The Use of Iron Sucrose Complex for Christian Breymann

The Use of Iron Sucrose Complex for
Anemia in Pregnancy and the Postpartum Period
Christian Breymann
Iron-deficiency anemia resulting in reduced blood reserves is one the most common
problems in pregnancy. It is estimated that 20% to 50% of the world population is suffering
from iron deficiency and iron-deficient states, pregnancy being one of the most important
“risk factors” for iron deficiency and iron-deficiency anemia. The traditional treatments, ie,
oral iron therapy and blood transfusion, involve significant drawbacks. High doses of oral
iron frequently cause side effects, and noncompliance is common. Therefore, intravenous
iron, alone or in association with recombinant human erythropoietin (rHuEPO) therapy, has
been considered as an alternative in the management of iron deficiency in this setting.
There is increasing evidence that iron sucrose is safe for the mother and the fetus using the
recommended dosages and therapy regimens. Iron sucrose is effective in pregnant and
postpartum patients who do not respond to oral iron, who are noncompliant to oral iron, or
who are treated with rHuEPO. In both cases, according to the present data, the expected
hemoglobin increase and time for therapy are predictable in responding patients. Whether
it is reasonable to wait for a response to oral iron in moderate to severe anemia is therefore
questionable. Indications for the use of iron sucrose complex are: preexisting (moderate–
severe) anemia; no effect of oral iron; side effects of oral iron; refusal of blood transfusion
(eg, Jehovah’s Witness patients); limited time until delivery; coexisting risks (eg, bowel
disease, renal disease); pre- and postoperative period and postpartum anemia. Future fields
of research are the evaluation of patient satisfaction and quality of life, impact on costs and
hospital stay, impact on blood transfusion frequency and mortality rate, and finally impact
on other factors such as breast feeding behavior and neonatal outcome such as birth
weight, prematurity and neonatal iron stores.
Semin Hematol 43(suppl 6):S28-S31 © 2006 Elsevier Inc. All rights reserved.
I
ron-deficiency anemia is one the most common problems
in pregnancy. It is estimated that 20% to 50% of the world
population is suffering from iron deficiency and iron-deficient states, pregnancy being one of the most important “risk
factors” for iron deficiency and iron-deficiency anemia.1-3 According to World Health Organization (WHO) data presented at the Federation International d’Obstetrique e Gynecology (FIGO) meeting in 2003 in Chile, around 500,000
maternal death cases per year and 20,000,000 morbidity
cases per year are related to iron deficiency and anemia. In
view of the fetal and maternal risks associated with irondeficiency anemia, it is obvious that treating anemia efficiently would lead to a considerable reduction in the risk
factors affecting pregnancy and fetal outcome (Table 1).
Feto Maternal Medicine, Obstetric Research, Feto Maternal Hematology Research Group, University Hospital Zurich, Zurich, Switzerland.
Address correspondence to Christian Breymann, MD, University Hospital
Zurich, Frauenklinikstr. 10, 8091 Zurich, Switzerland. E-mail: christian.
[email protected]
S28
0037-1963/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminhematol.2006.08.002
The traditional treatments, ie, oral iron therapy and blood
transfusion, involve significant drawbacks. High doses of oral
iron frequently cause side effects, and noncompliance is common. In addition, such therapy has to be given for a long time
in cases of severe iron deficiency, and absorption and red
blood cell production are influenced by additional pathologies such as renal disease or chronic inflammatory bowel
disease in pregnancy. As far as blood transfusions are concerned, because of the risk of infection (bacterial, viral, prions) and immunomodulation associated with allogeneic
blood products, especially in this young and otherwise
healthy population, transfusions are used only in the most
severe cases and particularly in life-threatening situations.4-6
Therefore, intravenous iron, alone or in association with recombinant human erythropoietin (rHuEPO), has been considered as an alternative in the management of iron deficiency in this setting.7-15 Since the early 1990s, iron sucrose
(Venofer®, Vifor, St. Gallen, Switzerland) has been the only
parenteral iron preparation used during pregnancy and the puerperium at the Zurich University Hospital Obstetrics Clinic.
