Postpartum anemia I: Definition, prevalence, causes, and consequences

Abstract

This review provides a status on the definition, prevalence, causes, and consequences of anemia in women who have given childbirth, i.e., postpartum anemia. The diagnosis of iron deficiency anemia relies on a full blood count including hemoglobin, serum ferritin, and serum soluble transferrin receptor, which appear to be reliable indicators of anemia and iron status 1 week postpartum while serum transferrin saturation is an unreliable indicator several weeks after delivery. It is recommended that postpartum anemia should be defined by hemoglobin <110 g/L at 1 week postpartum and <120 g/L at 8 weeks postpartum. The major causes of postpartum anemia are prepartum anemia combined with acute bleeding anemia due blood losses at delivery. Normal peripartum blood losses are approximately 300 ml, but hemorrhage >500 ml occur in 5-6% of the women. In healthy women after normal delivery, the prevalence of anemia (hemoglobin <110 g/L) 1 week postpartum is 14% in iron-supplemented women and 24% in non-supplemented women. In consecutive series of European women, the prevalence of anemia 48 h after delivery is approximately 50%. In developing countries, the prevalence of postpartum anemia is in the range of 50-80%. Postpartum anemia is associated with an impaired quality of life, reduced cognitive abilities, emotional instability, and depression and constitutes a significant health problem in women of reproductive age.

Full text

REVIEW ARTICLE
Postpartum anemia II: prevention and treatment
Nils Milman
Received: 3 October 2011 / Accepted: 25 November 2011 /Published online: 9 December 2011
#Springer-Verlag 2011
Abstract This review focuses on the prevention and treat-
ment of anemia in women who have just given childbirth
(postpartum anemia). The problem of anemia both prepar-
tum and postpartum is far more prevalent in developing
countries than in the Western societies. The conditions for
mother and child in the postpartum, nursing, and lactation
period should be as favorable as possible. Many young
mothers have a troublesome life due to iron deficiency and
iron deficiency anemia (IDA) causing a plethora of symptoms
including fatigue, physical disability, cognitive problems, and
psychiatric disorders. Routine screening for postpartum ane-
mia should be considered as part of the national maternal
health programs. Major causes of postpartum anemia are
prepartum iron deficiency and IDA in combination with ex-
cessive blood losses at delivery. Postpartum anemia should be
defined as a hemoglobin level of <110 g/l at 1 week postpar-
tum and <120 g/l at 8 weeks postpartum. Bleeding exceeding
normal blood losses of approximately 300 ml may lead to
rapid depletion of body iron reserves and may, unless treated,
elicit long-standing iron deficiency and IDA in the postpartum
period. The prophylaxis of postpartum anemia should begin
already in early pregnancy in order to ensure a good iron status
prior to delivery. The most reliable way to obtain this goal is to
give prophylactic oral ferrous iron supplements 30–50 mg
daily from early pregnancy and take obstetric precautions in
pregnancies at risk for complications. In the treatment of
slight-to-moderate postpartum IDA, the first choice should
be oral ferrous iron 100 to 200 mg daily; it is essential to
analyze hemoglobin after approximately 2 weeks in order to
check whether treatment works. In severe IDA, intravenous
ferric iron in doses ranging from 800 to 1,500 mg should be
considered as first choice. In a few women with severe anemia
and blunted erythropoiesis due to infection and/or inflamma-
tion, additional recombinant human erythropoietin may be
considered. Blood transfusion should be restricted to women
who develop circulatory instability due to postpartum hemor-
rhage. National health authorities should establish guidelines
to combat iron deficiency in pregnancy and postpartum in
order to facilitate a prosperous future for both mothers and
children in a continuing globalized world.
Keywords Anemia, Iron deficiency .EPO protein, Human .
Hemoglobins .Iron .Iron i.v. .Postpartum hemorrhage .
Postpartum period .Pregnancy
Introduction
Anemia after the delivery of a child (postpartum anemia) is
a common problem throughout the world [1,2]. The preva-
lence of postpartum anemia is highest in developing countries
[1,2] where it is a major cause of maternal morbidity and
mortality [3–5]. It has been estimated that of the ~500,000
maternal deaths occurring each year on a global scale in
association with delivery, 20% are caused by peripartum
hemorrhage and anemia [3–5]. However, postpartum anemia
also constitutes a significant and partly unrecognized problem
even in developed countries [6,7].
In the Western societies, more than 40% of women of
reproductive age have small body iron reserves [8]and
N. Milman
Departments of Clinical Biochemistry and Obstetrics,
Næstved Hospital,
Næstved, Denmark
N. Milman (*)
Lindevangen 87B,
2830 Virum, Denmark
e-mail: nils.milman@webspeed.dk
Ann Hematol (2012) 91:143–154
DOI 10.1007/s00277-011-1381-2

consequently display an iron status that is not favorable
when the women become pregnant.
Postpartum anemia is closely connected with the pres-
ence of anemia in pregnancy prior to delivery (prepar-
tum anemia) [1,9], which inevitably will be aggravated
after delivery due to the obligatory and sometimes un-
foreseen blood losses [7]. In the Western countries, the
prevalence of prepartum anemia in the third trimester is
markedly lower in women who have taken iron supplements
during pregnancy compared with nonsupplemented
women [9]. In other words, adequate prevention of iron
deficiency and iron deficiency anemia (IDA) during pregnancy
also prevents and reduces the prevalence of postpartum
anemia.
