Hindawi Publishing Corporation
Journal of Pregnancy
Volume 2012, Article ID 630519, 10 pages
Pathophysiology and Effectof
OralversusIntravenous Iron Therapy
Alhossain A.Khalafallah1,2and AmandaE.Dennis2,3
1Department of Haematology, Launceston General Hospital, Launceston, Tasmania 7250, Australia
2School of Human Life Sciences, University of Tasmania, Australia
3Department of Obstetrics and Gynaecology, Launceston General Hospital, Tasmania 7250, Australia
Correspondence should be addressed to Alhossain A. Khalafallah, firstname.lastname@example.org
Received 3 February 2012; Revised 4 April 2012; Accepted 18 April 2012
Academic Editor: Nils Milman
Copyright © 2012 A. A. Khalafallah and A. E. Dennis. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
Nutritional iron-deficiency anaemia (IDA) is the most common disorder in the world, affecting more than two billion people. The
World Health Organization’s global database on anaemia has estimated a prevalence of 14% based on a regression-based analysis.
Recent data show that the prevalence of IDA in pregnant women in industrialized countries is 17.4% while the incidence of IDA
in developing countries increases significantly up to 56%. Although oral iron supplementation is widely used for the treatment
of IDA, not all patients respond adequately to oral iron therapy. This is due to several factors including the side effects of oral
iron which lead to poor compliance and lack of efficacy. The side effects, predominantly gastrointestinal discomfort, occur in a
large cohort of patients taking oral iron preparations. Previously, the use of intravenous iron had been associated with undesirable
and sometimes serious side effects and therefore was underutilised. However, in recent years, new type II and III iron complexes
have been developed, which offer better compliance and toleration as well as high efficacy with a good safety profile. In summary,
intravenous iron can be used safely for a rapid repletion of iron stores and correction of anaemia during and after pregnancy.
Nutritional iron deficiency is the most common deficiency
disorder in the world, affecting more than two billion
people worldwide, 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 an average of 14% of pregnant women in industrialized
countries to an average of 56% (range 35–75%) in develop-
ing countries [2, 3].
Furthermore, IDA not only affects a large number of
women and children in the developing world, but is also
considered the only nutrient deficiency that is significantly
prevalent in the developed world also. The number of
patients with ID and IDA is overwhelming as more than 2
billion people, approximately 30% of the world’s population,
are iron deficient with variable prevalence, distribution, and
contributing factors in different parts of the world [1–3].
Iron deficiency affects more women than any other
condition, constituting an epidemic public health crisis. It
is usually present with subtle manifestations and should
be considered as a chronic slowly progressing disease that
is often underestimated and untreated worldwide despite
several warnings and awareness campaigned by the WHO
The high prevalence of IDA in women has substantial
health consequences with subsequent socioeconomic haz-
ards, including poor pregnancy outcome, impaired edu-
cational performance, and decreased work capacity and
productivity [1, 4].
Because of the magnitude and consequences of iron
deficiency anaemia in the world, especially in women in
their childbearing period, several international conferences
2 Journal of Pregnancy
on nutrition have addressed this issue in order to reduce the
prevalence of iron deficiency in women of childbearing age
without major success [1–6]. The consequences of IDA have
been widely studied [7–10]. However, there remains a lack of
data about its effects on patient’s wellbeing.
Targeted iron supplementation, an iron-rich diet, or
both, can improve iron deficiency. However, the variability
of bioavailable iron compounds limits its value against
nutritional iron deficiency. Therefore, laboratory measures
of iron stores should be utilised to determine iron deficiency
and monitor therapy [3–6].
This review highlights the importance of IDA in preg-
nancy and discusses appropriate treatment in order to avoid
serious complications of anaemia.