Intravenous iron sucrose in obstetric anemia
S29
Table 1 Fetal and Maternal Risks as a Consequence of Anemia
Fetus
Mother
Growth retardation
Prematurity
Quality of life
Anemia symptoms (dizziness,
cardiovascular, etc)
Death in utero
Lactation habits (insufficient
milk syndrome)
Amnion rupture
Physical performance
Infection
“Baby blues”
Fetal programming
Infection rate
(feto-placental miss-ratio) Wound healing, fever
Prolonged hospital stay
Data on the safety of the iron sucrose complex were first collected in a multicenter study in 1998. The side effect rate following the administration of 2000 ampoules, with a maximum single dose of 200 mg intravenously, was found to be less than
0.5%.16 Our data are in accordance with previously published studies showing that iron sucrose complex produces
no side effects during pregnancy.
In accordance with Obstetrics Clinic guidelines, an incremental treatment plan is used in anemia management.4 Prerequisites for the use of parenteral iron include diagnostic
investigations and fulfillment of the following inclusion criteria:
● Hemoglobin (Hb) ⬍10 g/dL
● No effect of oral iron therapy (160 –200 mg/d) over 2
weeks (ie, no Hb increase and/or reticulocyte response)
● Proven iron deficiency (serum ferritin ⬍15 ␮g/L)
● Exclusion of hemoglobinopathy or other red cell disorders
● Exclusion of acute inflammatory state (C-reactive protein determination)
● Gestational age over 16 weeks
The first Hb determination is normally carried out during
the first trimester, with oral iron prescribed in the first instance only if the Hb value is less than 10 g/dL. If the Hb level
on oral iron treatment falls below 10 g/dL within 2 to 4
weeks, or if the Hb level on the first diagnostic test is already
less than 10 g/dL, we use the iron sucrose complex as the
treatment of first choice.
Practical Use of Iron Sucrose at
the Zurich Clinic of Obstetrics
The substance is administered through a venous butterfly
canula, once correct positioning in the vein has been tested
with NaCl. Iron sucrose can be administered undiluted as a
bolus or diluted, eg, to 100 to 200 mL of isotonic NaCl
solution as a short infusion. Administration of a test dose (1
mL) is required in different countries. The bolus injection
may be given over 5 to 10 minutes; however, a short infusion
over approximately 20 minutes is considered safer. The maximum single dose is 200 mg. We generally give two doses a
week to achieve a target Hb value of 11 g/dL. The treatment can
be given on an outpatient basis without any problems; in our
experience, a long period of monitoring is not usually necessary
following administration.
Anemia of Pregnancy
Between 1992 and 2005, more than 500 pregnant women
with anemia were treated at the Zurich Obstetrics Clinic. The
mean treatment duration was 25 (8 to 29) days, with a mean
total dose of 1,000 mg (400 to 1,600 mg) iron sucrose, corresponding to five doses of 200 mg. There are several studies
on, and clinical experience with, the use of iron sucrose during pregnancy and in the postpartum period. Overall, a high
level of efficacy and safety was demonstrated in all studies.
Similarly, parenteral iron therapy with the iron sucrose complex was superior to oral iron in all studies so far. Concerning
evidence of effectiveness of iron sucrose in pregnancy, it can
be concluded that iron sucrose is effective:
● in patients not responding to oral iron
● in combination with rHuEPO, particularly in the case of
a significant inflammatory state
● in severe anemia (Hb ⬍9 g/dL)
Baseline hematologic values and results of intravenous
iron sucrose therapy of pregnant anemic women are given in
Table 2. The study of Bayoumeu et al showed no advantage of
iron sucrose over oral iron with regard to Hb increase but an
advantage concerning ferritin levels at the end of treatment.7
In the Cochrane Database Review (2001) of 54 studies on
the use of intravenous iron during pregnancy, only one study
showed a favorable Hb response at 36 weeks and pre-delivery, using intravenous iron compared to oral iron in anemic
women.17 It should be noted that this review includes only
studies with other intravenous iron preparations such as iron
dextran and ferric gluconate, while most positive experiences
with iron sucrose complex in pregnancy were published from
2000 onwards. These studies should be included in a forthcoming new edition of this review.