The major causes of postpartum anemia are prepartum iron
deficiency/anemia in combination with excessive blood losses
at delivery [1,7]. Normal peripartum blood losses are approx-
imately 250–300 ml, but peripartum hemorrhage of >500 ml
occurs in 5%–6% of the women [1,7,10,11]. In Europe, in
selected series of healthy women after normal delivery, the
prevalence of anemia (hemoglobin level <110 g/l) 1 week
postpartum is ~14% in women who have taken iron supple-
ments in pregnancy vs. ~24% in nonsupplemented women
[1]. In unselected series of women who have not taken
iron supplements, the prevalence of anemia (hemoglobin
level <110 g/l) 48 h after delivery is approximately 50%
[7]. In developing countries, the prevalence of postpartum
anemia is considerably higher, in the range of 70%–80%
[1,2]. These figures emphasize that postpartum iron deficiency
and anemia are continuing major health problems that should
be given more attention.
The first part of the review analyzed the definition, prev-
alence, causes, and consequences of postpartum anemia [1].
This second part of the review focuses on the prevention and
treatment of postpartum anemia.
Evaluation of postpartum anemia
In the majority of women, postpartum anemia is caused by
moderate-to-heavy blood losses in association with delivery
[7], which, in turn, may induce acute or subacute anemia,
which can be confirmed by measurement of the hemoglobin
concentration 24–48 h after delivery. The most commonly
used biomarkers of iron status, plasma ferritin and serum
soluble transferrin receptor, both appear to be reliable 1 week
after delivery [1,12,13], while plasma transferrin saturation
appears to be an unreliable biomarker several weeks after
delivery [1,12].
From the data available [1], it is suggested that postpartum
anemia should be defined as a hemoglobin concentration
of <110 g/l at 1 week postpartum and <120 g/l at 8 weeks
postpartum.
If IDA can be ruled out, further evaluation for anemia
should be performed dependent on the history, ethnicity, and
region of the world, for example, plasma folate and plasma
cobalamin status as well as other vitamin deficiencies and
examination for hemolytic anemia, hemoglobinopathy, in-
flammation, infection, and parasitic infestations [2].
We know that iron deficiency is the most prevalent nu-
tritional deficiency disorder in women of reproductive age
[2,14]. There are, however, major differences in iron nutri-
tion between women from developing and developed
countries [1,2]. In developing regions of the world, prepar-
tum IDA is extremely frequent with a prevalence of more
than 50% [2,14]. In the affluent Western societies, the
prevalence is lower, ~25% in women not taking iron supple-
ments [9,12] and <5% in women taking ferrous iron 40 mg
or more daily [9,15].
Iron requirements postpartum
Requirements for absorbed iron in the entire gestation period
are on the average ~4.4 mg/day [16,17], increasing from
0.8 mg/day in the first trimester to 7.5 mg/day in the third
trimester. The net iron loss, associated with pregnancy per se,
is ~630 mg [16,17].
After a normal pregnancy and delivery without iron defi-
ciency, absorbed iron requirements decline to obligatory iron
losses of ~0.8 mg/day plus losses of ~0.3 mg/day associated
with lactation [18], that is, ~1.1 mg/day as long as menstrua-
tion has not recurred. Iron requirements of this magnitude
should be possible to fulfill through a well-composed normal
diet [19]. Consequently, the postpartum period has, by many,
been interpreted as a period with low iron requirements.
However, a prerequisite for these relatively low require-
ments is (a) that the woman has a good iron status prior to
delivery, which, in turn, implies that she has taken iron supple-
ments during pregnancy [12,15] and (b) that blood losses at
delivery are slight to moderate and do not exceed ~250 ml.
Among women supplemented with 66 mg ferrous iron daily
during pregnancy, 16% had low iron status, that is, serum
plasma ferritin ≤20 μg/l 8 weeks postpartum, but none had
IDA, that is, a hemoglobin level of <121 g/l (7.5 mmol/l) [12].
Among women taking placebo, 40% had low-iron status and
4% had IDA 8 weeks postpartum, indicating that these women
had iron requirements, which were not fulfilled.
The magnitude of peripartum bleeding is the other
factor, which has a significant impact on postpartum iron
requirements. Bleeding exceeding the normal median losses
of ~300 ml (corresponding to iron losses of ~130 mg) may
lead to rapid depletion of body iron reserves, and besides
inducing acute anemia [7], it may elicit long-standing iron
deficiency and IDA in the postpartum period. The larger the
blood losses, the larger the iron requirements of the mother in
144 Ann Hematol (2012) 91:143–154

the lactation period. These mothers have iron requirements,
which are considerably higher than the basal requirements
shown above. For example, a blood loss of 500 ml contains
~203 mg iron. With a dietary iron intake of ~9 mg/day [19],
even the maximum absorption of dietary iron will not be
adequate to compensate for iron losses of this magnitude
within a reasonable period of time.
Guidelines for prevention of prepartum/postpartum
anemia
The prophylaxis of postpartum IDA begins by securing an
adequate iron status in the women already during pregnancy.
