Intravenous iron use in pregnancy: Ironing out the issues and evidence

Over the past few years there has been a marked change in the screening and management of iron deficiency in pregnancy. This has been fuelled by the increasing use of ferritin for the screening of iron deficiency in the mother and the availability and marketing of newer parenteral preparations to treat such deficiency. Real questions exist around this significant practice change. Iron is essential during pregnancy to support expansion of the red blood cell mass, growth of maternal tissues, and for fetal and placental development. It is present in all human cells and has several vital functions, including carrying oxygen from the lungs to the tissues in the form of haemoglobin. Iron present in the body beyond what is immediately required for functional purposes is stored primarily as ferritin, with smaller amounts stored as haemosiderin. Iron is transported in blood by the protein transferrin. Pregnant women are particularly vulnerable to iron deficiency due to the high demand for iron associated with growth in both the maternal and fetoplacental compartments. Iron deficiency represents a spectrum ranging from iron depletion to iron deficiency anaemia (IDA).1, 2 In iron depletion, the amount of stored iron (as measured by serum ferritin concentration) is diminished but the amount of transport and functional iron may not be affected. Women who have iron depletion have no iron stores to mobilise should the body require additional iron. In iron-deficient erythropoiesis, stored iron and transport iron (as measured by transferrin saturation) are depleted, with the amount of iron absorbed insufficient to replace that which is lost or required for growth and function. Erythrocyte production is limited by the iron shortage resulting in increased erythrocyte protoporphyrin concentration. In IDA, the most severe form of iron deficiency, inadequate amounts of stored, transport and functional iron result in impaired haemoglobin synthesis. Anaemia is generally defined as a haemoglobin concentration less than two standard deviations below the mean for a specific population.2, 3 However, defining IDA in pregnant women is imprecise because of pregnancy-associated changes in plasma volume and red cell mass, normal differences in haemoglobin concentrations, and ethnic variation.4 Consequently, the definition of anaemia in pregnancy is variable, with there being no agreed normal range for haemoglobin concentration in pregnancy in Australia.3 The World Health Organization (WHO) defines anaemia in pregnancy as a haemoglobin concentration <110 g/L at any stage of pregnancy,5 whereas UK guidelines define anaemia as <110 g/L in the first trimester and <105 g/L in the second and third trimesters.1 The US Centers for Disease Control and Prevention (CDC) use cut-offs of <110 g/L for the first and third trimesters, and <105 g/L for the second trimester to diagnose anaemia.2 The longstanding use of haemoglobin to determine a threshold at which to offer iron replacement is being replaced in some settings by the measurement of serum ferritin. There is no universal cut-off for ferritin on which to define iron deficiency in pregnancy. Presently, WHO defines iron deficiency as a serum ferritin concentration <15 μg/L.5 This threshold has not been adopted in the UK1 and Australia6 where a ferritin concentration <30 μg/L is considered abnormal in pregnant women. For the clinician, an additional confusion in diagnosing iron deficiency is that laboratories may use different reference ranges depending on the method of ferritin analysis and the population in which the assay was validated.7 Furthermore, ferritin is an acute phase reactant and it can be elevated in inflammatory states such as infection, liver disease and malignancy. Despite inconsistency in the definition of IDA, recommendations for current practice in Australia and New Zealand (and the UK) are to assess a woman's haemoglobin level at the first antenatal visit and at 28 weeks gestation, and ensure that any anaemia is investigated and treated.1, 8 Routine iron supplementation is not recommended for all pregnant women.1, 3, 8 In contrast, authorities such as the CDC,2 WHO5 and Society of Obstetricians and Gynaecologists of Canada9 recommend universal iron supplementation in pregnant women. Oral iron is recommended as first line therapy for women with IDA. Intravenous (IV) iron is recommended when oral iron is poorly tolerated, absorption is likely to be impaired, the response to oral iron is inadequate, or when rapid restoration of haemoglobin and iron stores is required.1, 3, 8, 10 In this issue of ANZJOG, Qassim and colleagues examine the use, safety and efficacy of IV iron polymaltose (IPM; Ferrosig®, Ferrum H®) in the management of iron deficiency in pregnancy.11 The findings of the current study, together with those of their ANZJOG 2017 systematic review of the safety and efficacy of three commonly used IV iron preparations in pregnancy,12 are timely and important. Data from the Australian Government Department of Health show that the number of women of reproductive age receiving IV iron more than doubled in Australia between 2014 and 2017 (M. Keaney, personal correspondence). Although the data do not provide the indication for usage, the relative increase in prescriptions for IV iron was particularly high among obstetricians and gynaecologists, suggesting that a large proportion of this increase is likely in the pregnant population. Notably, the increase in IV iron use has been entirely the result of increased ferric carboxymaltose (FCM; Ferinject®) administration following its listing on the Australian Pharmaceutical Benefits Scheme (PBS) in June 2014.13 Interestingly, FCM was approved for funded access by the Pharmaceutical Management Agency (PHARMAC) in New Zealand in October 2017. If the Australian experience is replicated, considerably more women in New Zealand may receive IV FCM during pregnancy. Moreover, as shown in the study by Qassim