Table 2 Baseline Hematologic Values and Values After Therapy of Pregnant Anemic Women With Iron Sucrose Complex
(200 mg IV twice weekly)
Hb (g/dL)
Reticulocytes (%)
MCV (fL)
MCH (pg)
Transferrin saturation (%)
Ferritin (␮g/L)
Baseline
End
(day 25)
9.1
2.2
79
25
6
6
11.0*
4.2*
87*
28*
20*
180*
Abbreviations: IV, intravenous; Hb, hemoglobin; MCV, mean corpuscular volume; MCH, mean corpuscular volume.
Data from Huch and Breymann.4
*P <.01 v baseline values.
C. Breymann
S30
Postpartum Anemia
The treatment of postpartum anemia depends on the severity
of the anemia and/or additional maternal risk factors or comorbidities. A young, healthy woman can compensate for
heavy blood losses far better than a puerpera with a heart
defect who may decompensate even after less severe losses. In
addition, blood losses need to be viewed in relation to the
body mass and the estimated total blood volume. Another
consideration is that significant errors can be made particularly when estimating blood loss. Blood loss is often underestimated, which can readily be verified by comparing
prepartum and postpartum Hb levels.
In addition to volume replacement, treatment options include the administration of oral iron, parenteral iron and
allogeneic blood transfusion. Another option to be considered is the administration of rHuEPO.4,11,18-23
Oral iron should be prescribed at hemoglobin levels of
over 9.5 g/dL; 80 to 100 mg/d is sufficient in such cases. The
iron supplementation should be continued for a period of
several months, so as to normalize not only the Hb but also
the iron stores. In one study, we were able to show that
puerperae with iron deficiency, but no anemia can replenish
their iron stores through iron supplementation only.24
Thus, puerperae who have iron deficiency and anemia are
particularly likely to have high iron requirements. We therefore
continue to give iron for at least 6 months. In most cases, giving
oral iron is not enough when treating severe anemia, since the
endogenous iron stores are usually depleted and not enough
iron is provided to ensure sufficient erythropoiesis. As mentioned earlier, the reasons for this include limited absorption,
poor compliance at high doses due to adverse effects, and low
plasma transferrin saturation levels, which lead to functional
iron deficiency. In addition, an inflammatory reaction can occur, particularly following surgically assisted deliveries and cesarean section, leading to iron sequestration in the macrophages
and decrease of intestinal absorption, so that the administered
iron is not available for hemopoiesis.10,18
One alternative is the parenteral administration of iron
sucrose. The high plasma iron concentrations that occur
shortly after intravenous administration bypass the limited
release of iron from the reticuloendothelial system and the
inhibited absorption through the intestinal mucosa, thus delivering sufficient quantities of iron for erythropoiesis. As in
pregnancy, we follow an incremental treatment plan using
parenteral iron sucrose at Hb levels below 9.5 g/dL.4
Since 1996 we have published several studies on the use of
iron sucrose (with or without rHuEPO) for postpartum anemia in various dosages between 100 and 800 mg (total dose).