Prepartum iron deficiency and IDA are closely associated with
the occurrence of postpartum anemia [1,6,7,12]. In an iron
supplementation study from North Carolina [6], anemia during
pregnancy was the strongest predictor of postpartum anemia.
The European Commission [20] concludes that: “The
physiologic solution for covering the high iron requirements
in pregnancy is to use iron from stores. The problem, however,
is that very few women, if any, have iron stores of this
magnitude. Therefore, daily iron supplements are recommen-
ded in the latter half of pregnancy.”
There exist no common European guidelines on prepartum/
postpartum iron prophylaxis, and many countries have no
national guidelines. The National Collaborating Centre for
Women's & Children's Health in England and Wales [21]
and the National Board of Social Welfare and Health
in Norway [22] both recommend screening for anemia at 10
and 28 weeks' gestation. Routine iron supplementation is not
advocated. Both guidelines state that: “Iron supplementation
should not be offered routinely to all pregnant women. It does
not benefit the mother's or the baby's health and may have
unpleasant maternal side effects”[21,22].
In contrast, other countries advocate oral iron supplemen-
tation. The health authorities in the United States, that is, the
Centers for Disease Control and Prevention [23] and the
International Food Information Council Foundation [24],
recommend general iron prophylaxis with 27–30 mg ferrous
iron/day from the first visit at the maternity clinic to delivery
[23,24]. In Denmark, the National Board of Health [25]
recommends general iron prophylaxis to all pregnant women
with 40–50 mg of ferrous iron/day from 10 weeks' gestation to
delivery, while the Advisory Board of Nutrition [26]advo-
cates individual iron prophylaxis from early pregnancy to
delivery using ferrous iron in doses adjusted according to iron
status, that is, serum plasma ferritin [26]. In Sweden, the
National Board of Nutrition and the Swedish Society for
Obstetrics and Gynecology in 2007 recommended screening
for anemia and measurement of serum plasma ferritin in early
pregnancy; iron supplements should be adjusted according to
serum plasma ferritin levels [27]. These recommendations
were implemented as official guidelines by the Swedish Board
of Health in 2011.
Prophylaxis of prepartum/postpartum anemia
Dietary iron intake
Overall, women do not make major changes in their dietary
habits during pregnancy [28], which means that the results of
nutrition surveys in nonpregnant women can be transferred to
pregnant and postpartum women. Danish women of repro-
ductive age have a mean dietary iron intake of ~9 mg/day [19],
which means that more than 90% of the women have an intake
below the recommended daily allowance of ~18 mg/day [29].
In a Scandinavian survey of pregnant women [28], the mean
energy intake was ~9 MJ/day, that is, the same as in nonpreg-
nant women [19]; 96% of the women had a dietary iron intake
below the recommended 18 mg/day [29]. It appears that the
majority of the women of reproductive age in the Western
countries have a dietary iron intake that cannot fulfil their
demands in the second and third trimesters.
Even under favorable conditions, at the most 30% of die-
tary iron can be absorbed, corresponding to 3 mg iron/day
from a dietary iron intake of 9 mg/day, that is, i.e., consider-
ably less than the daily iron requirements during pregnancy. In
the average Scandinavian diet, the bioavailability of iron is
15%–18%. Estimates from the United States suggest that the
recommended dietary allowance of iron should be ~27 mg/
day, with a bioavailability of at least 25% in order to fulfil the
needs during pregnancy [24]. As dietary iron cannot fulfil iron
requirements in the majority of pregnant women, the Nordic
Nutrition Recommendations advocate oral iron supplements
to women with iron stores <500 mg (corresponding to a serum
plasma ferritin level of <70 μg/l) [29]; in Sweden, iron supple-
ments are recommended to women with a serum plasma
ferritin level of <60 μg/l [27].
Oral iron prophylaxis
All placebo-controlled studies have shown that pregnant
women taking oral iron supplements have higher-iron status
and a lower frequency of anemia both prepartum [1,12,15,
16] and postpartum [1,12] compared with women taking
placebo tablets.
European studies have shown that a supplement of 45–
66 mg ferrous iron/day from 12–20 weeks' gestation pre-
vents IDA in pregnant women [1,16]. In Danish pregnant
women [15], 40 mg ferrous iron/day taken between meals
was adequate to prevent IDA, whereas 20 mg ferrous iron/
day was inferior to 40 mg/day with regard to prevention of
iron deficiency. There was no extra benefit on iron status by
giving iron doses above 40 mg [15]. In women taking 66 mg
Ann Hematol (2012) 91:143–154 145

ferrous iron/day during pregnancy, anemia (hemoglobin
level <110 g/l) at 1 week postpartum was observed in 14%
vs. in 22% of women taking placebo tablets [1,12]. Eight
weeks postpartum, anemia (hemoglobin level <121 g/l) was
observed in 6%–8% of women who had been taking iron vs.
16% in women taking placebo [1,12,15]. Surely, iron
supplements appear to be effective in the prevention of
postpartum anemia.
The absorption of iron from multivitamin–mineral supple-
ments taken with meals is probably very low [9]. For this reason,
iron should be administered in separate tablets, taken between
meals, in order to ensure an optimal absorption [15,30,31].
