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Published on 27 January 2010

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Postpartum anaemia-a global healthcare problem

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Treatment of severe postpartum anaemia with ferric carboxymaltose (ferinject)- efficacy and tolerability in clinical practice

Maria Gunthner-Biller

Julia Knabl

Bernd Kost

Barbara Schiessl

Franz Kainer

Ludwig-Maximilian-
University, Obstetrics
and Gynaecology,
Munich, Germany

Globally, 42% of pregnant women are anaemic and even for Europe a high prevalence of 25% is reported.1 Anaemia is often caused by iron deficiency since the daily uptake of iron does not suit the increased requirement of up to 7.5mg/day during pregnancy. Furthermore, 40% of women have already an unfavourable iron status prior to pregnancy.2,3 Anaemia and iron deficiency can be further aggrevated by the blood loss during delivery resulting in an overall, pregnancy-related net iron loss of approximately 580-630mg.[4,5]

The combination of suboptimal iron stores prior to  pregnancy, increased iron demand during pregnancy and blood loss during delivery often results in postpartum iron deficiency anaemia (IDA). Accordingly, postpartum anaemia is a worldwide obstetric problem and even in the US, 10% of mothers are anaemic and 13% iron deficient within the first six months postpartum. Prevalence further increases among low-income women (22% and 30%, respectively).[6]

Consequences of IDA include postpartum depression, reduced cognitive function and milk production, and an increased risk of cardiac failures and blood transfusions.[7,8,9,10] However, despite the substantial impact on the mother, postpartum IDA is often underestimated and remains untreated in clinical practice.

Establishment of an I.V. iron treatment protocol for severe postpartum anaemia
In 2008, a protocol for the treatment of severe postpartum anaemia with intravenous ferric carboxymaltose (FCM) was established at the department of Obstetrics and Gynaecology at the Ludwig-Maximillians-University, Munich.

During the introduction phase of the protocol we considered clinically stable patients who experienced a blood loss >1000mL during delivery or a postpartum Hb <7g/dL eligible for treatment with FCM. Ferric carboxymaltose was administered as a single-dose infusion of 1000mg iron over 15 min (maximum dose 15mg iron/kg body weight).

Haematologic parameters, woundhealing as well as signs for postpartum depression were evaluated at a median time of 14 days after discharge (range 14-21 days).

Experience with ferric carboxymaltose in severe postpartum anaemia
Since June 2008 we have treated thirty patients with severe postpartum anaemia. Median Hb of eligible patients postdelivery was 7.6g/dL (range 6.9-8.8g/dL) and median blood loss during delivery was 1650ml (1000-3000ml). All but one patient responded to treatment comprising a 97% response rate (response defined as increase in Hb >3 g/dL two weeks post discharge). Median Hb-levels increased to 11.9g/dL (9.8-13.3g/dL) at two to three weeks after treatment with FCM (p<0.0001, Figure 1). Serum ferritin increased from 25ng/mL (9-70ng/mL) to 235ng/mL (43-401ng/mL) (p<0.0001, Figure 2). Although the increase in haemoglobin and ferritin went in parallel, postpartum ferritin levels have to be handled with caution due to activation of the acute phase response system. Of note, none of the patients showed evidence of an infection during follow-up. The non-responding patient became clinically unstable (tachycardia) and collapsed two times. Despite administration of two red blood cell concentrates her Hb remained low at 9.8g/dL for unknown reason.

Patients reported improvement in quality of life (QoL) on an observational basis. For quantitative assessment of changes in QoL, we recently initiated systematic collection of QoL-data with the standardised SF-36 evaluation form. Data on woundhealing and postpartum depression are currently being analysed.

Single dose infusion of 1000mg iron was well tolerated without any signs of anaphylactoid or injection site reactions. No severe side-effects were observed. Two patients reported headaches but there was no evidence for relation to the treatment.

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Clinical trials and expert recommendations on I.V. iron in postpartum anaemia

Our results confirm the efficacy and tolerability of intravenous ferric carboxymaltose administration for the treatment of postpartum anaemia in clinical practice.[11,12] In these studies, 96.4% and 91.4% of patients with postpartum anaemia (Hb <10g/dL) responded to intravenous FCM, with response defined as an increase in Hb>12g/dL and achievement of Hb >12g/dL, respectively. Median time to success was 7 days and 14 days, and in both studies it was significantly shorter compared to treatment with oral iron.