The balance of iron metabolism in healthy individuals
predominantly reflects three variables: nutritional intake,
iron loss, and current demand. The nutritional iron intake
relates to the amount of digested iron in food and the ability
to absorb iron from the digestive tract . The amount of
iron absorbed depends largely on the presence or absence
of pathology of the gastrointestinal tract or a comorbidity
(such as chronic inflammatory diseases) that may result in
expression of the iron regulatory proteins and a peptide
called hepcidin, which ultimately blocks iron absorption
The main source of iron in humans comes from the
destruction of erythrocytes by macrophages of the reticu-
recycled internal iron supply. Recentstudies have shown how
the human body up- and downregulates iron absorption in
response to changing iron status via intestinal and hepatic
2.1. Iron Metabolism in Pregnancy. During pregnancy, fetal
hepcidin controls the placental transfer of iron from mater-
tions are low, iron enters blood plasma at a high rate. When
hepcidin concentrations are high, ferroportin is internalized,
and iron is trapped in enterocytes, macrophages, and
hepatocytes [11, 15]. The daily requirement of external iron
remains as little as between 1 to 8mg daily . However,
more external iron is required to balance increased demand
for iron especially with physiological requirements during
growth, pregnancy, and lactation [16, 17]. This significant
increased demand for iron is required to develop the fetus
and placenta in addition to support mother’s blood volume.
and after delivery [16–18].
The total iron loss associated with pregnancy and
lactation is approximately 1000mg [16, 17]. Therefore the
recommended daily dietary allowance for iron in preg-
nancy is 27mg instead of 8mg in the adult nonpregnant
population. Lactation requires a daily dietary allowance
of 10mg [16–18].
3.1. Definition of Anaemia in IDA in Pregnant and Non-
pregnantWomen. Anaemia of pregnancyis generallydefined
as Hb <110g/L or <115g/L in some clinical practice
pregnancy. However, a haemoglobin level <100g/L indicates
anaemia at any stage during pregnancy that should initiate
investigations and treatment because of potentially serious
consequences for the mother and her baby, with an increased
risk of intrauterine growth retardation and premature birth.
In the meantime, anaemia in women of reproductive age is
defined as Hb <120g/L or in some studies <115g/L as this is
laboratory and population specific [7–10].
3.2. Definition of Iron Deficiency (ID). Iron deficiency can
be classified as severe ID when the serum ferritin level is
level is below 70–100µg/L. Ferritin level is considered the
surrogate marker for ID. However, serum ferritin is an acute
phase reactant and may be raised in cases of inflammation
or infection, therefore a concurrent test for inflammatory
markers is advisable in cases of anaemia with raised ferritin
to exclude reactive causes. ID is most likely not present if the
ferritin level is above 100µg/L .
Although a study of bone marrow iron stores is generally
regarded as the definitive marker of iron deficiency, it
remains an impractical and invasive procedure to apply
for most patients. Measurement of both soluble transferrin
receptor and serum ferritin provides a tool for accurate
diagnosis of IDA [19–21]. However, transferrin receptor is
not a well-standardized test that can be reliably reproduced
with high precision in most laboratories worldwide .
test to perform in most laboratories in the world; however,
its use is limited in cases of inflammation or infection as it
is considered to be influenced by acute phase responses and
hence negatively influences its value in clinical interpretation
of the test results [19, 20]. The commonly available labo-
ratory tests that determine iron status, namely, serum iron,
transferrin, total iron-binding capacity (TIBC), transferrin
saturation, and ferritin are widely used in worldwide clinical
practice [19, 20].
Soluble TfR (sTfR) is present in human plasma and
is considered as a truncated form of the tissue receptor
that exists as a transferrin-receptor complex and therefore
it reflects tissue iron deficiency . Another protein that
plays a crucial role in iron metabolism is hepcidin, which is
primarily made by hepatocytes and secreted into the blood
circulation. Hepcidin is a small-sized molecule composed
of 25-amino acid peptide, which is renally excreted and
therefore can be detected and measured in urine [14, 15].
Furthermore, hepcidins rapid excretion suggests that it is
regulation triggered at the level of production sites. Hepcidin
circulates in the ferroportins plasma and responds to various
stimuli that regulate iron stores and serum iron .