In conclusion, oral iron supplementation, whether general
or individual [9,30,31] in pregnant women starting in early
pregnancy, is clearly efficient in the prevention of both
prepartum as well as postpartum anemia.
Intravenous iron in the third trimester
IDA in the third trimester is a serious condition, and iron
deficiency should be treated by replenishing body iron needs
as soon as possible. Otherwise, postpartum anemia will inev-
itably be aggravated, and there will be an increased risk of
postpartum blood transfusions. In the third trimester, there is
too short time for oral iron treatment to be effective in the
correction of anemia due to the limited iron absorption capac-
ity. Consequently, the only reliable treatment is intravenous
(i.v.) administration of iron. Guidelines on the treatment of
prepartum anemia by Schweizerische Gesellschaft für Gynäko-
logie und Geburtshilfe (Swiss Society for Gynecology and
Obstetrics) [32] and by the Network for Advancement of Trans-
fusion Alternatives [33] advocate the use of i.v. iron in the third
trimester. Regarding treatment with i.v. iron, see below.
Obstetric prophylaxis and treatment of postpartum
hemorrhage
Many conditions, both medical disorders such as coagulo-
pathiesandothers,aswellasgynaecological/obstetrical
disorders predispose to peripartum bleeding, postpartum
hemorrhage, and postpartum anemia [34–36]. A careful
obstetric evaluation and treatment prior to delivery is essen-
tial to reduce the frequency of both expected and unexpect-
ed complications and bleeding. It is beyond the scope of this
review to go into details with obstetric prophylaxis per se,
which has been thoroughly described in obstetric guidelines
[35,37].
Screening for postpartum anemia
There is an ongoing debate whether or not to screen for
postpartum anemia [6,38]. Anemia screening per se is
inexpensive [39], so clinics may choose general screening
over selective screening, but there exist no cost–benefit
analyses in the postpartum setting. Evidently, the cost–benefit
will be low in countries with a high prevalence of postpartum
anemia and higher in countries with a low prevalence.
Currently, the Centers for Disease Control and Prevention
recommends selective screening for anemia at 4–6 weeks
postpartum in women who have had “anemia continued
through the third trimester, excessive blood loss during
delivery, and multiple births”[39].
In Denmark, mothers are routinely discharged from the
birth clinic 3–6 h after uncomplicated deliveries, without
any check of hemoglobin. In case of early postpartum hem-
orrhage, hemoglobin is usually checked prior to discharge.
Women are offered a routine checkup at 8 weeks postpartum
by their general physician.
However, in order to ensure a good puerperal and lactation
period for both mothers and children, the author suggests to
introduce a general screening for anemia and iron deficiency
with measurement of hemoglobin and plasma ferritin at
1 week postpartum, followed by adequate therapeutic meas-
ures in mothers with anemia. If a woman had prepartum
anemia and/or excessive bleeding at delivery, it is mandatory
that hemoglobin should be checked prior to discharge.
Treatment of postpartum anemia
There are a few official guidelines for the treatment of
postpartum IDA issued by Schweizerische Gesellschaft für
Gynäkologie und Geburtshilfe [32] and the Network for
Advancement of Transfusion Alternatives [33]. These
guidelines are summarized in Table 1.
Table 1 Guidelines for treatment of postpartum IDA associated with
blood losses
Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe [32]
Slight IDA0hemoglobin 95–120 g/l
Oral iron 80–200 mg/day
Moderate IDA0hemoglobin 80–95 g/l
I.v. iron 500–1,000 mg
Severe IDA0hemoglobin <80 g/l
I.v. iron 500–1,000 mg
Consider erythropoietin 10,000–20,000 U subcutaneously
Network for Advancement of Transfusion Alternatives [33]
Moderate to severe IDA0hemoglobin 80–95 g/l
I.v. iron 500–1,000 mg
Consider erythropoietin 10,000–20,000 U subcutaneously
Very severe IDA0hemoglobin <60 g/l
Consider blood transfusion
146 Ann Hematol (2012) 91:143–154

IDA should be treated by replenishing body iron deficits
either by oral or i.v. administration of iron dependent on the
severity of the anemia and how fast the anemia needs to be
corrected. An overview of the present therapeutic studies
assessing the effect of i.v. iron with or without recombinant
human erythropoietin (rhEPO) has been published in a
Cochrane Review [40].
Oral iron
Gastrointestinal iron absorption is regulated according to
body iron reserves and the intensity of erythropoiesis.
Exhausted body iron reserves in otherwise healthy women
will increase the intestinal iron absorption [41]. Further-
more, as a consequence of postpartum bleeding and post-
partum IDA, the accelerated EPO-stimulated erythropoiesis
[42,43] will tend to increase iron absorption.
This setting with high iron absorption capacity is quite
favorable for treatment of IDA with oral iron in women post-
partum. There is consensus that oral iron therapy should be the
first therapeutic option in women having slight-to-moderate
IDA with hemoglobin levels of 95–120 g/l. They should ini-
tially be treated with ferrous iron 100–200 mg/day [32,33].
Such high doses of iron should preferably be administered
between meals as a sustained release iron preparation in order
to optimize absorption and reduce gastrointestinal side effects
[44]. Following treatment for 2 weeks, the therapeutic response
should be checked by measurement of hemoglobin. If the
hemoglobin level has increased ≥10 g/l, oral iron therapy
should continue during the remaining postpartum period with
subsequent check of hemoglobin and serum ferritin after
8 weeks of treatment. When hemoglobin has reached a level
of >120 g/l, the iron dose can be reduced to 100 mg/day.
A failing hemoglobin response to treatment could be the
consequence of noncompliance due to psychological mecha-
nisms, noncompliance due to gastrointestinal side effects, and
impaired gastrointestinal iron absorption due to Helicobacter
pylori infection, gastric hypochlorhydria or achlorhydria, in-
flammatory bowel disease, and gastric or intestinal resection or
bypass. It may also be due to prolonged late postpartum uterine
bleeding with continuing iron losses. In women who do not
respond to oral iron, i.v. iron therapy should be considered as an
Table 2 Treatment of postpartum IDA with oral vs. i.v. iron and effect on hemoglobin: summary of studies
Reference Women
(n)
Iron treatment Hb at
inclusion (g/l)
Outcome p-Value
Breymann
et al. [56]
<100 Mean increase
in Hb day 14
20 80 mg Fe
2+
/day oral 14 days 24± 8 g/l NS
20 800 mg iron sucrose i.v. 29± 8 g/l
Bhandal and
Russell [57]
<90 Mean Hb day 14 Mean Hb day 40
21 400 mg Fe
2+
/day oral 40 days 90± 4 g/l
p<0.01
112± 12 g/l
NS
22 400 mg iron sucrose i.v. 111±6 g/l 115± 13 g/l
Van Wyck
et al. [55]
≤100 Increase Hb ≥20 g/l
day 14
Hb ≥120 g/l
day 14
169 195 mg Fe
2+
/day oral 42 days 73% 28% <0.001
168 ~1,400 mg ferric
carboxymaltose i.v.
88% 74%
Westad
et al. [60]
≤85 Mean Hb day 28
70 200 mg Fe
2+
/day oral 84 days 123 g/l
58 600 mg iron sucrose i.v NS
+ 200 mg Fe
2+
/day oral iron,
56 days
119 g/l
Seid et al. [59]≤100 Hb >120 g/l day 14 Hb >120 g/l day 42
148 195 mg Fe
2+
/day oral 42 days 30% 65% <0.0001
168 ~1,400 mg ferric
carboxymaltose i.v.
58% 90%
Giannoulis
et al. [58]
<80 Mean increase
in Hb day 28
26 800 mg Fe
3+
/day oral 28 days 23± 5 g/l <0.001
78 300 mg iron sucrose i.v. 46± 4 g/l
Hb, hemoglobin; NS, not significant
Ann Hematol (2012) 91:143–154 147

alternative in order to obtain a swift improvement in their health
status and quality of life during the remaining period of lacta-
tion. It is essential to consider that after successful treatment of
IDA with oral iron, during continued treatment, it takes a long
time, that is, months or even years, to replenish body iron stores
and obtain an appropriate serum plasma ferritin level of 30–
50 μg/l.
Intravenous iron
Intravenous iron preparations contain more or less tightly
bound ferric iron. Among others, second-generation prod-
ucts include iron sucrose (Venofer®; Vifor Pharma Ltd.,
Glattbrugg, Switzerland) [45] and low-molecular-weight
iron dextran (Cosmofer®; Pharmacosmos Ltd., Holbæk,
Denmark) [46]. The recently introduced third-generation
i.v. iron compounds are ferric iron carboxymaltose (Ferinject®;
Vifor Pharma Ltd.) [47,48] and ferric iron isomaltoside 1000
(Monofer®; Pharmacosmos Ltd.) [49].
After the first trimester, treatment of IDA with i.v. iron
appears superior to oral iron therapy with respect to a faster
increase in the hemoglobin concentration and faster replen-
ishment of body iron stores [50–54]. The use of i.v. iron
prior to delivery may reduce the need for blood transfusions
in the postpartum period and constitutes an alternative to
blood transfusion in profound IDA [52].
In postpartum IDA, a number of studies have demon-
strated the efficacy of i.v. iron therapy [40]. Tables 2and 3
summarize the therapeutic studies of postpartum anemia
with i.v. iron vs. oral iron [55–60].
Intravenous iron produces a faster and higher increase in
the hemoglobin concentration than oral iron (Fig. 1)[59].
Furthermore, i.v. iron administered as total dose infusion
yields replenishment of body iron reserves within a few
days (Fig. 2) compared with oral iron where therapy must
continue for a prolonged period in order to establish appro-
priate iron reserves [40,59]. The total dose of iron needed to
correct anemia and replenish iron stores is usually calculated
by a modified Ganzoni formula [55,61].
Provided the manufacturer's instructions for administra-
tion of i.v. iron are followed, the frequency of adverse
events is below 0.5% [50–54]. Infusion of iron should be
Table 3 Treatment of postpartum IDA with oral vs. i.v. iron and effect on serum ferritin: summary of studies
Reference Women
(n)
Iron treatment Ferritin at
inclusion (μg/l)
Outcome p-Value
Breymann
et al. [56]
Mean, ~32 Mean SF day 14
20 80 mg Fe
2+
/day oral 14 days 22± 10 μg/l <0.01
40 800 mg iron sucrose i.v. 81± 30 μg/l
Bhandal and
Russell [57]
<15 Mean SF day 14 Mean SF day 40
21 400 mg Fe
2+
/day oral 40 days 16± 4 μg/l 15± 3 μg/l <0.01
22 400 mg iron sucrose i.v. 38± 5 μg/l 42± 7 μg/l
Van Wyck
et al. [55]
Mean increase
SF day 14
Mean increase
SF day 42
169 195 mg Fe
2+
/day oral 42 days 0 μg/l 0 μg/l <0.001
168 ~1,400 mg ferric
carboxymaltose i.v.
560 μg/l 210 μg/l
Westad
et al. [60]
Mean, 24 Mean SF day 28 Mean increase
SF day 28
70 200 mg Fe
2+
/day oral 84 days 25± 15 μg/l 4 μg/l <0.001
58 600 mg iron sucrose i.v.
+ 200 mg Fe
2+
/day
oral iron, 56 days
40± 23 μg/l 14 μg/l
Seid et al. [59] Mean, 24 Mean increase
SF day 14
Mean increase
SF day 42
148 195 mg Fe
2+
/day
oral 42 days
0μg/l 0 μg/l <0.0001
168 ~1,400 mg ferric
carboxymaltose i.v.
595 μg/l 215 μg/l
Giannoulis
et al. [58]
<10 Mean increase
SF day 28
26 800 mg Fe
3+
/day oral 28 days 68 μg/l <0.001
78 300 mg iron sucrose i.v. 105 μg/l
SF. serum ferritin
148 Ann Hematol (2012) 91:143–154

given in a setting where equipment for cardiopulmonary
resuscitation is available. Infusion should be given in pe-
ripheral veins, and care should be taken to avoid chemical
phlebitis at the infusion site.
The third-generation preparations ferric iron carboxymal-
tose and ferric iron isomaltoside appear to have an even
lower frequency of side effects compared with the second-
generation preparations iron sucrose and low-molecular-
weight iron dextran. Altogether, our present knowledge
indicates that i.v. iron appears to be an effective and safe
treatment in the postpartum period [59].
Treatment with i.v. iron for postpartum IDA should be
considered: (a) as the first option in profound IDA with a
hemoglobin level of <95 g/l and (b) as the second option in
moderate anemia with a hemoglobin level of 95–120 g/l if
oral iron fails to increase hemoglobin after 2 weeks.
The dose of i.v. iron should be adequate to obtain a hemo-
globin level of at least 120 g/l. When this level has been
reached, the women may, if indicated, switch to maintenance
treatment with oral ferrous iron 100 mg/day, provided that
they have a normal gastrointestinal iron absorption. In the
majority of women, a total dose of 600–1,500 mg i.v. iron is
adequate to correct anemia and replenish iron reserves.
Iron sucrose should be given in repetitive doses of max-
imum 200 mg iron per dose. In order to keep the solution
stable, iron sucrose should be dissolved in a maximum of
200 ml isotonic saline, infused over a minimum of 30 min;
repetitive doses should be administered with a minimum of
3-days interval [32,45].
Concerning low-molecular-weight iron dextran, a test
dose of 25 mg iron dissolved in 100 ml isotonic saline
should be infused over 15 min. If no adverse reaction has
occurred 60 min after the test, 500–1,000 mg iron should be
dissolved in 500 ml isotonic saline and infused over 4 h.
This means that low-molecular-weight iron dextran can be
administered as a “total-dose-infusion”where up to
1,000 mg iron is given in a single infusion [46].
Ferric iron carboxymaltose has recently been introduced
on the European market and has proven effective in the
treatment of postpartum anemia [48,55]. According to the
manufacturer's instructions, up to 1,000 mg iron dissolved in
250 ml isotonic saline can be given as a single infusion over
15–60 min [47].
Ferric iron isomaltoside was introduced on the Danish
market in 2010but has not yet been evaluated in the treatment
of postpartum anemia. According to the manufacturer's
instructions, up to 1,000 mg iron dissolved in 100–500 ml
isotonic saline can be given as a single total dose infusion over
15–60 min, depending on the dose of iron [49].
The total-dose-infusion concept is convenient for the
patient and can save resources in the health care system. A
medicotechnical report from the Swedish Dental and Phar-
maceutical Benefits Agency [62] concluded that “total-dose-
infusion is cost-effective in patients with iron deficiency
who need i.v. iron when at least one extra visit to the clinic
can be omitted.”Third-generation i.v. iron preparations have
improved the quality of treatment by reducing serious
adverse reactions and simplifying the mode of administration.
Intravenous iron treatment appears effective in correcting
both the anemia and quality-of-life deficits and should be
Fig. 2 Postpartum anemia treated with i.v. ferric iron carboxymaltose
(Ferinject®) (total dose, 1,000–2,500 mg iron) vs.. oral ferrous iron
sulphate 195 mg elemental iron daily for 6 weeks. Mean changes in
serum ferritin were statistically significant vs. baseline at each time
point in the ferric carboxymaltose group only (p<0.0001). Reproduced
with permission from Seid et al. [59]
Fig. 1 Postpartum anemia treated with i.v. ferric iron carboxymaltose
(Ferinject®) (total dose, 1,000–2,500 mg iron) vs. oral ferrous iron
sulfate 195 mg elemental iron daily for 6 weeks. The percentage of
women who obtained hemoglobin concentrations >120 g/l was signif-
icantly higher in the ferric carboxymaltose group than in the oral
ferrous sulfate group (p<0.0001). Reproduced with permission from
Seid et al. [59]
Ann Hematol (2012) 91:143–154 149

incorporated as a therapeutic option in the management of
postpartum IDA.
A Norwegian study has evaluated the effect of i.v. iron
sucrose vs. oral iron on fatigue in postpartum anemia [60].
The improvements in physical, mental, and total fatigue
scores were significantly more pronounced in women treated
with i.v. iron than in women taking oral iron [60]. In contrast,
the study of Van Wyck et al. [55] did not find any significant
difference in fatigue score between women treated with i.v.
ferric iron carboxymaltose and oral iron.
Erythropoietin in combination with i.v. iron
In order to add a further stimulus on erythropoiesis than
nature by itself can produce, rhEPO has been tried to obtain
a faster correction of postpartum anemia. Initial studies on
Table 4 Treatment of postpartum anemia with oral or i.v. iron and rhEPO: summary of studies
Reference Women
(n)
Iron treatment Hb at
inclusion (g/l)
Outcome p-Value
Lebrecth
et al. [65]
<90 Mean Hb day 14 Mean Hb day 28
12 400 mg iron polymaltose i.v. 102 ± 7 g/l 116± 9 g/l
+ 200 mg Fe
2+
/day oral 28 days NS
20 400 mg iron polymaltose i.v.
+ 200 mg Fe
2+
/day oral 28 days 106 ± 12 g/l 120± 8 g/l
+ rhEPO 20,000 U i.v.
Breymann
et al. [66]
<100 Mean Hb day 14 Mean Hb day 42
30 100 mg iron polymaltose i.v. 110 g/l 125 g/l
+ 160 mg Fe
2+
/day oral 42 days
30 100 mg iron polymaltose i.v.
+ 160 mg Fe
2+
/day oral 42 days 107 g/l 126 g/l
+ rhEPO 300 U/kg b.w. s.c.
p<0.05 NS
30 100 mg iron polymaltose i.v
+ 160 mg Fe
2+
/day oral 42 days 116 g/l 127 g/l
+ rhEPO 300 U/kg b.w. i.v.
Macrydimas
et al. [67]
<100 Median Hb day 15
20 200 mg Fe
2+
/day oral 40 days 88 g/l
20 200 mg Fe
2+
/day oral 40 days <0.05
+ rhEPO 200 U/kg/day
s.c. 15 days
105 g/l
Breymann
et al. [56]
<100 Mean increase
Hb day 14
20 800 mg iron sucrose i.v. 29± 8 g/l
20 800 mg iron sucrose i.v. NS
+ rhEPO 300 U/kg b.w./day
i.v. 4 days
39± 7 g/l
Wågström
et al. [64]
≤80 Mean increase
Hb day 14
16 450 mg iron sucrose i.v. 30± 8 g/l
24 450 mg iron sucrose i.v. NS
+ rhEPO 10 000 or 20 000 U s.c. 26± 9 g/l
Krafft and
Breymann [43]
<85 Mean Hb day 14
20 200 mg iron sucrose/day i.v. 4 days 105± 7 g/l NS
20 200 mg iron sucrose/day i.v. 4 days
+ rhEPO 10 000 U/day i.v. 4 days 107± 12 g/l
b.w., body weight; Hb, hemoglobin level; NS, not significant; s.c., subcutaneous injection
150 Ann Hematol (2012) 91:143–154

the use of rhEPO in postpartum anemia were published in
the early 1990s [63], followed by additional studies [43,56,
64–67] and a Cochrane review in 2004 [40]. Table 4sum-
marizes the studies on i.v. iron and rhEPO in postpartum
anemia [43,56,64–67]. It appears that rhEPO treatment in
addition to i.v. iron has no clinically significant effect on the
temporal increase in the primary target parameter, that is, the
hemoglobin concentration [43,56,64–67](Fig.3). One
study using oral iron vs. oral iron + rhEPO found a higher
hemoglobin level after 2 weeks in the rhEPO group [67], but
in contrast to the other studies [56,64–66], rhEPO injections
was given daily [67]. Some studies reported a slight effect
on secondary haematological parameters, for example, retic-
ulocyte count and high fluorescent reticulocyte ratio [56,
66], but overall, the effect of rhEPO in addition to i.v. iron
appears to be of marginal clinical relevance.
The majority of postpartum women with anemia are
otherwise healthy with a normal immune function and most
likely have a maximum endogenous EPO response to ane-
mia caused by hemorrhage [12,43,64], which explains the
absent effect of treatment with rhEPO. However, postpartum
women who have blunted erythropoiesis due to low endog-
enous serum EPO levels, infections, inflammatory disor-
ders, or other specific organ disorders may benefit from
rhEPO [43,56,66]. Treatment with rhEPO may also be tried
in women with severe anemia due to hemorrhage who, for
religious [68] or other reasons, do not accept blood transfusion
[56,67].