et al.11 in this issue of ANZJOG, many women are likely to be prescribed IV FCM for iron deficiency without anaemia: an indication outside the PBS/PHARMAC criteria for use. Some may question why ANZJOG is publishing the study by Qassim and colleagues when the 2017 systematic review12 in this journal evaluated similar outcomes. The key reasons are that the current study further highlights the lack of evidence for improvement in important maternal and perinatal outcomes with IV iron use and the high incidence of related adverse drug reactions (ADRs). Of the 213 women receiving IPM, one-quarter suffered an ADR; a 10-fold higher prevalence than that found in the systematic review. The large majority of ADRs were systemic and moderate to severe, and required cessation of the iron infusion or treatment. Significantly, one woman experienced an anaphylactic reaction. The complete ascertainment of the medical records and close monitoring of the women receiving IPM ensure that these data are reliable. One stillbirth was reported three months after iron therapy. Critical appraisal of studies addressing the management of IDA in pregnancy leads to the conclusion that the enthusiasm and uptake of IV iron is driven by marketing and convenience rather than evidence of clinical benefit. With low-value health care an area of increasing scrutiny, this is a practice that our discipline should examine. Systematic reviews of daily oral iron supplementation during pregnancy14 and therapies for IDA during pregnancy15 in mainly low-resource settings found no effect on clinically relevant outcomes, including low birthweight, preterm birth, infection, postpartum haemorrhage and blood transfusion. Indeed, there is no high-grade evidence that maternal IDA, particularly in developed countries, is associated with negative health outcomes for either women or their infants.4, 16 Large cohort studies demonstrate a U-shaped association between haemoglobin levels and adverse perinatal outcomes.17, 18 Many studies come from low-resource settings where low haemoglobin is caused not only by iron deficiency but other factors that may have a bearing on pregnancy outcomes. Perinatal death, low birthweight and preterm birth are increased with a high haemoglobin level. Data from the non-obstetric population show that high haemoglobin levels may be harmful.19 Moreover, rapid haemoglobin increase from the use of erythropoiesis-stimulating agents is also associated with increased mortality risk.20 The rapid increase in iron stores and haemoglobin with IV iron may carry risks. What then of the other IV iron preparations? The 2017 systematic review12 that included 21 randomised controlled trials and 26 observational studies actually found that IPM had the lowest median prevalence of ADRs (2.2%; range 0–4.5%) compared with FCM (5.0%; range 0–20%) and iron sucrose (IS: 6.7%; range 0–19.5%), although moderate and severe ADRs were less common with these latter iron formulations. All IV iron preparations are associated with anaphylaxis/anaphylactoid reactions and while the risk is small, it is not negligible.21 In a large cohort of Medicare patients in the USA, the cumulative anaphylaxis risk following total iron repletion of 1000 mg with IS was 21 per 100 000 persons.21 The risk with FCM (Ferinject®) has been reported to be ~0.1%,22 with several deaths (in the non-obstetric population) attributed to FCM use.23 In addition to hypersensitivity reactions/anaphylaxis, other risks associated with IV iron include the potential for inducing iron overload, oxidative stress, infection, and severe hypophosphataemia, among others.24, 25 The two papers by Qassim and colleagues clearly demonstrate that IV iron supplementation is effective in improving maternal haematological parameters (ferritin, haemoglobin) and in reducing the incidence of iron deficiency and IDA during pregnancy and at delivery. IV iron use improved maternal haemoglobin concentrations by 21.8 g/L and 30.1 g/L at 3–4 weeks post-infusion and at delivery, respectively.12 Compared with oral iron alone, IV iron was associated with an additional increase in haemoglobin of 6 g/L at four weeks following treatment and 6.8 g/L at delivery. However, the benefit of IV iron over oral iron is modest, as oral iron itself has been shown to increase haemoglobin by 13.4 g/L compared with placebo.14 Notably, the improvement in maternal haematological measures with IV iron use was not shown to translate into better clinical outcomes, confirming the findings of a 2011 Cochrane review.15 It is important to note that many of the studies were from low-resource settings, lacked adequate sample size to detect important differences, and were frequently methodically poor. Very few studies examined clinically relevant maternal and perinatal outcomes. The increase in haemoglobin with IV iron is also likely to be less in developed countries where iron deficiency and anaemia are generally much milder. The lack of demonstrated improvement in important clinical end points with IV iron use during pregnancy, together with the potential to cause harm, should discourage the widespread dissemination of this practice. Reversal of medical practice once established, even when new evidence becomes available, is often difficult.26 Measurement of haemoglobin should remain the practice for screening for IDA with assessment of ferritin concentration reserved for those women who are anaemic. Oral iron should remain the first line treatment of IDA. IV iron should only be used in appropriately selected cases of severe IDA, and not for iron deficiency in the absence of IDA. The use of ferritin to screen for women at risk of adverse pregnancy outcomes and the use of IV iron as a superior form of iron replacement should be reserved for high-quality research studies that evaluate meaningful clinical outcomes for the mother and baby. The authors would like to acknowledge Dr Megan Keaney who provided data on intravenous iron use in Australia.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.