriateness of red blood cell
transfusions in the peripartum patient. Obstet Gynecol 2004;104:
1000–4.
7 Morrison JC, Morrison FG. Rational use of blood products in obstetrics
and gynecology. J Matern Fetal Invest 1994;4:147–53.
8 Hallberg L, Ryttinger L, Solvell L. Side effects of oral iron therapy. A
double-blind study of different iron compounds in tablet form. Acta
Med Scand Suppl 1966;459:3–10.
9 Solvell L. Oral iron therapy-side effects. In: Hallberg L, Harwerth HG,
Vannotti A, editors. Iron Deficiency: Pathogenesis, Clinical Aspects,
Therapy, 1st edn. London: Academic Press; 1970. p. 573–83.
10 Perewunsnyk G, Huch R, Huch A, Breymann C. Parenteral iron therapy
in obstetrics: 8 years experience with iron-sucrose complex. Br J Nutr
2002;88:3–10.
11 Mei Z, Cogswell ME, Parvanta I, Lynch S, Beard JL, Stoltzfus RJ, Grummer-
Strawn LM. Haemoglobin and ferritin are currently the most efficient
indicators of population response to iron interventions: an analysis
of nine randomised controlled trials. J Nutr 2005;135:1974–80.
12 van den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in
pregnant women: which measurements are valid? Br J Haematol
1998;103:817–24.
13 Beshara S, Lundqvist H, Sundin J, Lubberink M, Tolmachev V, Valind S,
et al. Pharmacokinetics and red cell utilization of iron (III) hydroxide-
sucrose complex in anaemic patients: a study using positron emission
tomography. Br J Haematol 1999;104:296–302.
14 Danielson B. Intravenous iron therapy-efficacy and safety of iron
sucrose. In: Huch A, Huch R, Breymann C, editors. Prevention and
Management of Anemia in Pregnancy and Postpartum Haemorrhage.
Zurich, Switzerland: Schellenberg Druck AG, 1998. p. 93–106.
15 Danielson B, Salmonson T, Derendorf H, Geisser P. Pharmacokinetics of
iron hydroxide sucrose complex after a single intravenous dose in
healthy volunteers. Drug Res 1996;46:615–21.
16 Breymann C. Modern therapy concepts for severe anemia in pregnancy
and postpartum. In: Huch A, Huch R, Breymann C, editors. Prevention
and Management of Anemia in Pregnancy and Postpartum Haemor-
rhage. Zurich, Switzerland: Schellenberg Druck AG, 1998. p. 107–22.
17 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;69:121–4.
18 Stoltzfus RJ. Iron-deficiency anemia: re-examining the nature and mag-
nitude of the public health problem. Summary: implication for research
and programs. J Nutr 2001;131:697S–700S.
19 Corwin EJ, Murray-Kolb LE, Beard JL. Low haemoglobin is a risk factor
for postpartum depression. J Nutr 2003;133:4139–42.
20 Goodnough LT, Shander A, Brecher ME. Transfusion medicine: looking
to the future. Lancet 2003;361:161–9.
21 NHS Executive. Better Blood Transfusion Appropriate Use of Blood,
(Circular HSC 2002/009). London: NHS Executive, 2002.
ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology