# Patient blood management in obstetrics: management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement

M. Munoz, J. P Peña-Rosas, S. Robinson, N. Milman, W. Holzgreve, C.

Breymann, F. Goffinet, J. Nizard, F. Christory, C.-M. Samama, et al.

► To cite this version:

M. Munoz, J. P Peña-Rosas, S. Robinson, N. Milman, W. Holzgreve, et al.. Patient blood management in obstetrics: management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement. Transfusion Medicine, 2018, 28 (1), pp.22-39. 10.1111/tme.12443 . hal-01744656

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# Patient blood management in obstetrics: management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement

M. Muñoz,¹ ID J. P. Peña-Rosas,² S. Robinson,³ ID N. Milman,⁴ W. Holzgreve,⁵ C. Breymann,⁶ F. Goffinet,⁷ J. Nizard,⁸ F. Christory,⁹ C.-M. Samama¹⁰ & J.-F. Hardy¹¹

¹Perioperative Transfusion Medicine, Department of Surgical Specialties, Biochemistry and Immunology, University of Málaga, Málaga, Spain, ²Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, Geneva, Switzerland, ³Guy's and St Thomas' NHS Foundation Trust, Clinical Lead for Transfusion and Obstetric Haematology, London, UK, ⁴Departments of Clinical Biochemistry and Obstetrics, Naestved Hospital, University of Copenhagen, Naestved, Denmark, ⁵FIGO Representative, Professor of Gynaecology and Obstetrics, Medical Director and CEO, University Hospital Bonn, Bonn, Germany, ⁶Obstetric Research - Feto Maternal Haematology Research Unit, University Hospital Zurich, Zurich, Switzerland, ⁷Department of Obstetrics and Gynecology, Port-Royal Maternity, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Assistance Publique des Hôpitaux de Paris, Paris, France, ⁸Department of Obstetrics and Gynecology, Groupe Hospitalier Pitié Salpêtrière, Université Pierre et Marie Curie-Paris 6, Paris, France, ⁹Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA), Paris, France, ¹⁰NATA Chair, Professor of Anaesthesiology, Department of Anaesthesiology, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada, and ¹¹University of Montreal, Montreal, QC, Canada

Received 19 October 2016; accepted for publication 18 June 2017

## INTRODUCTION

Patient blood management (PBM) is the timely application of evidence-informed medical and surgical concepts designed to maintain haemoglobin concentration, optimise haemostasis and minimise blood loss in an effort to improve patient outcomes. The aim of this consensus statement is to provide recommendations on the management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period as part of PBM in obstetrics. A multidisciplinary panel of physicians with expertise in obstetrics, anaesthesia, haematology, policymaking and epidemiology was convened by the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) in collaboration with the International Federation of Gynaecology and Obstetrics (FIGO) and the European Board and College of Obstetrics and Gynaecology (EBCOG). Members

of the task force assessed the quantity, quality and consistency of the published evidence and formulated recommendations using the system developed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) working group. The recommendations in this consensus statement are intended for use by clinical practitioners managing the perinatal care of women in all settings and by policymakers in charge of decision making for the update of clinical practice in health-care establishments. They need to be tailored for application in individual patients or any population after consideration of the values and preferences of both health-care providers and patients, as well as equity issues; explicit assessment of harms and benefits of each recommendation; feasibility including resources, capacity and equipment; and implementability.

## SUMMARY OF RECOMMENDATIONS

### Anaemia in pregnancy

### Detection and classification

1. We recommend that a full blood count (FBC) be obtained to screen for anaemia at booking and at 28 weeks, as well as at any time during pregnancy if symptoms of anaemia are present (1A).

2. In a woman with microcytic or normocytic anaemia, iron deficiency (ID) should be confirmed by a trial of oral iron (unless she is known to have a haemoglobinopathy) or a serum ferritin measurement (1B).

A multidisciplinary consensus statement developed by the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) in collaboration with the International Federation of Gynaecology and Obstetrics (FIGO) and the European Board and College of Obstetrics and Gynaecology (EBCOG).

Correspondence: Prof. Manuel Muñoz, MD, PhD, Department of Surgical Specialties, Biochemistry and Immunology, School of Medicine, University of Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain. Tel.: +34 952 131 540; fax: +34 952 131534; e-mail: mmunoz@uma.es
3. In the absence of an haemoglobin (Hb) increment in response to a trial of oral iron conducted correctly, we recommend the further evaluation of iron status by checking serum ferritin and considering whether additional laboratory testing is needed (1C).

4. In anaemic women of Mediterranean, Middle and Far East and African origin, we recommend confirming the presence or absence of a haemoglobinopathy either by selective (based on a family of origin questionnaire) or universal screening for haemoglobinopathies depending on regional demographics (1C).

5. Anaemic women with a known haemoglobinopathy should have their serum ferritin checked and should only be offered oral iron therapy if their serum ferritin level is <30 ng mL⁻¹ (1B).

### Prevention

6. In areas with a high prevalence of anaemia in pregnancy, we recommend daily oral iron (30–60 mg) and folic acid (400 µg) supplementation as part of routine antenatal care to reduce the risk of maternal anaemia and ID and infant low birthweight (1B).

7. In areas with a low prevalence of anaemia in pregnancy, non-anaemic women identified to be at an increased risk of ID should have their serum ferritin checked early in pregnancy and be offered oral supplements (30–60 mg/day) if serum ferritin is <30 ng mL⁻¹ (1C).

### Treatment: oral iron

8. We recommend treating mild to moderate iron-deficiency anaemia (IDA) (Hb ≥80 g L⁻¹) in early pregnancy (first and second trimesters) with oral ferrous iron (80–100 mg/day elemental iron) and folic acid (400 µg/day) (1B).

9. Once the Hb concentration is in the normal range, we recommend that iron supplementation be continued for at least 3 months to replenish iron stores (1A).

### Treatment: IV iron

10. We recommend that the administration of intravenous (IV) iron be considered in women with severe IDA (Hb <80 g L⁻¹) or newly diagnosed IDA beyond 34 weeks of gestation (1B).

11. We recommend that the administration of IV iron be considered in women with confirmed IDA who fail to respond to the correct administration of oral iron (Hb concentration increase <10 or 20 g L⁻¹ in 2 or 4 weeks, respectively) or are intolerant to oral iron treatment, if the gestational age is >14 weeks (1B).

### Treatment: ESA

12. We suggest that administration of an erythropoiesis-stimulating agents (ESA) be considered in women with moderate to severe anaemia not responding to IV iron due to inappropriate synthesis of, and/or response to, endogenous erythropoietin levels, in consultation with a haematologist (2C).

### Treatment: RBC transfusion

13. We recommend that referral to a secondary care clinic be considered if there are significant symptoms of anaemia and/or severe anaemia (Hb <70 g L⁻¹) or late gestation (>34 weeks) (1C).

14. We recommend that obstetric units have guidelines for red blood cell (RBC) transfusion in women with antenatal and post-natal anaemia who are not actively bleeding (1C).

15. In the absence of bleeding, should transfusion be deemed necessary, we recommend a single-unit transfusion followed by clinical reassessment and/or Hb measurement to determine the need for further transfusion (1C).

### Post-partum anaemia

#### Detection and classification

16. We recommend that pregnant women, especially those with antenatal anaemia, have an Hb determination prior to delivery (1C).

17. We recommend that the Hb concentration be determined in all women after significant peri-partum bleeding (1C).

### Prevention

18. We recommend that every effort be made to correct anaemia prior to delivery (1A).

19. We recommend that women with moderate to severe anaemia or at high risk of haemorrhage be advised to deliver in a hospital setting (1C).

20. We recommend active management of the third stage of labour to minimise blood losses (1A).

21. We recommend cell salvage for women undergoing Caesarean section in whom excessive blood losses are anticipated (1C).

22. We recommend that a clear multidisciplinary, multimodal protocol for management of major obstetric haemorrhage be in place. This protocol should be activated as soon as major obstetric haemorrhage is identified (1C).

### Treatment: oral iron

23. Oral iron supplementation, either alone or in combination with folic acid, is recommended for 6–12 weeks following delivery to reduce the risk of anaemia in settings where gestational anaemia is a public health concern (1B).

24. We recommend that 80–100 mg elemental iron daily for 3 months be given to women with mild to moderate post-partum anaemia (PPA) (Hb 90–110 g L⁻¹) who are haemodynamically stable and asymptomatic or mildly symptomatic (1B).
**Treatment: IV iron**

25. We recommend that women who fail to respond to the correct administration of oral iron (Hb increase <10 or 20 g L⁻¹ in 2 or 4 weeks, respectively) or are intolerant to oral iron be switched to IV iron (1B).

26. We recommend the administration of IV iron to cover individually calculated total ID in women with moderate to severe PPA (Hb <90 g L⁻¹) (1B).

**Treatment: ESA**

27. In severely anaemic patients with blunted erythropoiesis due to infection and/or inflammation who do not respond adequately to IV iron treatment, as well as in severely anaemic patients who refuse blood transfusions, we suggest considering treatment with an ESA after consultation with the haematologist (2B).

**Treatment: RBC transfusion**

28. We recommend that all pregnant women should be typed for blood groups (ABO and D) and screened for the presence of red cell antibodies early in pregnancy (at booking) and at 28 weeks gestation. In D-negative women, the 28-week sample should be taken before the administration of routine antenatal anti-D Ig prophylaxis (1B) (White et al., 2016).

29. We recommend that RBC transfusion not be dictated by Hb levels alone (1C).

30. We recommend that transfusion be considered in non-bleeding patients with an Hb <60 g L⁻¹, taking clinical signs and symptoms (risk of bleeding, cardiac compromise or symptoms requiring immediate attention) into consideration (1A).

31. In the absence of bleeding, should transfusion be deemed necessary, we recommend a single-unit transfusion followed by clinical reassessment and/or Hb measurement to determine the need for further transfusion (1C).

## PATIENT BLOOD MANAGEMENT

PBM has become the buzzword in transfusion medicine. A few years ago, clinicians who spoke about PBM at meetings were considered abstruse visionaries. With time, their vision has evolved and come into focus. This has allowed the health-care community to better understand the concept and, most importantly, to apply it in everyday clinical practice.

**Definition of PBM**

PBM or, more precisely, patient-centred blood management “is the timely application of evidence-informed medical and surgical concepts designed to maintain haemoglobin concentration, optimise haemostasis and minimise blood loss in an effort to improve patient outcomes” (Shander *et al*., 2016). By definition, the approach is multidisciplinary and focuses on

the treatment of each individual patient in whom significant blood losses are likely to occur and where transfusion of blood products is part of the established treatment (Gombotz, 2012). PBM involves – but is not restricted to – the appropriate use of blood products, defined by the World Health Organisation (WHO) as “the transfusion of safe blood products to treat a condition leading to significant morbidity or mortality that cannot be prevented or managed effectively by other means.” (WHO, 2001a).

Although PBM is known best in the management of elective surgical procedures, it can (and should) also be applied to any procedure likely to result in excessive bleeding, post-procedural anaemia and the use of blood products. The “three pillars” of PBM require that (i) perioperative erythropoiesis be optimised, (ii) blood losses be minimised and (iii) tolerance to anaemia be harnessed appropriately (Isbister, 2013). PBM is a continuous process, initiated early in the preoperative period and continued intra- and post-operatively. The whole concept of PBM has been elegantly summarised by Hofmann *et al*. (Hofmann *et al*., 2007) (Figure S1, Supporting Information).