Recent studies demonstrate that hepcidin levels are
urine hepcidin levels can be achieved by mass spectrometry
Journal of Pregnancy3
and immunoassays in serum, plasma, and urine .
However, the diagnostic utility of serum hepcidin in iron
deficiency has not yet been defined in clinical application
. Nevertheless, hepcidin estimation seems a potentially
accurate test that reflects the actual iron status with less
Altogether, new technology such as hypochromic reticu-
locytes and reticulocyte haemoglobin testing, sTfR, and hep-
cidin have reportedly been developed with higher sensitivity,
specificity, reproducibility, and cost effectiveness [19–24].
This may offer a reliable screening tool for iron deficiency
in the future. It is worth noting that there are no specific data
addressing the difference of these markers in the pregnant
versus nonpregnant population. However, in principle, no
essential change should occur in iron metabolism in the
pregnant versus non-pregnant population except for the
increased iron demand as discussed before.
3.3. Current Strategy to Assess Iron Deficiency during Preg-
nancy. Full blood count and MCV value allowing the
diagnosis of microcytic anaemia is considered a good
screening tool for IDA. However, in areas of the world where
haemoglobinopathies are prevalent and these may be asso-
ciated with microcytosis, iron studies, in particular ferritin
level remains the surrogate marker for IDA. According to
the ferritin level, iron deficiency can be classified as severe
ID when the ferritin level is <30µg/L or mild-moderate ID
if ferritin <100µg/L and >30µg/L (there is a wide normal
range between 20 and 464 and is laboratory and method
specific) . In cases of elevated ferritin >100µg/L with
a concurrent anaemia, a reactive common cause such as
infection should be excluded and other causes of anaemia
should be examined accordingly. Other complementary tests
in iron studies such as serum iron, iron binding capacity, and
transferrin saturationarehelpfulin confirmingthe diagnosis
4.Oral versusIntravenousIronfor Treatment
of Iron Deficiency in Women of Reproductive
Oraliron therapy is themost widelyprescribed treatmentfor
iron deficiency anaemia, however, there are many issues that
may prevent oral iron supplementation from successfully
managing IDA. For instance, many patients do not respond
adequately to oral iron therapy due to difficulties associated
with ingestion of the tablets and their side effects. Side effects
may play a significant role in rates of compliance [25, 26].
Furthermore, the presence of bowel disease may affect the
absorption of iron and thereby minimize the benefit received
from oral iron therapy [27–29].
The side effects of oral iron therapy include gastroin-
testinal disturbances characterized by colicky pain, nausea,
50% of patients taking iron preparations [13, 27–29].
Furthermore, the most widely prescribed oral iron is
mainly composed of ferrous salts [25–27]. Ferrous salt
is characterized by low and variable absorption rates. Its
absorption can be limited by ingestion of certain foods
as well as mucosal luminal damage [27–29]. Therefore,
ferric compounds were introduced to avoid such obstacles.
However, these compounds are generally less soluble and
have poor bioavailability .
The usual recommended oral iron sulphate dose for
the treatment of iron deficiency is at least 80mg daily of
elemental iron, which is equivalent to 250mg of oral iron
sulphate tablets (Abbott, Australasia Pty Ltd.).
Iron absorption requires an acidic medium, therefore
its absorption may be decreased by intake of antacids or
proton pump inhibitors and histamine receptor antagonists.
Interference of iron absorption may occur with the intake
of certain medications, which thereby minimises the benefit
received from oral iron treatment .
The major challenges in the management of IDA are
related to the tolerability and side effects of iron therapy
in its different forms. Therefore, it is crucial to determine
the most appropriate form and dose of iron as well as
duration of treatment in order to successfully replenish iron
stores. Although oral iron is widely used worldwide, the
effectiveness of oral iron is largely compromised by lack of
absorption, poor compliance, increased adverse effects (up
to 56%), and discontinuation of treatment (up to 20%)
[4, 26, 29].