Depending on the selected total dose, Hb increases between 2.1
and 3.5 g/dL were observed after 14 days (Fig 1).4,19,20,22,23 In
our studies, a reduction of transfusion frequency was not
detected since transfusion was not an outcome parameter, ie,
we would consider transfusion only in emergency cases and
not as a regular treatment option. Gravier et al showed a Hb
increase of 3.8 g/dL after 14 days (400 to 600 mg total dose)
and a time difference of 14 days versus 30 days (with oral
iron) until target Hb was reached.11
Delta-Hb
3.5
3
2.5
2
(g/dL)
Day 14
1.5
1
0.5
0
100 mg
400 mg
800 mg
Iron Sucrose total dose
FERRITIN
200
180
160
140
120
(mg/dL) 100
80
60
40
20
0
Baseline
Day 14
100 mg
400 mg
800 mg
Iron Sucrose Total Dose
Figure 1 Hemoglobin increase (delta Hb from baseline) and ferritin
(absolute increase) 14 days after therapy with iron sucrose complex
in various total dosages in women with postpartum anemia.18-20
More recently, Broche et al retrospectively analyzed data
from 4,292 patients who gave birth in their institution between April 2001 and March 2003. All patients who presented with postpartum anemia (Hb ⬍8 g/dL) within 48
hours of delivery (n ⫽ 217, ie, 5% of all parturients), were
included in the study. Two groups were distinguished based
on the availability of intravenous iron sucrose in the institution at the time of delivery. The analysis comprised clinical
and laboratory outcomes. Between April 2001 and March
2002, 103 patients received either blood transfusions (n ⫽
15 [14.6%]) or oral iron (n ⫽ 88), whereas between April
2002 and March 2003, 114 patients received either blood
transfusion (n ⫽ 5 [4.4%]), oral iron (n ⫽ 66), or intravenous
iron sucrose (n ⫽ 43). The mean total dose of intravenous
iron administered was 359 mg (range, 200 to 600 mg). The
mean increase in Hb concentration over 7 days in patients
who received iron sucrose was significantly higher compared
to those who received oral iron exclusively (1.86 ⫾ 0.91 [0 to
3.8] v 0.87 ⫾ 0.65 [⫺0.4 to 1.8] g/dL; P ⫽ 3.9 ⫻ 10⫺8).
The authors concluded that since the availability of intravenous iron sucrose in their institution, the number of transfused patients had been divided by three; the increase in Hb
concentrations was significantly higher with iron sucrose
than with oral iron in patients with postpartum anemia. Iron
sucrose was well tolerated.25
In summary, iron sucrose improves postpartum anemia in
a dose-dependent manner with a maximum increase for an
800-mg total dose. Iron status is improved in all patients;
Intravenous iron sucrose in obstetric anemia
however, a lasting (depot) effect over several weeks has not
been shown. Blood transfusion frequency was reduced in one
study.25 Two studies showed that iron sucrose is superior to
oral iron already at day 7, again depending on the dosage.11
In contrast, a recent study by Dede et al showed no difference
between iron sucrose and oral iron until 28 days after delivery with regard to hematological parameters, although the
effect on iron status was greater with iron sucrose.26
The Cochrane Collaboration reports on several trials comparing different iron compounds (with or without rHuEPO)
for the treatment of postpartum anemia. The authors conclude that a favorable outcome was seen in patients who were
additionally treated with rHuEPO, and that further trials,
focusing on iron administration, the role of dietary iron and
blood transfusion, are needed.27
Conclusion
With regard to the use of intravenous iron in obstetrics, there
is increasing evidence that iron sucrose is safe for the mother
and the fetus using the recommended dosages and therapy
regimens. Iron sucrose is effective in pregnancy and in the
postpartum period in patients who do not respond to oral
iron, who are non-compliant to oral iron, or who are treated
with rHuEPO (rHuEPO is not currently registered for use in
pregnancy and postpartum). In both cases, according to the
present data, the expected hemoglobin increase and time for
therapy are predictable in responding patients. Whether it is
reasonable to wait for a response to oral iron in moderate to
severe anemia is therefore questionable.
Indications for the use of iron sucrose complex are: preexisting (moderate–severe) anemia; no effect of oral iron; side
effects of oral iron; refusal of blood transfusion (eg, Jehovah’s
Witness patients); limited time until delivery; coexisting risks
(eg, bowel disease, renal disease); and pre- and postoperative
period and postpartum anemia. According to our experience,
the effectiveness of iron sucrose is increased by the use of
rHuEPO in patients with a profound postpartum inflammatory state such as anemic patients after cesarean section.19
Future fields of research are the evaluation of patient satisfaction and quality of life, impact on costs and hospital stay,
impact on blood transfusion frequency and mortality rate,
and finally impact on other factors such as breast feeding
behavior and neonatal outcome such as birth weight, prematurity and neonatal iron stores.
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