**Importance of PBM**

At present, preoperative anaemia is often ignored, surgery proceeds as planned, and RBCs are transfused when deemed necessary (Muñoz *et al*., 2015; Meier *et al*., 2016) Yet, cohort studies (in cardiac, non-cardiac and vascular surgery) have shown that preoperative anaemia is associated with an increased incidence of post-operative adverse events, including mortality (Wu *et al*., 2007; Ranucci *et al*., 2012; Gupta *et al*., 2013) In addition, preoperative anaemia and low intraoperative haemoglobin (Hb) concentration are important predictors of perioperative allogeneic RBC transfusions (Muñoz *et al*., 2015).

Blood transfusions entail a number of known risks (e.g. transmission of infectious agents, transfusion reactions, ABO mismatch, transfusion-related acute lung injury, transfusion-associated circulatory overload, etc.) and other less well-known ones. The latter are related, in essence, to emergent pathogens and to immunomodulation (increased incidence of infections and cancer recurrence) (Goodnough & Shander, 2012). At present, it remains difficult to determine whether the observed adverse events and mortality are related to preoperative anaemia *per se* or to the increase in allogeneic transfusions secondary to anaemia (Figure S2). Notwithstanding, the overall outcome is negative, so preoperative anaemia must be managed in a timely fashion (Muñoz *et al*., 2015). PBM implementation remains inadequate, even in centres where audits are conducted on a regular basis (Gombotz *et al*., 2014; Van der Linden & Hardy, 2016). That being said, it has not been unequivocally demonstrated that correction of preoperative anaemia is associated with improved outcomes (Muñoz *et al*., 2015). High-quality evidence in that direction would definitely improve adherence to PBM principles.
# CONSENSUS ORGANISATION

## Scope and purpose

This consensus statement reflects the position of the NATA, the FIGO and the EBCOG. It includes recommendations on the management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period as part of PBM in obstetrics. The prevention and treatment of post-partum haemorrhage (PPH) will be addressed in a separate consensus statement.

## Target audience

The recommendations in this consensus statement are intended for use by clinical practitioners managing perinatal care of women in all settings and by policymakers in charge of decision making for the update of clinical practice in health-care establishments. It is important to note that these recommendations need to be tailored for application in individual patients or any population after consideration of the values and preferences of both health-care providers and patients, as well as equity issues; explicit assessment of harms and benefits of each recommendation; feasibility including resources, capacity and equipment; and implementability. Further involvement of relevant stakeholders at the local level is advised.

## Development process

A multidisciplinary panel of physicians with expertise in obstetrics, anaesthesia, haematology, policymaking and epidemiology was convened in Paris, France on 28 February 2015 by NATA in collaboration with FIGO and EBCOG with the aim of developing a consensus statement on the detection, evaluation and management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period. The experts were asked to:

1. Determine the scope of the problem;

2. Identify the optimal methods to detect the problem and establish a differential diagnosis;

3. Assess the evidence and its quality for the detection, evaluation and management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period;

4. Agree on recommended methods to minimise peri-partum blood losses;

5. Define the role of RBC transfusions in pregnancy and in the post-partum period and

6. Issue recommendations on the use of oral iron, IV iron and ESA to treat anaemia during pregnancy and in the post-partum period.

Members of the task force assessed the quantity, quality and consistency of the published evidence and formulated recommendations using the system developed by the GRADE working group (Guyatt *et al.*, 2008) (Figure S3). A preliminary version of the consensus statement was drafted by M. M. and circulated among the members of the panel for additional input

and editing. The document was further reviewed by two experts in the field (F. G. and N. M.) who were not previously involved in the process. The document was then submitted for publication and underwent the journal's regular peer-review process. The recommendations in this statement are expected to remain valid for an estimated standard period of 10 years.

## Plans for dissemination, adaptation and evaluation

This statement will be disseminated to all members of NATA, FIGO and EBCOG, and open access will be provided. Additionally, the recommendations will be presented at international forums and specialised events targeting clinicians in charge of the management of anaemia and haematinic deficiencies in pregnant and post-partum women.

# ANAEMIA IN PREGNANCY

Anaemia occurs frequently during pregnancy. Anaemia can be aggravated by childbirth and is associated with adverse events. In most cases, it is possible to identify and correct the situation prior to childbirth, thereby improving patient outcomes.

## Definitions

During pregnancy, there is a considerable increase (40–45%) in plasma volume (Sanghavi & Rutherford, 2014). The maternal plasma erythropoietin level also increases during pregnancy, with a peak in the third trimester, to accelerate erythropoiesis and help compensate for the dilution effect. These changes, resulting in an increase in total blood volume, are important to meet the increased demands of blood flow for the uterus and foetus, and may protect pregnant woman against the adverse effects of blood loss during labour. However, the disproportion in volume expansion between the plasma and RBC volumes results in haemodilution, and therefore, cut-off values for the definition of anaemia during pregnancy should be lower than those for non-pregnant women (Milman, 2008).

The definition of a normal Hb concentration in pregnancy is controversial and lacks consistency across studies. Ideally, the cut-off values for pre-partum anaemia should be derived from studies of healthy iron-replete (as well as folate- and vitamin B₁₂-replete) women who had a normal singleton pregnancy and delivery (Milman *et al.*, 2000; Milman *et al.*, 2007). The WHO has defined anaemia in pregnancy as an Hb <110 g L⁻¹ and classified anaemia as mild (Hb 100–109 g L⁻¹), moderate (Hb 70–99 g L⁻¹) or severe (Hb <70 g L⁻¹) (WHO, 2011). There are no WHO recommendations on the use of different Hb cut-off points by trimester, but it is recognised that during the second trimester of pregnancy, Hb concentration decreases by approximately 5 g L⁻¹. Additionally, the WHO states that 'mild' anaemia is a misnomer as iron deficiency is already advanced by the time anaemia is detected. Iron deficiency has consequences even when no anaemia is clinically apparent. The American
College of Obstetricians and Gynaecologists (ACOG) and British Committee for Standards in Haematology (BCSH) guidelines define anaemia in pregnancy as an Hb <110 g L⁻¹ in the first trimester and <105 g L⁻¹ in the second and third trimesters (ACOG, 2008; Pavord *et al.*, 2012).

*Prevalence*

It is estimated that in 2011, 38% of pregnant women worldwide were anaemic, with wide variations between regions (Stevens *et al.*, 2013). The prevalence of anaemia among pregnant women was 48.7% in the Southeast Asian region, compared with 46.3% in the African region and 25.8% in the European region.

*Causes*

IDA accounts for most cases of anaemia in pregnant women (Stevens et al., 2013) as iron stores are often insufficient to meet the increasing demands of pregnancy due to the increase in RBC mass (450 mg), foetal growth (225 mg), placental development (80 mg) and blood losses during normal vaginal delivery (250 mg). A total of approximately 1000 mg of extra iron is required during a normal pregnancy, equivalent to 6.3 mg day⁻¹. In addition, lactation will require an additional supply of 1 mg day⁻¹ (Bothwell, 2000). Without supplementation, 80% of women at term will have no detectable iron stores according to bone marrow samples, and it will take 2 years of normal dietary iron to replace the iron lost with each pregnancy (De Leeuw et al., 1966).

Although most of the burden of anaemia is assumed to be due to ID, other contributors should be considered. Nutritional deficiencies of folate and vitamin B₁₂, infectious diseases, parasitic infections and haemoglobinopathies are additional and often neglected causes of anaemia (WHO, 2001c; Kassebaum et al., 2014).

*Consequences*

Iron depletion reduces iron availability for erythropoiesis and results in decreased Hb and oxygen delivery to tissues, resulting in clinical signs and symptoms. These include reduced exercise tolerance, tiredness and fatigue, impaired cognitive performance tests, decreased mental concentration ability, irritability, tendency of depression, palpitations, headaches, pallor, glossitis, angular cheilitis, nail ridging, koilonychias, reduced immunity, increased frequency of infections and pica. Anaemia is the most common indirect cause of adverse maternal outcomes, including maternal mortality (Filippi et al., 2016). Low Hb concentrations indicative of moderate or severe anaemia during pregnancy have been associated with an increased risk of premature delivery and child mortality and infectious diseases (Filippi et al., 2016). An Hb <70 g L⁻¹ is an associated cause in up to half of the maternal mortalities worldwide. Moreover, IDA may affect growth and development both of the foetus *in utero* and of the newborn child

in the long term (Lumbiganon et al., 2014; Vogel et al., 2014; New & Wirth, 2015) (Table S1).

There are significant concerns about the suboptimal management of maternal anaemia even in high-resource areas, likely due in part to a lack of consistent good-quality evidence mandating therapeutic interventions (Parker et al., 2012). The development of more standardised approaches to reporting outcomes of maternal anaemia, together with the impact of therapy, is a research priority (Allard, 2015).

*Detection and classification*

The National Institute for Health and Care Excellence (NICE) in the UK recommends that screening for haematological conditions in pregnancy should be offered at booking and at 28 weeks, thus allowing adequate time for treatment should anaemia be detected (NICE, 2008). Hb concentrations below the normal range for pregnancy should be investigated and iron supplementation considered if indicated. It has been proposed that the first antenatal haematological screening should also include serum ferritin, thus allowing the early assessment of body iron status and an immediate decision whether or not there is an indication for oral iron supplementation in early pregnancy (Milman, 2006). However, there is currently no consensus on this issue. The 2015 U.S. Preventive Services Task Force recommendation concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for IDA in pregnant women to prevent adverse maternal health and birth outcomes (Siu, 2015). The authors indicate, however, that this recommendation does not apply to pregnant women who are malnourished, have symptoms of IDA or have special haematological conditions or nutritional needs that increase iron requirements. In the UK, unselected screening with routine use of serum ferritin is generally not recommended, although guidelines note that it may be helpful in individual centres with a particularly high prevalence of women at risk of ID (Pavord et al., 2012).

A FBC screening test to detect anaemia in pregnancy may reveal an Hb below the defined threshold. Following detection of anaemia, a standard haematological approach is generally applied to determine if the anaemia is secondary to increased blood loss or decreased production of red cells. Red cell indices, other FBC parameters and a blood film are usually reviewed. Blood film reviews may identify variation in size and shape of cells, uniformity, fragments, inclusion bodies or sickle cells. However, they are time consuming and are hardly ever performed at diagnosis. The mean red cell volume (MCV) may suggest a microcytic (ID, haemoglobinopathy), macrocytic (vitamin B₁₂ or folate deficiency, thyroid disease, reticulocytosis, increased alcohol intake or liver dysfunction) or normocytic (anaemia of chronic disease, marrow suppression or dual haematinic deficiency) cause for anaemia. Additional blood tests may be considered, including haematinics (iron, vitamin B₁₂, folate), and in certain cases, reticulocytes, haemoglobin electrophoresis, lactate dehydrogenase, haptoglobin, bilirubin and a direct antiglobulin test (to exclude haemolysis) would be
needed for a definite classification of anaemia (Hallberg *et al*.,
1993; van den Broek *et al*., 1998; Muñoz *et al*., 2011).

In the presence of IDA during pregnancy, the MCV, the mean red cell haemoglobin (MCH) and the mean red cell haemoglobin concentration (MCHC) may be low, and the blood film may confirm microcytic, hypochromic red cells and elliptocytes. However, the increased erythropoietic drive in pregnancy leads to a higher proportion of young, large, red cells and may mask the effect of ID on MCV. A normal MCV does not exclude ID, whereas microcytic, hypochromic indices may occur in haemoglobinopathies. The red cell distribution width, i.e. the variation in the volumes of red cells, can help differentiate ID from other microcytic anaemias, for instance, thalassaemia. Therefore, it is important to confirm whether a haemoglobinopathy is present. Plasma or serum ferritin is a measure of iron stores. It declines early in the development of ID and is not affected by ingestion of iron. Because serum ferritin is an acute-phase protein, it is recommended to determine the C-reactive protein level at the same time if inflammation is present or suspected. In pregnancy, a serum ferritin concentration <30 ng mL⁻¹ indicates insufficient body iron reserves and hence a high risk for developing IDA; a serum ferritin concentration <12 ng mL⁻¹ indicates established ID at all stages of pregnancy (Hallberg *et al*., 1993; van den Broek *et al*., 1998; Muñoz *et al*., 2011).

A trial of oral ferrous iron therapy (100 mg elemental iron/day) has also been considered a first-line diagnostic test for IDA (ACOG, 2008; Pavord *et al*., 2012). In women of Mediterranean, Middle and Far East and Africa descent who may have haemoglobinopathies, an oral iron trial could be offered whilst waiting for their haemoglobinopathy status to be determined. The chances of iron overload would be minimal, and the benefits would outweigh the risks. An Hb increment in 2–4 weeks (positive response) is supportive of a diagnosis of IDA. In case of negative response, further investigation including serum vitamin B₁₂ and folate should be considered (Annex S1).

Recommendations

* **Recommendation 1:** We recommend that an FBC be obtained to screen for anaemia at booking and at 28 weeks as well as at any time during pregnancy if symptoms of anaemia are present (1A).

* **Recommendation 2:** In a woman with microcytic or normocytic anaemia, ID should be confirmed by a trial of oral iron (unless she is known to have a haemoglobinopathy) or a serum ferritin measurement (1B).

* **Recommendation 3:** In the absence of an Hb increment in response to a trial of oral iron conducted correctly, we recommend the further evaluation of iron status by checking serum ferritin and considering whether additional laboratory testing is needed (1C).

* **Recommendation 4:** In anaemic women of Mediterranean, Middle and Far East and African origin, we recommend

confirming the presence or absence of a haemoglobinopa-
thy either by selective (based on a family of origin ques-
tionnaire) or universal screening for haemoglobinopathies
depending on regional demographics (1C).

* **Recommendation 5:** Anaemic women with a known haemoglobinopathy should have their serum ferritin checked and should only be offered oral iron therapy if their serum ferritin level is <30 ng mL⁻¹ (1B).

Good practice points

* Aside from the oral iron trial, the serum ferritin level is the most useful and easily available laboratory parameter for assessing ID during pregnancy.

* Serum ferritin levels <12 ng mL⁻¹ indicate established ID. A serum ferritin level <30 ng mL⁻¹, with or without anaemia, indicates insufficient body iron reserves and should prompt treatment. However, as ferritin is an acute-phase reactant, a serum ferritin level within the normal range may not rule out ID in the presence of inflammation.

Prevention

Interventions aimed at preventing ID and IDA in pregnancy include iron- and folic acid-containing supplements, fortification of staple foods with iron and other vitamins and minerals, health and nutrition education, control of parasitic infections and improvement in sanitation (INACG, 1977). A supplemental daily dose of 30–60 mg of elemental ferrous iron is recommended by the WHO for all pregnant women in all settings (WHO, 2012). In most countries, a prenatal supplement containing 30 mg iron is offered, although iron content may vary (e.g. 45 mg in the USA and 60 mg in the UNICEF product). A study of Danish women showed that a supplement of 40 mg ferrous iron/day for 18 weeks of gestation appears adequate to prevent ID in 90% of the women and IDA in at least 95% of the women during pregnancy and the post-partum period (Milman et al., 2005). Prophylactic iron supplementation should be started as soon as pregnancy is confirmed and maintained throughout its entire duration. In settings where anaemia in pregnant women is a severe public health problem (prevalence of 40% or higher), a daily dose of 60 mg of elemental ferrous iron is preferred over a lower dose (WHO, 2012).

Two recent meta-analyses concluded that daily prenatal use of iron substantially reduces the risk of maternal anaemia and ID in pregnancy but that the positive effect on other maternal and infant outcomes is less clear (Haider *et al*., 2013; Peña-Rosas *et al*., 2015a). Implementation of iron supplementation recommendations improves birthweight, probably leading to a reduction in the risk of low birthweight, but it produces heterogeneous results depending on the population's background risk for low birthweight and anaemia, as well as the level of adherence to the intervention (Peña-Rosas *et al*., 2015a).

A Cochrane systematic review suggests that intermittent
iron and folic acid supplementation regimens produce similar
maternal and infant outcomes at birth as daily supplementa-
tion and are associated with fewer gastrointestinal side effects
and increased compliance (Peña-Rosas *et al.*, 2015b). The risk
of reaching high Hb in mid and late pregnancy was reduced,
whereas the risk of having mild anaemia near term increased.
Thus, intermittent oral ferrous iron may be a feasible alterna-
tive to daily iron supplementation among those pregnant women
who are not anaemic and have adequate antenatal care.

The 2015 U.S. Preventive Services Task Force recommenda-
tion states that the current evidence is insufficient to assess the
balance of benefits and harms of routine iron supplementation
for pregnant women in order to prevent adverse maternal health
and birth outcomes (Siu, 2015). Similarly, routine iron supple-
mentation for all pregnant women has not been recommended
in the UK (Pavord *et al*., 2012).

As for folic acid, a prophylactic dose of 400 µg (0.4 mg) per day, peri-conceptionally and throughout pregnancy, is recommended for the prevention of neural tube defects. If supplementation is started after the first trimester of pregnancy, it will not help prevent congenital anomalies. Therefore, folic acid supplementation should begin as early as possible (ideally prior to conception).

Daily oral iron and folic acid supplementation during preg-
nancy is a strong WHO recommendation, with overwhelming
implications for patients, clinicians, policymakers, quality mon-
itors and funding agencies (WHO, 2012). There are currently no
specific recommendations for prophylactic vitamin B₁₂ supple-
mentation in pregnancy.

Recommendations

* **Recommendation 6:** In areas with a high prevalence of anaemia in pregnancy, we recommend daily oral iron (30–60 mg) and folic acid (400 µg) supplementation as part of routine antenatal care to reduce the risks of maternal anaemia and ID and infant low birthweight (1B).

* **Recommendation 7:** In areas with a low prevalence of anaemia in pregnancy, non-anaemic women identified to be at increased risk of ID should have their serum ferritin checked early in pregnancy and be offered oral supplements (30–60 mg day⁻¹) if serum ferritin is <30 ng mL⁻¹ (1C).

Good practice points

* According to the United Nations International Multiple Micronutrient Preparation, in high-risk areas, supplements may be formulated to include, in addition to iron and folic acid, other vitamins and minerals to overcome other possible maternal micronutrient deficiencies.

* In malaria-endemic areas, provision of iron and folic acid supplements should be implemented in conjunction with measures to prevent, diagnose and treat malaria (WHO, 2012). In cases where a combined folic acid-iron tablet is not available, a daily dose of 400 µg folic acid can be used separately (RBMP, 2015).

* Non-anaemic women at risk of ID include those with previous anaemia, multiparity, consecutive pregnancy <1 year following delivery and vegetarians. Special attention should also be given to pregnant teenagers, women at high risk of bleeding or with a recent history of bleeding, and Jehovah's Witnesses (Pavord *et al*., 2012). When logistically difficult, these women should receive daily oral iron (30–60 mg) without checking serum ferritin.

* All pregnant women should be counselled and receive plain-language written information regarding diet and iron-rich food sources, factors that may inhibit or promote iron absorption and the importance of maintaining adequate iron stores during pregnancy (Pavord *et al*., 2012).

Treatment: Oral iron

The primary treatment for mild to moderate cases of IDA (Hb 70–105 g L⁻¹) during the first and second trimesters is daily oral iron therapy, and doses ranging from 40 to 200 mg day⁻¹ of elemental ferrous iron, ideally on an empty stomach, have been recommended. The same also applies to depleted iron stores without anaemia (serum ferritin <30 ng mL⁻¹) at the beginning of pregnancy (60 mg day⁻¹ elemental iron) because of the additional requirement for iron during the course of the pregnancy (ACOG, 2008; Breymann *et al*., 2011; Pavord *et al*., 2012; WHO, 2012).

However, lower-dosage iron supplements can be effective for
the treatment of IDA and are associated with less gastrointestinal
side effects. In non-anaemic young women with plasma ferritin
levels <20 ng mL⁻¹, providing lower dosages (40–60 mg iron)
and avoiding twice-daily dosing was found to maximise frac-
tional absorption due to the effect of absorbed iron on hepcidin
release (Moretti et al., 2015). Whether these data also apply to
anaemic women is not known. As anaemia-induced hypoxia and
erythropoietin production down-regulate the expression of hep-
cidin, this may counterbalance the stimulatory effect of iron,
allowing the use of higher oral iron doses (Muñoz et al., 2011).

Recommendations

* **Recommendation 8:** We recommend treating mild to moderate IDA (Hb ≥80 g L⁻¹) in early pregnancy (first and second trimesters) with oral ferrous iron (80–100 mg day⁻¹ elemental iron) and folic acid (400 µg day⁻¹) (1B).

* **Recommendation 9:** Once the Hb concentration is in the normal range, we recommend that iron supplementation be continued for at least 3 months to replenish iron stores (1A).

Good practice points

* Women should be advised on the appropriate intake of oral iron to optimise absorption (empty stomach, preferably 1 h before breakfast, with a vitamin C-containing drink).

* Systems must be in place for rapid review and follow up of blood results.
* Clinical staff should be familiar with the iron content of over-the-counter supplements that women take during pregnancy as many contain insufficient elemental iron to be therapeutic.

## Treatment: Intravenous iron

A switch to an IV iron preparation can be advantageous in certain cases, including: (i) a lack of response to oral iron (Hb levels rising by less than 10 or 20 g L⁻¹ within 14 or 28 days, respectively) due to impaired intestinal absorption; (ii) lack of compliance or intolerance of oral iron preparations (gastrointestinal side effects); (iii) severe, advanced or progressive anaemia (Hb <80 g L⁻¹); and (iv) desire for rapid anaemia treatment (e.g. advanced gestational age, Jehovah's Witness faith) (Breymann et al., 2011; WHO, 2011; WHO, 2012) (for a summary of the characteristics of available IV iron formulations, Table S2).

We identified 12 randomised controlled trials (RCT) comparing oral and IV iron in a total of 1519 pregnant women (14–37 weeks of gestation) with anaemia (Hb 69–109 g L⁻¹) (al-Momen et al., 1996; Singh et al., 1998; Bayoumeu et al., 2002; Al et al., 2005; Khalafallah et al., 2010; Neeru et al., 2012; Shafi et al., 2012; Froessler et al., 2013; Kochhar et al., 2013; Abhilashini et al., 2014; Gupta et al., 2014; Breymann et al., 2017) (Table S3). Compared with oral iron, antenatal IV iron administration hastened recovery from anaemia, led to a higher rate of anaemia correction and resulted in better replenishment of iron stores and lower rates of adverse drug events or poor treatment compliance. No study showed superiority of oral iron over IV iron.

One study assessed the long-term effect of iron therapy during pregnancy on well-being and health-related quality of life (HRQoL) during a 3-year follow-up period (Khalafallah et al., 2012). Patients receiving IV iron had significantly higher Hb and serum ferritin levels (*P* < 0.001). There were strong associations between iron status and a number of HRQoL items, including improved general health, improved physical energy, less psychological downheartedness, less clinical depression and overall improved mental health. The duration of breastfeeding was longer in women who had received IV iron. In a more recent trial, in which a significantly larger proportion of women treated with IV iron vs oral iron achieved correction of anaemia (Hb ≥110 g L⁻¹; 83.5 vs 70.2%; *P* < 0.05) and did so within a shorter time frame (3.4 vs 4.3 weeks; *P* < 0.05), changes in all SF-36 components favoured IV iron, with significant improvements in vitality and social functioning (Breymann et al., 2017).

The available evidence suggests benefits of IV iron administration, especially for patients with moderate to severe anaemia. Intramuscular iron administration is less effective (Wali et al., 2002; Singh & Singh, 2013) and no longer recommended in the majority of clinical situations; however, it may be an option in certain clinics in case of high throughput or community administration. Two observational studies found no differences

between different IV iron formulations (Christoph et al., 2012; Myers et al., 2012). IV iron formulations allowing the administration of large doses in a single session may facilitate treatment and be more convenient both for the patient (fewer venepunctures, less time out from work) and for the health system (shorter administration time, fewer visits to day hospital and fewer ambulance transfers) (Table S2).

Neither serious life-threatening adverse events attributable to IV iron nor significant differences in maternal or foetal outcomes were reported in the studies reviewed above. Nonetheless, these studies commonly used Hb and iron indices as endpoints and were usually underpowered to evaluate the impact of IV iron therapy on more clinically relevant outcomes.

On 27 June 2013, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) completed a review of IV iron-containing medicines and concluded that all IV iron preparations carry a small risk of adverse reactions that can be life-threatening if not treated promptly. "During pregnancy, the CHMP noted, allergic reactions are of particular concern as they can put both the mother and unborn child at risk. IV iron medicines should therefore not be used during pregnancy unless clearly necessary. Treatment should be confined to the second or third trimester, provided the benefits of treatment clearly outweigh the risks to the unborn baby (such as anoxia and fetal distress)" (EMA, 2013). A number of iron experts disagree with this statement because overemphasising the avoidance of IV iron may not only be counterproductive but also potentially harmful (Auerbach et al., 2015). Guidance for risk minimisation and management of hypersensitivity reactions to IV iron has been published (Rampton et al., 2014). If minor infusion reactions occur with one IV iron formulation, switching to another is appropriate and safe (Auerbach et al., 2015). Nevertheless, we should be aware of the small risk of reactions, and as such, it is not appropriate to go straight for IV iron in all cases. First-line treatment is oral iron based on safety and cost, and the benefits of IV iron outweigh its risks when the oral route is insufficient or poorly tolerated, provided measures are taken to minimise the risk of hypersensitivity reactions (EMA, 2013). Women should be informed of potential side effects of IV iron, and written information should be provided.

## Recommendations

* **Recommendation 10:** We recommend that the administration of IV iron be considered in women with severe IDA (Hb <80 g L⁻¹) or newly diagnosed IDA beyond 34 weeks of gestation (1B).

* **Recommendation 11:** We recommend that the administration of IV iron be considered in women with confirmed IDA who fail to respond to correct administration of oral iron (Hb concentration increase <10 or 20 g L⁻¹ in 2 or 4 weeks, respectively) or are intolerant to oral iron treatment if the gestational age is >14 weeks (1B).
## Good practice points

* IV iron should not be given together with oral iron or in the presence of an active infection.

* Health-care staff should be trained to detect, evaluate and manage hypersensitivity reactions in accordance with published guidelines.

## Treatment: Erythropoiesis-stimulating agents

There is only one each of an RCT, observational study and case series including a total of 135 women with confirmed IDA (Hb 83–95 g L⁻¹; >16 weeks of pregnancy) treated with iron sucrose or iron sucrose plus an ESA (Breymann et al., 1995; Breymann et al., 2001; Krafft et al., 2009) (Table S2). Compared with IV iron alone, addition of an ESA, namely recombinant human erythropoietin (rHuEPO), resulted in higher Hb increments and higher rates of anaemia correction, especially if endogenous erythropoietin levels were low at baseline. Thus, patients not adequately responding to IV iron treatment might benefit from the additional administration of ESAs, although the level of evidence is low.

Neither serious life-threatening adverse events attributable to ESAs nor significant differences in maternal or foetal outcomes were reported in the studies reviewed above. However, it must be remembered that ESAs are not approved for treating anaemia in pregnant women without chronic kidney disease (off-label use). Women should be informed of potential side effects, and written information should be provided.

### Recommendation

* **Recommendation 12:** We suggest that administration of an ESA be considered in women with moderate to severe anaemia not responding to IV iron due to inappropriate synthesis of and/or response to endogenous erythropoietin levels, in consultation with a haematologist (2C).

## Treatment: Red blood cell transfusion

Our literature search identified only one small multicentre RCT (n=72) examining the effect of prophylactic vs indication-driven (restrictive) transfusion in pregnant women, and this study was restricted to women with sickle cell anaemia (Koshy et al., 1988). No other studies have been identified that report on the effect of RBC transfusion on maternal or neonatal mortality, functional or performance status or measures of foetal outcome in a general maternity population. Therefore, any recommendations are based on expert consensus regarding maternal or foetal indications for blood transfusion.

In the context of severe bleeding, there is no question that blood transfusion can save lives; however, it is less certain whether blood transfusion is of benefit to maternity patients not actively bleeding. Furthermore, many inherent risks are involved with blood transfusion, and certain women may refuse blood transfusions due to religious beliefs. Therefore, blood

transfusion should be reserved for those at risk of further bleeding, imminent cardiac compromise or symptoms requiring immediate attention (maternal indications).

Severe anaemia with a maternal Hb <60 g L⁻¹ has been associated with abnormal foetal oxygenation, resulting in non-reassuring foetal heart rate patterns, reduced amniotic fluid volume, foetal cerebral vasodilatation and foetal mortality (Sifakis & Pharmakides, 2000; Carles et al., 2003). In such a case, maternal transfusion should be considered for foetal indications (ACOG, 2008; NICE, 2008). Transfusion indications should be backed up by local guidelines and effective patient information (Pavord et al., 2012).

### Recommendations

* **Recommendation 13:** We recommend that referral to a secondary care clinic be considered if there are significant symptoms of anaemia and/or severe anaemia (Hb <70 g L⁻¹) or late gestation (>34 weeks) (1C).

* **Recommendation 14:** We recommend that obstetric units have guidelines for RBC transfusion in women with antenatal and post-natal anaemia who are not actively bleeding (1C).

* **Recommendation 15:** In the absence of bleeding, should transfusion be deemed necessary, we recommend a single-unit transfusion followed by clinical reassessment and/or Hb measurement to determine the need for further transfusion (1C).

## Good practice points

* Women receiving an RBC transfusion should be given full information regarding the indication for transfusion and alternatives available, according to national policy procedures (WHO, 2001b).

* Informed consent should be given by the patient and documented in the clinical notes.

* One red cell concentrate contains approximately 240 mg of iron, which is insufficient to replace total ID and replenish iron reserves. Therefore, concomitant IV iron to replete the iron reserves in order to minimise the number of transfusions may be considered. Concomitant ESA may also be considered to maximise erythropoiesis and minimise transfusions.

# POST-PARTUM ANAEMIA

Anaemia as well as ID without anaemia are common in the post-partum period and represent significant health problems in women of reproductive age. Predisposing factors should be identified and modified when possible, and routine screening should be considered in order to provide early and appropriate treatment.

## Definition

Ideally, the cut-off value for PPA should be derived from the studies of healthy iron-replete women who had a normal
singleton pregnancy and delivery without excessive blood losses (<500 mL). However, PPA is usually defined by an Hb <100 g L⁻¹ within 24–48 h after delivery, although a recommendation has been made to define PPA as an Hb <110 g L⁻¹ at 1 week post-partum and Hb <120 g L⁻¹ at 8 weeks, the latter corresponding to the definition of anaemia in non-pregnant women of reproductive age proposed by the WHO (Milman, 2011; WHO, 2011; Milman, 2012).

## Prevalence

PPA is common. In a consecutive series of German women (n = 43 807) who delivered in 1993–2008, the prevalence of PPA (Hb < 100 g L⁻¹) 24–48 h after delivery was 22% (up to 50% if PPA was defined as Hb <110 g L⁻¹) (Bergmann et al., 2010). In Danish healthy women, the prevalence of PPA 1 week after normal delivery was 14% with iron supplementation and 24% without iron supplementation (Milman et al., 1991). In developing countries, the prevalence of PPA is in the range of 50–80% and represents a major cause of maternal morbidity and mortality. It has been estimated that peri-partum haemorrhage and anaemia are responsible for approximately 100 000 delivery-associated maternal mortalities yearly on a global scale.

## Causes

In some countries, pre-partum IDA and/or acute bleeding during delivery are the main causes of PPA (Patel et al., 2006; Bergmann et al., 2010; Allary et al., 2013). Normal peri-partum blood losses range from 200 to 300 mL, whereas PPH is defined as blood losses ≥500 mL and severe PPH as blood losses ≥1000 mL (RCOG, 2009; Rajan & Wing, 2010). In a fraction of women, factors such as ethnicity, multiple birth, folate and vitamin B₁₂ deficiencies, inflammatory response (especially after Caesarean section), infectious disorders and haemoglobinopathies may contribute to PPA (Krafft et al., 2003; Milman, 2008; Murray-Kolb & Beard, 2009; Bergmann et al., 2010).

## Consequences

In the post-partum period, anaemia as well as ID without anaemia are associated with decreased physical performance (tiredness, breathlessness, palpitations), increased risk of infection (urinary tract), impaired lactation, reduced cognitive abilities, emotional instability and depression and thus represent significant health problems in women of reproductive age (Bergmann et al., 2010). They also interfere with mother–child interactions as women experience difficulties in caring for their newborn, which compromises the emotional bonds between the mother and baby (Perez et al., 2005). Maternal iron supplementation protects against these negative effects (Murray-Kolb & Beard, 2009). PPA may also increase health-care resource utilisation and costs (Duarte et al., 2014). Therefore, factors predisposing to PPA should be identified and modified when possible.

## Detection and classification

Routine screening for PPA should be considered in order to provide early and appropriate treatment. According to UK guidelines, every woman should have an Hb determination after significant peri-partum bleeding (Pavord et al., 2012). Due to the combination of peri-partum haemorrhage and haemodynamic changes, the post-partum Hb concentration should be allowed to stabilise after delivery for at least 48 h before a reliable diagnosis of PPA can be made. Hb concentration at 1 week post-partum allows a more reliable detection of PPA (Milman, 2012). In case of excessive blood loss (>1000 mL), a protocol should be in place to manage the haemorrhage (including sequential Hb measurements) (Pavord et al., 2012).

As is the case with antenatal anaemia, an algorithm for the diagnosis of PPA should be implemented. Some guidelines state that no treatment is required if the Hb concentration is >110 g L⁻¹.

## Recommendations

* **Recommendation 16:** We recommend that pregnant women, especially those with antenatal anaemia, have an Hb determination prior to delivery (1C).

* **Recommendation 17:** We recommend that the Hb concentration be determined in all women after significant peri-partum bleeding (1C).

### Good practice point

* A complete blood count plus a serum ferritin level at 4–8 weeks post-partum are adequate to assess anaemia and iron status and diagnose ID/IDA in the majority of women with antenatal anaemia or significant peri-partum bleeding (Milman, 2008).

## Prevention

As pre-partum ID and IDA are closely associated with the occurrence of PPA, securing an adequate iron status during pregnancy is the first step in the prevention of PPA; anaemic women are more at risk of bleeding and more vulnerable to even moderate amounts of blood loss. All placebo-controlled studies have shown that pregnant women taking oral iron supplements have an improved iron status and a lower rate of anaemia both during pregnancy and in the post-partum period compared with women taking placebo (Haider et al., 2013; Peña-Rosas et al., 2015a; Peña-Rosas et al., 2015b).

Many medical and gynaecological/obstetrical disorders predispose to peri-partum bleeding, PPH and PPA. Uterine atony is the most common aetiology for post-partum bleeding. Risk factors for uterine atony include prolonged second stage of labour, operative vaginal delivery, over-distention of the uterus (e.g. foetal macrosomia, multiple gestation, polyhydramnios), medications (e.g. nifedipine, magnesium sulphate, halogenated anaesthetic agents), abnormal placentation and retained conception
products. Traumatic lacerations of the uterus or vagina and con-
genital or acquired coagulation disorders, including anticoag-
ulant therapy, can also cause excessive blood loss at delivery
(Myers, Myers et al., 2012). Therefore, careful obstetric evalua-
tion and treatment prior to and during delivery is essential to
reduce the frequency of both expected and unexpected compli-
cations and bleeding (Milman, 2012).

Different approaches may be used to prevent PPH, depend-
ing on the setting and availability of skilled birth attendants and
resources, and international guidelines on PPH vary in their rec-
ommendations (Bohlmann & Rath, 2014). Active management
of the third stage of labour and post-partum care immediately
following placenta removal, regardless of third-stage manage-
ment (active vs expectant), reduces blood losses and transfu-
sion requirements. The usual components of active management
of the third stage of labour include: administration of oxytocin
(alternatively, ergometrine or misoprostol) within 1 min after
birth of the infant, cord clamping and controlled cord traction
and uterine massage after delivery of the placenta (Prendiville
et al., 2000; Lalonde and International Federation of Gynecology
and Obstetrics, 2012). Cell salvage is recommended for women
undergoing caesarean section in whom blood loss >500 mL is
anticipated, provided that health-care teams have the necessary
expertise and experience and the patient's informed consent is
obtained (RCOG, 2009). Recent publications suggest that adher-
ing to local guidelines significantly reduces the prevalence of
severe PPH (Bohlmann & Rath, 2014).

Even with major advances in the prevention of PPH, some
women will still require treatment for excessive bleeding. Timely
interventions and appropriate access or referral and transfer to
basic or comprehensive emergency obstetric care facilities for
treatment are essential to save the woman's life (Lalonde and
International Federation of Gynecology and Obstetrics, 2012).
Therefore, a protocol for PPH management should be in place
(RCOG, 2009; Rajan & Wing, 2010; Lalonde and International
Federation of Gynecology and Obstetrics, 2012; Pavord et al.,
2012). It is beyond the scope of this document to go into details
regarding the prevention and management of PPH, which will
be the topic of a separate consensus statement.

Recommendations

* **Recommendation 18:** We recommend that every effort be made to correct moderate to severe anaemia prior to delivery (1A).

* **Recommendation 19:** We recommend that women with anaemia or at high risk of haemorrhage be advised to deliver in a hospital setting (1C).

* **Recommendation 20:** We recommend active management of the third stage of labour to minimise blood losses (1A).

* **Recommendation 21:** We recommend cell salvage for women undergoing caesarean section in whom excessive blood losses are anticipated (1C).

* **Recommendation 22:** We recommend that a clear multidisciplinary, multimodal protocol for management of

major obstetric haemorrhage be in place. This protocol
should be activated as soon as major obstetric haemorrhage
is identified (1C).

Treatment: Oral iron

In women with mild to moderate anaemia who are haemo-
dynamically stable, asymptomatic or mildly symptomatic,
treatment should be initiated with oral ferrous iron (80–100 mg
elemental iron daily for at least 3 months) (WHO, 2016). The
interaction between food intake and absorption of iron supple-
ments should be taken into account and clearly explained to
the patient in order to increase the efficacy and reduce the side
effects of the treatment (Pavord et al., 2012).

In the three studies comparing oral iron with place-
bos, anaemia symptoms were not reported, and it remains
unknown whether benefits of oral iron outweigh documented
gastrointestinal harms (Markova et al., 2015). In addition,
implementation of oral iron therapy is inconsistent. In 2008, a
multicentre study across 11 maternity units in the UK (n = 2013)
found that 30% of women who had post-natal Hb levels checked
were anaemic, and depending on the centre, 16–86% of these
women received iron therapy (Barroso et al., 2011). These data
suggest that ensuring more effective iron replenishment during
the hospital stay could alleviate the burden of anaemia in the
post-partum period.

Recommendations

* **Recommendation 23:** Oral iron supplementation, either alone or in combination with folic acid, is recommended for 6–12 weeks following delivery to reduce the risk of anaemia in settings where gestational anaemia is a public health concern (1B).

* **Recommendation 24:** We recommend that 80–100 mg elemental iron daily for 3 months be administered to women with mild to moderate PPA (Hb 90–110 g L⁻¹) who are haemodynamically stable, asymptomatic or mildly symptomatic (1B).

Good practice points

* Whenever possible, Hb concentration in women receiving oral iron for PPA should be determined after approximately 2–4 weeks in order to evaluate the efficacy of the treatment.

* The interaction between food intake and absorption of ferrous and ferric iron supplements should be taken into account and clearly explained to the patient.

Treatment: Intravenous iron

Women with confirmed IDA and lack of response (Hb incre-
ment <10 or 20 g L⁻¹ in 2 or 4 weeks, respectively) or intoler-
ance to oral iron may benefit from IV iron. We identified 14
RCTs comparing oral and IV iron in a total of 2363 women with
PPA who were followed up for 2–12 weeks (Breymann et al.,
2000; Bhandal & Russell, 2006; Van Wyck et al., 2007; Breymann et al., 2008; Seid et al., 2008; Westad et al., 2008; Giannoulis et al., 2009; Daniilidis et al., 2011; Verma et al., 2011; Froessler et al., 2013; Jain et al., 2013; Perelló et al., 2014; (Holm et al., 2017); Rathod et al., 2015) (Table S4). Compared with oral iron (standard therapy), IV iron resulted in faster Hb increments during treatment, higher final Hb increments, higher rates of anaemia correction, higher ferritin increments and lower rates of drug-related adverse events. There were no significant differences in treatment compliance or transfusion rates, and no RCT showed superiority of oral iron over IV iron.

Regarding quality of life, in one RCT, the total fatigue score was significantly improved in the IV iron group at weeks 4, 8 and 12 compared with the oral iron group, whereas SF-36 scores did not differ (Van Wyck et al., 2007). In another study, a 1200-mg single-dose infusion of IV iron was associated with a statistically significant aggregated change of approximately 1 point on the 16-point Multidimensional Fatigue Inventory, suggesting less fatigue within 12 weeks after PPH (Holm et al., 2017). In contrast, an RCT found that patients assigned to IV iron or oral iron experienced similar increases in SF-36 scores and decreases in Fatigue Linear Analog Scale Assessment scores, and between-group differences were not significant at any study interval (Bhandal & Russell, 2006).

There were one RCT and one observational study comparing iron sucrose with ferric carboxymaltose in women with PPA (Pfenniger et al., 2012; Rathod et al., 2015). Mean post-partum Hb ranged between 77 and 82 g L⁻¹. The RCT showed that, compared with iron sucrose, ferric carboxymaltose administration produced greater and more rapid increases of Hb and serum ferritin as well as a higher rate of anaemia correction at the end of follow up (the same was true for both IV iron preparations compared with oral iron) (Rathod et al., 2015). In the observational study, no difference in efficacy was observed between iron sucrose and ferric carboxymaltose (Pfenniger et al., 2012). Overall, there were no differences in transfusion exposure or drug-related adverse events in these studies. As stated above, IV iron formulations allowing the administration of single high doses are more convenient both for the patient and for the health system.

No serious, life-threatening adverse events or increases in post-partum infection rates attributable to IV iron were reported in the studies reviewed above. IV iron was superior to oral iron regarding gastrointestinal harms; however, anaphylaxis occurred in three women and cardiac events occurred in two women (more data are needed to establish whether this was caused by IV iron) (Markova et al., 2015). This is in agreement with the European Medicines Agency's CHMP report concluding that the benefits of IV iron exceed its risks provided adequate measures are taken to minimise the risk of allergic reactions (EMA, 2013). All staff involved in IV iron administration should be aware of recommendations on the prevention and management of rare hypersensitivity reactions (Rampton et al., 2014).

Transient decreases in serum phosphate are frequent among patients receiving IV ferric carboxymaltose but also among those

receiving oral iron (Bhandal & Russell, 2006; Van Wyck et al., 2007; Breymann et al., 2008). Hypophosphataemia was asymptomatic and was not associated with reports of mortalities, adverse events or treatment discontinuation in this setting.

Breymann et al. did not observe a transfer of iron sucrose into maternal milk in women receiving a 100-mg dose during an observation period of 4 days (Breymann et al., 2007). However, mean iron values in breast milk increased transitorily after ferric carboxymaltose administration (mean dose, 1350 mg) (Breymann et al., 2008) or iron isomaltoside 1000 (1200 mg) (Holm et al., 2017) when compared to control, although no differences in breastfed infant outcomes were observed.

Currently available information suggests IV iron administration is beneficial, especially for patients with moderate to severe anaemia. However, a recent Cochrane review suggests that RCTs with clinical endpoints are needed (Markova et al., 2015). Women should be informed about the potential side effects of IV iron therapy, and written information should be provided.

## Recommendations

* **Recommendation 25:** We recommend that women with confirmed ID who fail to respond to the correct administration of oral iron (Hb increase <10 or 20 g L⁻¹ in 2 or 4 weeks, respectively) or are intolerant to oral iron be switched to IV iron (1B).

* **Recommendation 26:** We recommend the administration of IV iron to cover individually calculated total ID in women with moderate to severe PPA (Hb <90 g L⁻¹) (1B).

## Good practice points

* IV iron should not be given together with oral iron or in the presence of an active infection.

* Staff should be trained to detect, evaluate and manage hypersensitivity reactions in accordance with published guidelines.

## Treatment: Erythropoiesis-stimulating agents

Women with a higher post-partum inflammatory response (e.g. after caesarean section) may show a poor response to iron therapy, an inadequate erythropoietin secretion for the level of anaemia and/or blunted response to endogenous erythropoietin, as seen in anaemia of chronic diseases (Weiss & Goodnough, 2005). These women, as well as those severely anaemic refusing blood transfusion, may benefit from adjuvant therapy with an ESA, but the quality of the evidence is moderate to low.

There are two RCTs including a total 114 women with moderate to severe PPA who received oral iron sulphate (80–200 mg day⁻¹) or oral iron sulphate plus ESA (rHuEPO 40 000–180 000 IU) and were followed up for 6 weeks (Huch et al., 1992; Makrydimas et al., 1998). Compared with oral iron alone, rHuEPO plus oral iron resulted in faster Hb increments during treatment, higher Hb increments at 6 weeks, similar rates
of drug-related adverse events and no significant differences in transfusion rates, which were very low (Table S4).

There are five RCTs including a total of 272 women with moderate to severe PPA who received iron sucrose (300–1600 mg) or iron sucrose plus ESA (rHuEPO 20 000–40 000 IU) and were followed up for between 2 and 6 weeks (Lebrecht *et al.*, 1995; Breymann *et al.*, 1996; Breymann *et al.*, 2000; Wågström *et al.*, 2007; Krafft & Breymann, 2011). Most women also received oral iron (80–160 mg day⁻¹) after discharge. Compared to IV iron alone, rHuEPO plus IV iron resulted in a trend to faster Hb increment during treatment, similar Hb and ferritin increments at the end of the study period, similar rates of drug-related adverse events and no significant differences in transfusion rates, which were very low. The benefit seemed to be greatest in the blunted erythropoiesis subgroup with elevated C-reactive protein levels after caesarean section (Breymann *et al.*, 1996; Krafft & Breymann, 2011) (Table S3).

No serious, life-threatening adverse events attributable to ESA therapy were reported in the studies reviewed above. However, it must be remembered that in pregnant women without chronic kidney disease, administration of ESAs is off label. Women should be informed of potential side effects, and written information should be provided.

### Recommendation

* **Recommendation 27:** In severely anaemic patients with blunted erythropoiesis due to infection and/or inflammation and not responding adequately to IV iron treatment, as well as in severely anaemic patients who refuse blood transfusion, we suggest considering treatment with an ESA after consultation with the haematologist (2B).

### Treatment: Red blood cell transfusion

The 2009–2012 MBRRACCE-UK Perinatal Mortality Surveillance Report identified 17 direct mortalities due to obstetric haemorrhage (Knight *et al.*, 2014). Three of these women were anaemic antenatally. The report included a review of how care could have been improved and suggested actions including follow up of abnormal blood results and treatment of antenatal anaemia. The decision to prescribe RBC transfusion is mainly based on post-partum Hb concentration: RBC transfusion may be recommended when the Hb concentration is <60 g L⁻¹, whereas it is rarely appropriate in women with an Hb concentration >90 g L⁻¹.

In a series of 1954 Finnish women with moderate PPA (Hb 70–100 g L⁻¹), 13.3% received 1–2 RBC units (Palo *et al.*, 2007). RBC transfusions resulted in higher Hb levels on discharge but had no impact on length of hospital stay. Thus, in the absence of risk of bleeding, cardiac compromise or symptoms requiring immediate attention, transfusion is unlikely to be appropriate when the Hb is 70–90 g L⁻¹.

In a recent non-inferiority trial, 521 women with acute anaemia (estimated blood loss >1000 mL, Hb 48–79 g L⁻¹,

12–24 h post-partum) who did not have severe symptoms of anaemia or severe comorbidities were randomised to non-intervention (iron and folic acid supplementation; RBC transfusion permitted in case of severe symptoms of anaemia) or RBC transfusion (target Hb ≥89 g L⁻¹) (Prick *et al.*, 2014a, 2014b). Overall, 517 RBC units were transfused in the intervention arm vs 88 in the non-intervention arm. Adverse events and Hb concentration at 6 weeks were comparable. Although non-inferiority could not be demonstrated, there was only a small difference in physical fatigue at 3 and 7 days post-partum and no differences in secondary outcomes. Additionally, a cost-effectiveness analysis showed that RBC transfusion was, on average, €249 more expensive than non-intervention (Prick *et al.*, 2014a, 2014b).

Although the implementation of a restrictive approach seems clinically justified, RBC transfusions were needed in 33 (12.6%) women in the non-intervention group (Prick *et al.*, 2014a, 2014b). Using data from 262 randomised and 362 non-randomised women, the authors derived a model where clinical variables (primiparity, multiple pregnancy, total blood loss during delivery >1500 mL and Hb concentration 12–24 h post-partum) and HRQoL were independent predictors for the need of RBC transfusion (Prick *et al.*, 2015). This model may be an important tool for patient counselling and decision making in clinical practice.

In summary, RBC transfusion should be restricted to severely anaemic women who develop circulatory instability due to PPH, should be given in the minimal amount required to stabilise the patient and should be followed by pharmacological treatment of anaemia.

### Recommendations

* **Recommendation 28:** We recommend that all pregnant women should be ABO and D typed and screened for the presence of red cell antibodies early in pregnancy (at booking) and at 28 weeks gestation. In D-negative women, the 28-week sample should be taken before the administration of routine antenatal anti-D Ig prophylaxis (1B) (White *et al.*, 2016).

* **Recommendation 29:** We recommend that RBC transfusion not be dictated by Hb levels alone (1C).

* **Recommendation 30:** We recommend that transfusion be considered in non-bleeding patients with an Hb <60 g L⁻¹, taking clinical signs and symptoms (risk of bleeding, cardiac compromise or symptoms requiring immediate attention) into consideration (1A).

* **Recommendation 31:** In the absence of bleeding, should transfusion be deemed necessary, we recommend a single-unit transfusion followed by clinical reassessment and/or Hb measurement to determine the need for further transfusion (1C).

### Good practice points

* In post-partum women who refuse RBC transfusions and are not actively bleeding, there is the option of using a
plasma expander, IV iron and ESA for the treatment of anaemia.

* Women receiving RBC transfusion should be given full information regarding the indication(s) for transfusion and alternatives available. Consent should be given by the patient and documented in the clinical notes.

## ACKNOWLEDGMENTS

Financial support for this project was provided by Vifor (International) Inc. through an unrestricted educational grant to NATA. The sponsor had no influence on the development process or the content of the manuscript.

## DISCLAIMER

The authors are responsible for the views expressed in this article, which do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. They have aimed high and provided what they consider at the present to be ‘optimal’ guidelines. However, they also acknowledge that the evidence is not clear-cut for all circumstances. Feasibility, costs, values and preferences and balance of harms–benefits need to be considered in the adoption and adaptation of these recommendations. Budget, equipment and capacity also need consideration. Therefore, these recommendations have to be adapted to the specific situations, the resources and the strategies of the individual countries and regions.

## REFERENCES

Abhilashini, G.D., Sagili, H., Reddi, R. (2014) Intravenous iron sucrose and oral iron for the treatment of iron deficiency anaemia in pregnancy. *Journal of Clinical and Diagnostic Research, 8*, OC04–OC07.

ACOG (2008) American College of Obstetricians and Gynecologists practice Bulletin no. 95: anemia in pregnancy. *Obstetrics and Gynecology, 112*, 201–207.

Al, R.A., Unlubilgin, E., Kandemir, O., Yalvac, S., Cakir, L., Haberal, A. (2005) Intravenous versus oral iron for treatment of anemia in pregnancy: a randomized trial. *Obstetrics and Gynecology, 106*, 1335–1340.

Allard, S. (2015) Anaemia in pregnancy-a renewed focus needed. *BJOG, 122*, 169.

Allary, J., Soubirou, J.F., Michel, J. et al. (2013) An individual scoring system for the prediction of postpartum anaemia. *Annales Françaises d'Anesthésie et de Rèanimation, 32*, e1–e7.

Auerbach, M., Adamson, J., Bircher A. et al. (2015) On the safety of intravenous iron, evidence trumps conjecture. *Haematologica, 100*, e214–e215.

Barroso, F., Allard, S., Kahan, B.C., Connolly, C., Smethurst, H., Choo, L., Khan, K., Stanworth, S. (2011) Prevalence of maternal anaemia and its predictors: a multi-centre study. *European Journal of Obstetrics, Gynecology, and Reproductive Biology, 159*, 99–105.

Bayoumeu, F., Subiran-Buisset, C., Baka, N.E., Legagneur, H., Monnier-Barbarino, P., Laxenaire, M.C. (2002) Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. *American Journal of Obstetrics and Gynecology, 186*, 518–522.

Bergmann, R.L., Richter, R., Bergmann, K.E., Dudenhausen, J.W. (2010) Prevalence and risk factors for early postpartum anemia. *European Journal of Obstetrics, Gynecology, and Reproductive Biology, 150*, 126–131.

Bhandal, N. & Russell, R. (2006) Intravenous versus oral iron therapy for postpartum anaemia. *BJOG, 113*, 1248–1252.

Bohlmann, M.K. & Rath, W. (2014) Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines. *Archives of Gynecology and Obstetrics, 289*, 555–567.

Bothwell, T.H. (2000) Iron requirements in pregnancy and strategies to meet them. *The American Journal of Clinical Nutrition, 72*, 257S–264S.

Breymann, C., Major, A., Richter, C., Huch, R., Huch, A. (1995) Recombinant human erythropoietin and parenteral iron in the treatment of pregnancy anemia: a pilot study. *Journal of Perinatal Medicine, 23*, 89–98.

Breymann, C., Zimmermann, R., Huch, R., Huch, A. (1996) Use of recombinant human erythropoietin in combination with parenteral iron in the treatment of postpartum anaemia. *European Journal of Clinical Investigation, 26*, 123–130.

Breymann, C., Richter, C., Huch, R., Huch, A. (2000) Effectiveness of recombinant erythropoietin and iron sucrose vs. iron therapy only, in patients with postpartum anaemia and blunted erythropoiesis. *European Journal of Clinical Investigation, 30*, 154–161.

Breymann, C., Visca, E., Huch, R., Huch, A. (2001) Efficacy and safety of intravenously administered iron sucrose with and without adjuvant recombinant human erythropoietin for the treatment of resistant

iron-deficiency anemia during pregnancy. *American Journal of Obstetrics and Gynecology, 184*, 662–667.

Breymann, C., von, Seefried, B., Stahel, M., Geisser, P., Canclini, C. (2007) Milk iron content in breast-feeding mothers after administration of intravenous iron sucrose complex. *Journal of Perinatal Medicine, 35*, 115–118.

Breymann, C., Gliga, F., Bejenariu, C., Strizhova, N. (2008) Comparative efficacy and safety of intravenous ferric carboxymaltose in the treatment of postpartum iron deficiency anemia. *International Journal of Gynaecology and Obstetrics, 101*, 67–73.

Breymann, C., Bian, X.M., Blanco-Capito, L.R., Chong, C., Mahmud, G., Rehman, R. (2011) Expert recommendations for the diagnosis and treatment of iron-deficiency anemia during pregnancy and the postpartum period in the Asia-Pacific region. *Journal of Perinatal Medicine, 39*, 113–121.

Breymann, C., Milman, N., Mezzacasa, A., Bernard, R., Dudenhausen, J.; FER-ASAP investigators. (2017) Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: an international, open-label, randomized controlled trial (FER-ASAP). *Journal of Perinatal Medicine, 45*, 443–453.

van den, Broek, N.R., Letsky, E.A. et al. (1998) Iron status in pregnant women: which measurements are valid? *British Journal of Haematology, 103*, 817–824.

Carles, G., Tobal, N., Raynal, P., Herault, S., Beucher, G., Marret, H., Arbeille, P. (2003) Doppler assessment of the fetal cerebral hemodynamic response to moderate or severe maternal anemia. *American Journal of Obstetrics and Gynecology, 188*, 794–799.
Christoph, P., Schuller, C., Studer, H., Irion, O., de Tejada, B.M., Surbek, D. (2012) Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose. *Journal of Perinatal Medicine, 40*, 469-474.

Daniilidis, A., Giannoulis, C., Pantelis, A., Tantanasis, T., Dinas, K. (2011) Total infusion of low molecular weight iron-dextran for treating postpartum anemia. *Clinical and Experimental Obstetrics & Gynecology, 38*, 159-161.

De Leeuw, N.K., Lowenstein, L., Hsieh, Y.S. (1966) Iron deficiency and hydremia in normal pregnancy. *Medicine (Baltimore)*, **45**, 291-315.

Duarte, R., Núñez, M.J., Marsac, A., Molina, A., Martín, E., Pavía J, Muñoz, M. (2014) Postoperative anaemia after obstetric and gynaecologic surgery: an audit for implementation of a patient blood management program. *Transfusion Medicine, 24*, 39 (abstract).

EMA (2013) *New Recommendations to Manage Risk of Allergic Reactions with Intravenous Iron-Containing Medicines*. European Medicines Agency, London, UK.

Filippi, V., Chou, D., Ronsmans, C., Graham, W., Say, L. (2016) Levels and causes of maternal mortality and morbidity. In: *Reproducive, Maternal, Newborn and Child Health: Disease Control Priorities* (3rd edn) (eds Black, R.E., Laxminarayan, L., Walker, N. & Temmerman, M.), 2. World Bank, Washington, DC.

Froessler, B., Cocchiaro, C., Saadat-Gilani, K., Hodyl, N., Dekker, G. (2013) Intravenous iron sucrose versus oral iron ferrous sulfate for antenatal and postpartum iron deficiency anemia: a randomized trial. *The Journal of Maternal-Fetal & Neonatal Medicine, 26*, 654-659.

Giannoulis, C., Daniilidis, A., Tantanasis, T., Dinas, K., Tzafettas, J. (2009) Intravenous administration of iron sucrose for treating anemia in postpartum women. *Hippokratia, 13*, 38-40.

Gombotz, H. (2012) Patient blood management: a patient-orientated approach to blood replacement with the goal of reducing anemia, blood loss and the need for blood transfusion in elective surgery. *Transfusion Medicine and Hemotherapy, 39*, 67-72.

Gombotz, H., Rehak, P.H., Shander, A., Hofmann, A. (2014) The second Austrian benchmark study for blood use in elective surgery: results and practice change. *Transfusion, 54*, 2646-2657.

Goodnough, L.T. & Shander, A. (2012) Patient blood management. *Anesthesiology, 116*, 1367-1376.

Gupta, P.K., Sundaram, A., Mactaggart, J.N. et al. (2013) Preoperative anemia is an independent predictor of postoperative mortality and adverse cardiac events in elderly patients undergoing elective vascular operations. *Annals of Surgery, 258*, 1096-1102.

Gupta, A., Manaktala, U., Rathore, A.M. (2014) A randomised controlled trial to compare intravenous iron sucrose and oral iron in treatment of iron deficiency anemia in pregnancy. *Indian Journal of Hematology and Blood Transfusion, 30*, 120-125.

Guyatt, G.H., Cook, D.J., Jaeschke, R., Pauker, S.G., Schünemann, H.J. (2008) Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). *Chest, 133*, 123S-131S.

Haider, B.A., Olofin, I., Wang, M., Spiegelman, D., Ezzati, M., Fawzi, W.W.; Nutrition Impact Model Study Group (Anaemia). (2013) Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. *British Medical Journal, 346*, f3443.

Hallberg, L., Bengtsson, C., Lapidus, L., Lindstedt, G., Lundberg, P.A., Hultén, L. (1993) Screening for iron deficiency: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. *British Journal of Haematology, 85*, 787-798.

Hofmann, A., Friedman, D. & Farmer, S.L. (2007) *Western Australian Patient Blood Management Project 2008–2012: Analysis, Strategy, Implementation and Financial Projections*. Western Australia Department of Health, Perth, WA, Australia.

Holm, C., Thomsen, L.L., Norgaard, A., Langhoff-Roos, J. (2017) Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial. *Vox Sanguinis, 112*, 219-228.

Huch, A., Eichhorn, K.H., Danko, J., Lauener, P.A., Huch, R. (1992) Recombinant human erythropoietin in the treatment of postpartum anemia. *Obstetrics and Gynecology, 80*, 127-131.

INACG (1977) *Guidelines for the use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia. A Report of the International Nutritional Anaemia Consultative Group*. The Nutrition Foundation, Washington, DC.

Isbister, J.P. (2013) The three-pillar matrix of patient blood management – an overview. *Best Practice & Research. Clinical Anaesthesiology, 27*, 69-84.

Jain, G., Palaria, U., Jha, S.K. (2013) Intravenous iron in postpartum anemia. *Journal of Obstetrics and Gynaecology of India, 63*, 45-48.

Kassebaum, N.J., Jasrasaria, R., Naghavi, M. et al. (2014) A systematic analysis of global anemia burden from 1990 to 2010. *Blood, 123*, 615-624.

Khalafallah, A.A., Dennis, A.E., Bates, J. et al. (2010) A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. *Journal of Internal Medicine, 268*, 286-295.

Khalafallah, A.A., Dennis, A.E., Ogden, K. et al. (2012) Three-year follow-up of a randomized clinical trial of intravenous versus oral iron for anaemia in pregnancy. *BMJ Open, 2*, e000998.

Knight, M., Kenyon, S., Brocklehurst, P., Neilson, J., Shakespeare, J., Kurinczuk, J.J. (eds). (2014) *Saving Lives, Improving Mothers' Care - Lessons Learned to Inform Future Maternity Care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-12*. National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.

Kochhar, P.K., Kaundal, A., Ghosh, P. (2013) Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial. *The Journal of Obstetrics and Gynaecology Research, 39*, 504-510.

Koshy, M., Burd, L., Wallace, D., Moawad, A., Baron, J. (1988) Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study. *The New England Journal of Medicine, 319*, 1447-1452.

Krafft, A. & Breymann, C. (2011) Iron sucrose with and without recombinant erythropoietin for the treatment of severe postpartum anemia: a prospective, randomized, open-label study. *The Journal of Obstetrics and Gynaecology Research, 37*, 119-124.

Krafft, A., Huch, R. & Breymann, C. (2003) Impact of parturition on iron status in nonanaemic iron deficiency. *European Journal of Clinical Investigation, 33*, 919-923.

Krafft, A., Bencaiova, G. & Breymann, C. (2009) Selective use of recombinant human erythropoietin in pregnant patients with severe anemia or nonresponsive to iron sucrose alone. *Fetal Diagnosis and Therapy, 25*, 239-245.
Lalonde, A. & International Federation of Gynecology and Obstetrics (2012) Prevention and treatment of postpartum hemorrhage in low-resource settings. *International Journal of Gynaecology and Obstetrics*, **117**, 108–118.

Lebrecht, A., Häberlin, F. & Eberhard, J. (1995) Anemia in puerperium; parenteral iron substitution renders erythropoietin therapy dispensable. *Geburtshilfe und Frauenheilkunde*, **55**, 167–170.

Lumbiganon, P., Laopaiboon, M., Intarut, N., Vogel, J.P., Souza, J.P., Gülmezoglu, A.M., Mori, R.; WHO Multicountry Survey on Maternal and Newborn Health Research Network. (2014) Indirect causes of severe adverse maternal outcomes: a secondary analysis of the WHO Multicountry Survey on maternal and newborn health. *BJOG*, **121** (Suppl 1), 32–39.

Makrydimas, G., Lolis, D., Lialios, G., Tsiara, S., Georgiou, I., Bourantas, K.L. (1998) Recombinant human erythropoietin treatment of postpartum anemia. Preliminary results. *European Journal of Obstetrics, Gynecology, and Reproductive Biology*, **81**, 27–31.

Markova, V., Norgaard, A., Jørgensen, K.J., Langhoff-Roos, J. (2015) Treatment for women with postpartum iron deficiency anaemia. *Cochrane Database of Systematic Reviews*, **8**, CD010861.

Meier, J., Filipescu, D., Kozek-Langenecker, S., Llau-Pitarch, J., Mallett, S., Martus, P., Matot, I.; ETPOS collaborators. (2016) Intraoperative transfusion practices in Europe. *British Journal of Anaesthesia*, **116**, 255–261.

Milman, N. (2006) Iron prophylaxis in pregnancy—general or individual and in which dose? *Annals of Hematology*, **85**, 821–828.

Milman, N. (2008) Prepartum anaemia: prevention and treatment. *Annals of Hematology*, **87**, 949–959.

Milman, N. (2011) Postpartum anemia I: definition, prevalence, causes, and consequences. *Annals of Hematology*, **90**, 1247–1253.

Milman, N. (2012) Postpartum anemia II: prevention and treatment. *Annals of Hematology*, **91**, 143–154.

Milman, N., Agger, A.O., Nielsen, O.J. (1991) Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in 207 Danish women. *Danish Medical Bulletin*, **38**, 471–476.

Milman, N., Byg, K.E., Agger AO. (2000) Hemoglobin and erythrocyte indices during normal pregnancy and postpartum in 206 women with and without iron supplementation. *Acta Obstetricia et Gynecologica Scandinavica*, **79**, 98–98.

Milman, N., Bergholt, T., Eriksen, L., Byg, K.E., Graudal, N., Pedersen, P., Hertz, J. (2005) Iron prophylaxis during pregnancy – how much iron is needed? A randomized dose-response study of 20-80 mg ferrous iron daily in pregnant women. *Acta Obstetricia et Gynecologica Scandinavica*, **84**, 238–247.

Milman, N., Bergholt, T., Byg, K.E., Eriksen, L., Hvas, A.M. (2007) Reference intervals for haematological variables during normal pregnancy and postpartum in 434 healthy Danish women. *European Journal of Haematology*, **79**, 39–46.

al-Momen, A.K., al-Meshari, A., al-Nuaim, L., Saddique, A., Abotalib, Z., Khashogji, T., Abbas, M. (1996) Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. *European Journal of Obstetrics, Gynecology, and Reproductive Biology*, **69**, 121–124.

Moretti, D., Goede, J.S., Zeder, C. et al. (2015) Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. *Blood*, **126**, 1981–1989.

Muñoz, M., García-Erce, J.A. & Remacha, A.F. (2011) Disorders of iron metabolism. Part II: iron deficiency and iron overload. *Journal of Clinical Pathology*, **64**, 287–296.

Muñoz, M., Gómez-Ramírez, S., Kozek-Langeneker, S. et al. (2015) 'Fit to fly': overcoming barriers to preoperative haemoglobin optimization in surgical patients. *British Journal of Anaesthesia*, **115**, 15–24.

Murray-Kolb, L.E. & Beard, J.L. (2009) Iron deficiency and child and maternal health. *The American Journal of Clinical Nutrition*, **89**, 946S–950S.

Myers, B., Myers, O. & Moore, J. (2012) Comparative efficacy and safety of intravenous ferric carboxymaltose (Ferinject) and iron(III) hydroxide dextran (Cosmofer) in pregnancy. *Obstetric Medicine*, **5**, 105–107.

Neeru, S., Nair, N.S., Rai, L. (2012) Iron sucrose versus oral iron therapy in pregnancy anemia. *Indian Journal of Community Medicine*, **37**, 214–218.

New, S. & Wirth, M. (2015) Anaemia, pregnancy, and maternal mortality: the problem with globally standardised haemoglobin cutoffs. *BJOG*, **122**, 166–169.

NICE (2008) *Antenatal Care for Uncomplicated Pregnancies*. NICE Guidelines [CG62]. National Institute for Health and Care Excellence, London, UK.

Palo, R., Ahonen, J., Salo, H., Salmenperä, M., Krusius, T., Mäki, T. (2007) Transfusion of red blood cells: no impact on length of hospital stay in moderately anaemic parturients. *Acta Anaesthesiologica Scandinavica*, **51**, 565–569.

Parker, J.A., Barroso, F., Stanworth, S.J., Spiby, H., Hopewell, S., Doree, C.J., Renfrew, M.J., Allard, S. (2012) Gaps in the evidence for prevention and treatment of maternal anaemia: a review of systematic reviews. *BMC Pregnancy and Childbirth*, **12**, 56.

Patel, A., Goudar, S.S., Geller, S.E. et al. (2006) Drape estimation vs. visual assessment for estimating postpartum hemorrhage. *International Journal of Gynaecology and Obstetrics*, **93**, 220–224.

Pavord, S., Myers, B., Robinson, S., Allard, S., Strong, J., Oppenheimer, C.; British Committee for Standards in Haematology. (2012) UK guidelines on the management of iron deficiency in pregnancy. *British Journal of Haematology*, **156**, 588–600.

Peña-Rosas, J.P., De-Regil, L.M., Garcia-Casal, M.N., Dowswell, T. (2015a) Daily oral iron supplementation during pregnancy. *Cochrane Database of Systematic Reviews*, **7**, CD004736.

Peña-Rosas, J.P., De-Regil, L.M., Gomez Malave, H., Flores-Urrutia, M.C., Dowswell, T. (2015b) Intermittent oral iron supplementation during pregnancy. *Cochrane Database of Systematic Reviews*, **10**, CD009997.

Perelló, M.F., Coloma, J.L., Masoller, N., Esteve, J., Palacio, M. (2014) Intravenous ferrous sucrose versus placebo in addition to oral iron therapy for the treatment of severe postpartum anaemia: a randomised controlled trial. *BJOG*, **121**, 706–713.

Perez, E.M., Hendricks, M.K., Beard, J.L. et al. (2005) Mother-infant interactions and infant development are altered by maternal iron deficiency anemia. *The Journal of Nutrition*, **135**, 850–855.

Pfenniger, A., Schuller, C., Christoph, P., Surbek, D. (2012) Safety and efficacy of high-dose intravenous iron carboxymaltose vs. iron sucrose for treatment of postpartum anemia. *Journal of Perinatal Medicine*, **40**, 397–402.

Prediville, W.J., Elbourne, D., McDonald, S. (2000) Active versus expectant management in the third stage of labour. *Cochrane Database of Systematic Reviews*, **3**, CD000007.
Prick, B.W., Duvekot, J.J., van der Moer, P.E. et al. (2014a) Cost-effectiveness of red blood cell transfusion vs. non-intervention in women with acute anaemia after postpartum haemorrhage. *Vox Sanguinis*, **107**, 381–388.

Prick, B., Jansen, A., Steegers, E.A. et al. (2014b) Transfusion policy after severe postpartum haemorrhage: a randomised non-inferiority trial. *BJOG*, **121**, 1005–1014.

Prick, B.W., Schuit, E., Mignini, L., Jansen, A.J., van Rhenen, D.J., Steegers, E.A., Mol, B.W., Duvekot, J.J.; EBM Connect Collaboration. (2015) Prediction of escape red blood cell transfusion in expectantly managed women with acute anaemia after postpartum haemorrhage. *BJOG*, **122**, 1789–1797.

Rajan, P.V. & Wing, D.A. (2010) Postpartum hemorrhage: evidence-based medical interventions for prevention and treatment. *Clinical Obstetrics and Gynecology*, **53**, 165–181.

Rampton, D., Folkersen, J., Fishbane, S. et al. (2014) Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. *Haematologica*, **99**, 1671–1676.

Ranucci, M., Di Dedda, U., Castelvecchio, S., Menicanti, L., Frigiola, A., Pelissero, G.; Surgical and Clinical Outcome Research (SCORE) Group. (2012) Impact of preoperative anaemia on outcome in adult cardiac surgery: a propensity-matched analysis. *The Annals of Thoracic Surgery*, **94**, 1134–1141.

Rathod, S., Samal, S.K., Mahapatra, P.C., Samal, S. (2015) Ferric carboxymaltose: a revolution in the treatment of postpartum anemia in Indian women. *International Journal of Applied and Basic Medical Research*, **5**, 25–30.

RBMP (2015) *Consensus Statement on Folic Acid Supplementation during Pregnancy*. *Malaria in Pregnancy Working Group*. Roll Back Malaria Partnership, Geneva, Switzerland.

RCOG (2009) *Postpartum Haemorrhage, Prevention and Management (Green-top Guideline No. 52)*. Royal College of Obstetricians and Gynaecologists, London, UK.

Sanghavi, M. & Rutherford, J.D. (2014) Cardiovascular physiology of pregnancy. *Circulation*, **130**, 1003–1008.

Seid, M.H., Derman, R.J., Baker, J.B., Banach, W., Goldberg, C., Rogers, R. (2008) Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anaemia: a randomised controlled clinical trial. *American Journal of Obstetrics and Gynecology*, **199**, e431–e437.

Shafi, D., Purandare, S.V., Sathe, A.V. (2012) Iron deficiency anaemia in pregnancy: intravenous versus oral route. *Journal of Obstetrics and Gynaecology of India*, **62**, 317–321.

Shander, A., Isbister, J., Gombotz, H. (2016) Patient blood management: the global view. *Transfusion*, **56** (Suppl 1), S94–102.

Sifakis, S. & Pharmakides, G. (2000) Anemia in pregnancy. *Annals of the New York Academy of Sciences*, **900**, 125–136.

Singh, S. & Singh, P.K. (2013) A study to compare the efficacy and safety of intravenous iron sucrose and intramuscular iron sorbitol therapy for anemia during pregnancy. *Journal of Obstetrics and Gynaecology of India*, **63**, 18–21.

Singh, K., Fong, Y.F., Kuperan, P. et al. (1998) A comparison between intravenous iron polymaltose complex (Ferrum Hausmann) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy. *European Journal of Haematology*, **60**, 119–124.

Siu, A.L. (2015) Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: U.S. Preventive Services task force recommendation statement. *Annals of Internal Medicine*, **163**, 529–536.

Stevens, G.A., Finucane, M.M., De-Regil, L.M., et al.; Nutrition Impact Model Study Group (Anaemia). (2013) Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. *The Lancet Global Health*, **1**, e16–e25.

Van der Linden, P. & Hardy, J.F. (2016) Implementation of patient blood management remains extremely variable in Europe and Canada: the NATA benchmark project. *European Journal of Anaesthesiology*, **33**, 913–921.

Van Wyck, D.B., Martens, M.G., Seid, M.H., Baker, J.B., Mangione, A. (2007) Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anaemia: a randomized controlled trial. *Obstetrics and Gynecology*, **110**, 267–278.

Verma, S., Inamdar, S.A., Malhotra, N. (2011) Intravenous iron therapy versus oral iron in postpartum patients in rural area. *Journal of South Asian Federation of Obstetrics and Gynaecology*, **3**, 67–70.

Vogel, J.P., Souza, J.P., Mori, R. et al. (2014) Maternal complications and perinatal mortality: findings of the World Health Organization Multicountry Survey on maternal

and newborn health. *BJOG*, **121** (Suppl 1), 76–88.

Wågström, E., Akesson, A., Van Rooijen, M., Larson, B., Bremme, K. (2007) Erythropoietin and intravenous iron therapy in postpartum anaemia. *Acta Obstetricia et Gynecologica Scandinavica*, **86**, 957–962.

Wali, A., Mushtaq, A., Nilofer. (2002) Comparative study--efficacy, safety and compliance of intravenous iron sucrose and intramuscular iron sorbitol in iron deficiency anemia of pregnancy. *The Journal of the Pakistan Medical Association*, **52**, 392–395.

Weiss, G. & Goodnough, L.T. (2005) Anemia of chronic disease. *The New England Journal of Medicine*, **352**, 1011–1023.

Westad, S., Backe, B., Salvesen, K.A. et al. (2008) A 12-week randomised study comparing intravenous iron sucrose versus oral ferrous sulphate for treatment of postpartum anemia. *Acta Obstetricia et Gynecologica Scandinavica*, **87**, 916–923.

White, J., Qureshi, H., Massey, E., Needs, M., Byrne, G., Daniels, G., Allard, S.; British Committee for Standards in Haematology. (2016) Guideline for blood grouping and red cell antibody testing in pregnancy. *Transfusion Medicine*, **26**, 246–263.

WHO (2001a) *The Clinical use of Blood in Obstetrics, Paediatrics, Surgery and Anaesthesia, Trauma and Burns*. World Health Organization, Geneva, Switzerland.

WHO (2001b) *Developing a National Policy and Guidelines on the Clinical use of Blood. Recommendations*. World Health Organization, Geneva, Switzerland.

WHO (2001c) *Iron Deficiency Anaemia Assessment, Prevention, and Control: A Guide for Programme Managers*. World Health Organization, Geneva, Switzerland.

WHO (2011) *Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System*. World Health Organization, Geneva, Switzerland.

WHO (2012) *Guideline: Daily Iron and Folic Acid Supplementation in Pregnant Women*. World Health Organization, Geneva, Switzerland.

WHO (2016) *Guideline: Iron Supplementation in Postpartum Women*. World Health Organization, Geneva, Switzerland.

Wu, W.C., Schiffner, T.L., Henderson, W.G. et al. (2007) Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. *JAMA*, **297**, 2481–2488.
**Supporting Information**

Additional Supporting Information may be found in the online version of this article:

**Figure S1.** The three pillars of patient blood management.

**Figure S2.** The relationship between anaemia, transfusion and adverse events.

**Figure S3.** The grading system used to evaluate the quality of the evidence and grade recommendations.

**Table S1.** Complications/adverse effects of anaemia during pregnancy.

**Table S2.** Some characteristics of the different intravenous iron formulations.

**Table S3.** Clinical studies of intravenous iron and/or erythropoiesis-stimulating agents for the treatment of iron-deficiency anaemia in pregnancy.

**Table S4.** Clinical studies of intravenous iron and/or erythropoiesis-stimulating agents for the treatment of iron-deficiency anaemia in the postpartum period.

**Annex S1.** Diagnosis of vitamin B₁₂ and folic acid deficiency.