Meta-analyses [40,63] conclude that rhEPO administra-
tion to women with postpartum anemia appears safe but is
associated only with a trend toward a faster elevation of
hemoglobin concentration [43]. However, its efficacy in
terms of diminishing postpartum blood transfusions remains
unproven because of the low frequency of transfusions in
the studies.
In those few women with severe IDA where a rapid rise
in hemoglobin level is mandatory and blood transfusion is
considered, i.v. iron therapy may be combined with rhEPO
in doses of ~20,000 U injected subcutaneously one or two
times [40]. However, this approach is not officially ap-
proved but is off-label.
Recently, concerns on the use of rhEPO have been raised
because some individuals develop autoantibodies that neu-
tralize the effect of rhEPO as well as endogenous erythro-
poietin [69]. Development of autoantibodies seems to
depend on the quality of the immune function. This empha-
sizes that we should use rhEPO with caution and restrict the
administration to well-defined indications.
Blood transfusion and plasma expanders
Women with obstetric problems, for example, multiple preg-
nancy, placenta previa, uterine bleeding in late pregnancy,
and anemia in pregnancy, have a higher prevalence of early
postpartum anemia [7]. However, the blood losses at deliv-
ery, especially in cesarean deliveries, are by far the most
important risk factor for postpartum anemia [7]. Cesarean
deliveries may be associated with blood losses of ~1,000 ml
[7,70–72].
In women with obstetric and metabolic disorders, which
predispose to heavy bleeding at delivery, the obstetricians
should be prepared for complications and ensure that iron
status is adequate prior to delivery. If a woman displays
prepartum anemia, including IDA as well as other forms
of anemia, this will be aggravated after delivery. Postpartum
hemorrhage requiring blood transfusion occurs in up to
1.6% of obstetric cases and is one of the leading causes of
maternal perinatal deaths [34].
Considering the potential side effects [73], blood trans-
fusion should be restricted to women with severe postpar-
tum haemorrhage causing circulatory instability with
hypotension. In such patients, blood transfusion may be
indicated as a lifesaving procedure [33,72,73].
If blood transfusion has been refused by the woman,
blood plasma and/or plasma expanders may be used instead.
When the bleeding has been stopped, and the circulation
and blood pressure have been restored, it is time to
reconsider a balanced strategy for treatment of anemia.
At profound anemia with hemoglobin level of <60 g/l,
blood transfusion should be considered [33]. If blood
transfusion is contraindicated or refused, plasma expand-
ers, i.v. iron, and probably rhEPO should be used.
Womenhavinghemoglobinlevelsof60–95 g/l should
be treated with i.v. iron in appropriate doses, and in
women having low endogenous serum EPO levels and
blunted erythropoiesis, rhEPO may be considered [56,
66]. With this strategy, a fraction of women may avoid
blood transfusion.
Fig. 3 Postpartum anemia treated with i.v. iron sucrose (Venofer®)
(total dose, 450 mg iron) and rhEPO by subcutaneous injection. The
graph shows changes in hemoglobin concentrations in relation to day 0
in the three treatment groups. Iron sucrose and rhEPO were given on
days 0 and 3. Reproduced with permission from Wågström et al. [64]
Ann Hematol (2012) 91:143–154 151

Conclusions
This review deals mainly with postpartum anemia in the
developed Western countries. However, the problem of ane-
mia both prepartum and postpartum is far more prevalent in
the developing countries. Mothers are fostering the future
citizens of our societies. The conditions for mother and child
in the postpartum, nursing and lactation period should be as
favorable as possible. Many young mothers have a trouble-
some life due to iron deficiency and IDA causing a plethora
of symptoms including fatigue, physical disability, cognitive
problems, and psychiatric disorders. Routine screening for
postpartum anemia should be considered as part of the
national maternal health programs.
The major causes of postpartum anemia are prepartum iron
deficiency/anemia in combination with excessive blood losses
at delivery. Bleeding exceeding the normal blood losses of
250–300 ml may lead to rapid depletion of body iron reserves
and may, unless treated, elicit long-standing iron deficiency
and IDA in the postpartum period. The prophylaxis of post-
partum anemia should begin already during pregnancy in
order to ensure a good iron status prior to delivery. The most
reliable way to obtain this goal is to give oral ferrous iron
supplements from early pregnancy in doses ranging from 30
to 50 mg daily and perform obstetric prophylactic measuresin
pregnancies at risk for complications.
In the treatment of slight-to-moderate postpartum IDA,
the first choice should be oral ferrous iron in doses ranging
from 100 to 200 mg daily; it is essential to analyze hemo-
globin after 2 weeks in order to check whether the treatment
works. In severe IDA after the first trimester, i.v. ferric iron
in individual doses of 800 to 1,500 mg should be considered
as the first choice. In women with severe anemia and
blunted erythropoiesis due to infection/inflammation,
rhEPO may be considered. Blood transfusion should be
restricted to women who develop circulatory instability
due to postpartum hemorrhage. National health authorities
should consider appropriate guidelines and measures to
combat iron deficiency in pregnancy and postpartum.
Conflicts of interest The author has given educational lectures for
Abbott International, Pharmacosmos Ltd., and Vifor Pharma Ltd.
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