Therefore, parenteral iron is seen to be an attractive
option in the treatment of IDA and is likely to be more
popular due to the introduction of new intravenous iron
preparations, which allow high doses of iron to be admin-
istered rapidly in a single treatment [30–32].
4.1. Side Effects of IV Iron. In the past, intravenous iron
had been associated with undesirable and sometimes serious
side effects and was therefore limited in use [33, 34].
However, in recent years, new type II and III iron com-
plexes have been developed which are better tolerated and
can be used for rapid repletion of iron stores [34, 35].
Despite the increasing evidence of the safety of the newer
preparations, both in pregnant and general populations,
intravenous iron continues to be underutilised because of
previous concerns with tolerability of older intravenous iron
preparations [7, 8, 30].
Review of infusions of iron dextran among 481 patients
of both sexes revealed that about 25% of patients had
mild side effects, which were self-limiting. However, about
2% experienced severe allergic reactions and about 0.6%
were considered as anaphylactic reactions. Most of these
reactions occurred immediately during the infusion of the
test dose .
Iron gluconate is considered to have a lower reaction
rate and therefore a test dose is not recommended with
only 3.3 allergic events per million doses per year with
iron gluconate reported . There were no life-threatening
reactions recorded as a result of iron gluconate infusion.
On the other hand, there were 31 fatalities among 196
allergic/anaphylactic reactions, which were reported for iron
The high incidence of adverse reactions to iron dextran,
including serious adverse events have limited its application
4 Journal of Pregnancy
in pregnancy [38–40, 43]. Whilst the application of iron
gluconate is considered safe, it remains impractical in theory
as it requires multiple infusions with huge implications on
the often limited health system resources as well as on
More recently new forms of intravenous iron that have
been developed and are available, are permitting treating
physicians to safely administer relatively high doses of iron
in a single dose treatment.
4.2. Intravenous versus Oral Iron Therapy in Pregnancy.
Intravenous iron, including iron sucrose, was employed in
randomised controlled trials with improved effectiveness of
intravenous iron only or in combination with oral iron,
compared to oral iron only, based on Hb levels [41–43].
A single IV iron sucrose dose has been reported to
be associated with an increased incidence of thrombosis
(9/41, 22%) . In contrast, 6 small doses of intravenous
iron sucrose administered over a three-week period were
without infusion-associated thrombosis, with intravenous
iron sucrose administered in 5 daily doses to 45 pregnant
women, also well tolerated . In the first study utilising
intravenous iron sucrose, there was no significant difference
in Hb levels at any time measured at days 8, 15, 21, and
30 and at delivery  between intravenous iron sucrose or
oral iron sulphate. In contrast, in another trial, with 6 small
doses of iron sucrose, there was a significant difference in
Hb levels in favour of the intravenous iron sucrose group as
measured at 2 and 4 weeks after administration of IV iron
and at delivery . However, both trials administered IV
iron sucrose at the expense of a vastly greater effort from
the patients to present to the hospital for 6 infusions in a
short period of time as well as the extra demands on hospital
resources [41, 42].
Furthermore, relatively older and established iron prepa-
rations such as intravenous iron polymaltose (Ferrosig,
Sigma Pharmaceuticals, Australia) demonstrated a high
safety profile in the treatment of IDA in both obstetric and
general populations without a maximum dose of treatment
. The total dose of IV iron polymaltose is calculated
according to the patient’s body weight and entry Hb level
with reference to the product guidelines as follows: iron dose
inmg (50mg per 1mL) = body weight in kg (maximum
90) × target Hb (120g/L) − actual Hb in g/L × constant
factor (0.24) + iron depot (500). Iron polymaltose infusion
showed high efficacy and safety profile during pregnancy in
the largest, recently published trial .