A German Expert Panel and the Swiss Society of Obstetrics and Gynaecology recommend parenteral iron therapy for patients with Hb <8.0-9.5g/dL.[4,13] Compared to these recommendations we considered only very severe cases with Hb <7g/dL during the introductory phase of our protocol. Based on the convincing results achieved in our patient population and the recently published recommendations,[4] we amended our protocol and administer intravenous FCM to patients with postpartum Hb <8.0g/dL or a blood loss >1000ml. Of note, diagnostic work-up for postpartum anaemia is already recommended in case of blood loss >500ml.[4] In addition to analysis of Hb levels, we included analysis of ferritin and C-reactive protein in the initial diagnostic routine to ensure that every patient with empty iron stores is captured. A more reliable measure of iron deficiency, in particular in cases of activated acute phase response, would be a transferrin saturation <15%. The established SOP at our postpartum ward is especially helpful for junior residents and nurses and guarantees that all patients are treated up to current standard.

Ferric carboxymaltose in clinical practice
The good results, in particular with respect to tolerability, confirmed the choice of ferric carboxymaltose as standard treatment for patients with severe postpartum anaemia. There are different effective I.V. iron preparations available that differ mainly in the amount of iron that can be administered at once and their composition that can influence tolerability. Other available I.V. iron preparations comprise iron dextran, iron gluconate, and iron sucrose. Whereas iron dextran can induce hypersensitivity reactions and anaphylactic shock, less robust iron complexes such as iron gluconate and to a lower extent iron sucrose do not allow for administration of high doses and release larger amounts of iron into the plasma. This can cause oxidative stress and loss of administered iron via renal excretion.

Ferric carboxymaltose has been developed as a novel I.V. iron repletion therapy that offers convenient administration and permits high doses of iron to be given in a short period. Especially the short infusion time (15 min) and the possibility for administration without a test dose are major advantages in the busy, high volume clinical setting of our outpatient clinic. Rapid administration of I.V. iron allows the physician to focus more on the multiple medical problems of the patients (eg, gestational diabetes, kidney transplants, cystic fibrosis, Type I diabetes etc) and minimises the burden of treatment for the patient. Intravenous iron therapy is also the treatment of choice for patients with intestinal problems and preexisting constipation who cannot absorb or tolerate oral iron. Of note, we observe an increasing number of patients with cystic fibrosis that become pregnant; most of them are anaemic and refractive or intolerant to oral iron.

Conclusion
Ferric carboxymaltose is a new, very effective and well tolerated drug for the treatment of severe postpartum anaemia that can be easily administered in either clinical or ambulatory setting.

References
1. World Health Organisation (WHO). Worldwide prevalence of anaemia 1993-2005. 2008; http://whqlibdoc.who.int/publications/2008/9789241596657_eng.pdf. Accessed 2009 Dec 10.
2. Scholl TO. Am J Clin Nutr 2005;81(5):12181222S.
3. Milman N. Ann Hematol 2008;87(12):949-959.
4. Bergmann R et al. Geburtsh Frauenheilk 2009;69(8):682-686.
5. Milman N. Ann Hematol 2006;85(9):559-565.
6. Bodnar LM et al. Am J Epidemiol 2002;156:903-912.
7. Corwin EJ et al. J Nutr 2003;133(12):4139-4142.
8. Beard JL et al. J Nutr 2005;135(2):267-272.
9. Breymann C et al. Int J Gynaecol Obstet 2008;101(1):67-73.
10. Reveiz L et al. Cochrane Database Syst Rev 2007;(2):CD003094.
11. Van Wyck DB et al. Obstet Gynecol 2007;110(2 Pt 1):267-278.
12. Seid MH et al. Am J Obstet Gynecol 2008;199(4):435-437.
13. Breymann C et al. Diagnostik und Therapie der Anamie in der Schwangerschaft und postpartal. Expertenbrief No.21. 2007;http://sggg.ch/files/Expertenbrief%20No%2022.pdf. Accessed 2009 Dec 10.

Disclosures
Data have been presented as Poster at 9th World Congress of Perinatal Medicine, Berlin, 2009.
Preparation of this manuscript has been supported by Vifor Pharma and the authors would like to thank Walter Fürst for editorial support.



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