In this study, two hundred Caucasian pregnant women
aged 18 years or above were identified with moderate
IDA, defined as Hb ≤115g/L (reference range (RR) 120–
160g/L) and low iron stores based on a serum ferritin level
<30µg/L (RR 30–440µg/L). The IV arm required a single
intravenous infusion of iron polymaltose (Ferrosig, Sigma
Pharmaceuticals, Australia) within 1 week after antennal
clinic booking, usually after 12 weeks of gestation, followed
the 2nd and 3rd trimesters only. The oral treatment arm
comprised iron sulphate 250mg tablets (elemental iron
80mg, Abbott, Australasia Pty Ltd.) to be taken daily within
two days after booking until delivery . At preenrolment,
or supplement intake between the two groups based on a
specially designed questionnaire addressing these issues. The
participants were followed up during the pregnancy and at a
postdelivery median follow-up period of 32 months (range
26–42). Iron status and haemoglobin were determined at
time of entry in the study as a baseline, then prior to delivery
and thereafter 4 weeks after delivery .
As reported in the original study, at delivery the propor-
tion of women with lower than normal ferritin levels was
to 4.5% for women who received IV iron (P < 0.001) .
The percentage of women at delivery with Hb level <116g/L
was 29% in the oral iron group versus 16% in the IV iron
group (P = 0.04) .
As a common practice at our institution, we have
performed more than 1000 IV iron polymaltose infusions
for the treatment of IDA in pregnancy during the last 5
years. Most of the women tolerated the IV iron polymaltose
well without major side effects. There was no recorded
anaphylaxis or mortality secondary to IV iron in this cohort
In unpublished data collected as a follow-up study of the
original trial ,therewasa significant improvement in the
general health of women who received IV iron polymaltose
versus oral iron (P < 0.001). The duration of breast feeding
was longer (P = 0.04) in those women who had received IV
iron polymaltose versus oral iron. Women with better iron
status were less downhearted (P = 0.005) and less likely to
develop postnatal clinical depression (P = 0.003).
This would indicate that it is worthwhile considering the
Hb and iron status as a surrogate marker for assessment
of women’s wellbeing, not only during pregnancy but also
during the postnatal period. However, further studies are
warranted to confirm and extend these findings.
Furthermore, recent reports demonstrate the feasibility
of rapid iron polymaltose infusion over 2 hours [30, 44, 45].
However, a test dose of iron polymaltose (100mg) should be
first administered over 30 minutes, and premedication with
antihistamine and/or low-dose steroids is recommended
prior to iron treatment for better toleration [44, 45].
A recent comprehensive meta-analysis and review by
Reveiz et al.  of the literature between 1970 till present on
different treatments for IDA of pregnancy showed paucity of
good quality trials assessing clinical maternal and neonatal
effects of iron administration in women with IDA in spite
of the high incidence and burden of disease associated with
IDA. During this period, there was only one prospective
treatment of IDA during pregnancy that fulfils the stringent
independent reviewer quality criteria [7, 30].
5.Recent Dataon Treatment of IDA inthe
The new preparations of intravenous iron (Table 1) are
seeking approval for use during pregnancy in phase II and
Journal of Pregnancy5
III clinical trials from the authorised organisational bodies
in Europe and the USA. Nevertheless, they can be potentially
used currently in the non-pregnant female population for
the treatment of postpartum, pre-, and postmenopausal iron
IDA, 227 women were assigned to IV ferric carboxymaltose
with 1000mg maximum dose (up to 3 weekly doses) versus
117 women who received oral ferrous sulphate 100mg
twice daily . Intravenous iron carboxymaltose was as
differences between groups at any time point despite the
1.3g IV iron versus 16.8g oral iron). Furthermore, in the
IV iron carboxymaltose group, the increases in ferritin levels
were significantly greater than in the ferrous sulphate (P <
0.0001) indicating a successful repletion of iron stores and
accessibility for erythropoiesis .
In a multicenter randomized, controlled study, 291
women directly after delivery with haemoglobin ≤100g/L
were randomized to receive 1000mg IV iron carboxymaltose
(143 women), repeated weekly to a calculated replacement
dose (maximum dose 2.5g), or ferrous sulfate (148 women)
325mg orally three times daily for 6 weeks (total dose
40.9g) . Ferric carboxymaltose-treated women achieved
a haemoglobin >120g/L in a shorter period of time with
a sustained haemoglobin >120g/L at day 42. Furthermore,
the achieved haemoglobin rise of ≥30g/L was significantly
more rapid in the IV iron group than the oral group in
achieving higher serum ferritin levels. Drug-related adverse
events occurred less frequently with ferric carboxymaltose
In a phase 3 randomised trial 174 women who received
IV ferric carboxymaltose with a mean total dose of 1.4g
versus 178 women who received 325mg ferrous sulfate three
times daily for 6 weeks (total dose 40.9g) were assessed
. Patients assigned to IV ferric carboxymaltose achieved
a haemoglobin rise >20g/L faster than the oral iron group
(7 days compared with 14 days in the oral iron group,
P < 0.001). The IV iron group significantly achieved a
haemoglobin rise >30g/L at any time (86.3% compared with
60.4% in the oral iron group, P < 0.001), and were more
likely to achieve a haemoglobin >120g/L (90.5% compared
with 68.6%, P < 0.001). In the meantime, there were no
serious adverse drug reactions in both groups .
In a large randomized, controlled phase 3 multicentre
trial, 477 women with IDA and heavy uterine bleeding were
assigned to receive either IV ferric carboxymaltose (230
women) with a maximum dose of 1000mg repeated weekly
to achieve a total calculated replacement dose, or 325mg of
for 6 weeks with a total dose of 40.9g in 226 women .
Twenty-one patients did not receive the assigned treatment
in this study.
≥20g/L versus 62% in the oral iron P < 0.001. Women who
group versus 36% in the oral iron group (P < 0.001). Also,
more women (73%) achieved normal haemoglobin >120g/L
in the IV iron group compared to 50% in the oral iron group
(P < 0.001). There were no serious adverse drug events.
This trial demonstrated that patients with IDA due to heavy
uterine bleeding who received IV iron carboxymaltose, are
more likely to have normal haemoglobin with replenished
iron stores .
Altogether, the new intravenous iron preparations rep-
resent a medical revolution in effective, rapid, and safe iron
55]. This will positively reflect on the treatment of IDA
in different populations by application of a single high-
dose intravenous iron treatment with effective subsequent
repletion of iron stores and hence improvement of subjective
and objective outcomes of the IDA. Although iron deficiency
is a precursor of IDA, many clinical studies treat it similarly
The cost of one iron sulphate tablet is approximately USD
$0.3, so the average cost throughout one pregnancy is calcu-
containing 500mg is $50, so the average treatment cost is
nursing time for the IV iron adds approximately $60–$100
to the drug cost subject to variations according to different
health systems. The cost of the new iron preparation ferric
carboxymaltose is approximately $272 per average 1000mg
total dose compared to $280 for 1000mg of iron sucrose
(Table 2). This cost analysis is subject to change according
to different health systems and countries.
In the case of severe IDA, a blood transfusion has been the
patients did not respond to oral iron therapy or when a rapid
correction of anaemia is clinically required. Although there
is a lack of data regarding the avoidance of blood transfusion
during pregnancy, a recent trial investigating treatment of
IDA with oral versus IV iron in pregnancy demonstrated
that none of both treatment arm participants received blood
transfusion for correction of anaemia during pregnancy.
However two patients (0.9%) in the oral iron arm received
blood transfusion in the postpartum period .
Currently, the development of new intravenous iron for-
mulations that offer higher doses in a single administration
has provided the treating physicians with the opportunity
to employ intravenous iron as an effective, rapid, and
safe treatment for IDA [46–55], avoiding the use of blood
transfusion with its known hazards . There is increasing
evidence-based research that supports the safety and efficacy
of IV iron in IDA. There is also increasing evidence for
inadequacy of oral iron in terms of adverse effects, lack of
compliance as well as lack of absorption and slow and often
questionable effect in IDA patients [34, 35, 42].