This survey is the best available representation of current practice towards treatment of ID in pregnancy by specialist obstetricians in Australia and New Zealand. Given that over three quarters of obstetricians surveyed work in public hospitals, these findings may be extrapolated to public hospitals. There are high rates of intravenous iron use by obstetricians in Australia and New Zealand for ID and IDAP, predominantly in hospital settings and most commonly in later gestation. While around half of obstetricians prescribe < 20 infusions per annum, almost a quarter prescribe 30 or more infusions a year. Interestingly, 8% of clinicians stated they prescribed intravenous iron in the first trimester for either IDAP and/or ID without anaemia, despite this being contraindicated [18].
The key point highlighted by our findings is that the prescribing of FRANZCOGs for the treatment of ID in pregnancy is not consistent with Australian antenatal care guidelines or patient blood management guidelines [1, 10, 11] There is an appropriate differentiation between IDAP and ID without anaemia in pregnancy, acknowledging the evidence of increased risk of adverse maternal and fetal outcomes with maternal anaemia [4, 5, 7]. Nonetheless, intravenous iron is commonly prescribed for women with ID without anaemia, a shift in practice that has been well recognised recently. This survey highlights that some instances of use in this cohort are established indications, for example women identifying as Jehovah’s witness or of high bleeding risk [10], however convenience (5%), poor tolerance of oral iron and severity of maternal symptoms as indications for use represent a clear departure between recommendations and practice [11]. This may be interpreted as failure to capture this shift in clinicians views’ or alternately that this reiterates the lack of quality clinical outcomes data, resulting in heterogenous practice. Irrespective, increasingly liberal use of intravenous iron may overlook the potential risk of serious, albeit uncommon side effects such as anaphylaxis and permanent skin tattooing [14], particularly in settings with less rigorous benefit data. Additionally, it must be noted that the fetal safety of intravenous iron remains unclear. It has been postulated that delivering large iron loads over a short time period in intravenous infusions, may increase the risk of iron free radicals inducing oxidative damage to vulnerable placental tissues [19, 20].
Intravenous iron unequivocally improves haematological parameters, with a recent meta-analysis finding a mean difference in maternal haemoglobin of 0.85 g/L and ferritin of 63.3μg/L [14]. However, clinical outcome data such as quality of life (QOL), breast feeding rates, preterm birth and postnatal depression was not well reported in the studies included in this meta-analysis, many of which were undertaken in low and middle income countries. The 2011 Cochrane review identified the need for assessment of clinical outcomes and effects of treatments of IDAP in large, quality randomised trials [8]. Secondary endpoints of a recent Australian RCT for IDAP comparing intravenous FCM, intravenous polymaltose (IPM) and oral iron sulphate (IS) found that higher overall serum ferritin was associated with an improvement in QOL [21]. Findings of this study are difficult to interpret given the association between QOL improvement and intravenous iron was indirect; QOL was improved with higher overall serum ferritin, which was achieved in groups of women receiving intravenous iron. Similarly, an international multi-centre RCT comparing first-line FCM and oral IS demonstrated that improved pre-delivery vitality scores and social functioning were significantly associated with FCM [22]. Both studies are biased by their open-label nature, a major limitation given QOL measures are self-reported. Additionally, the latter study was sponsored by a pharmaceutical company. Without substantial evidence of clinical superiority of intravenous iron, its use in first-line treatment of IDAP and ID highlights the importance of addressing non-evidence based treatment trends before they become common practice [9].
FCM was the most commonly used intravenous preparation, consistent with its favourable safety profile with moderate or severe ADRs occurring in the realm of 3.6/1000 for FCM versus 14.0/1000 for IPM and 7.9/1000 for IS [16]. FCM also has a shorter infusion time than IPM so may have lower administration (nursing) costs for outpatients, despite the preparation itself being more costly [14, 21]. FCM was listed on the Australian Pharmaceutical Benefits Scheme in 2014 and the New Zealand Pharmaceutical Management Agency in 2017, the former to which Seeho et al., (2018) largely attributes the rise in intravenous iron use [9]. Our findings also support the significant healthcare burden of ID with or without anaemia in pregnancy, with roughly one third of respondents treating at least fifty women per annum with IDAP (34%) and ID without anaemia (33%).
Oral iron intolerance was stated as a reason for intravenous iron prescription by some obstetricians. Although oral iron treatment strategies were not addressed in this survey, it is important to highlight the recently recognised role of ‘risk mitigation’ strategies used to improve tolerance and compliance, including reduced dose elemental iron, intermittent dosing, and avoidance of twice daily dosing [13]. The recently published British Society of Haematology guidelines outline the strategies that can be used to reduce symptoms of oral iron and lead to improve compliance and hence correction of iron deficiency anaemia [20].
The findings from our study support the acceptance of a potential RCT for firstline use of intravenous iron in pregnancy for IDAP (not ID alone) with a haemoglobin cut off of 100 g/L, where most clinicians would consider including their patients. While the lack of universal cut-offs for haematological measures of iron status in pregnancy is recognised as a research need [23], lowering inclusion thresholds could meaningfully reduce a potential IDAP study cohort in an Australian and New Zealand setting, where severe IDAP is uncommon. Indeed, Khalafallah et al’s recent Australian RCT used a haemoglobin threshold extending to ≤120 g/L, well above IDAP thresholds defined by Australian guidelines and those deemed acceptable by our cohort [21]. As such, understanding factors impacting a potential trial of first-line intravenous versus oral iron for IDAP is critical to ensuring a future study utilises appropriate and feasible inclusion thresholds and measures clinical outcomes that will meaningfully inform practice.
Limitations of this study
Strengths of this study include that it reflects current practice by specialist obstetricians in Australia and New Zealand in both urban and metropolitan areas. Our study was limited by the low response rate, however this was comparable to similar studies of the RANZCOG membership of 19–23%, and still represents a sizeable cohort [24, 25]. Nonetheless, potential self-selection bias must be acknowledged as a limitation, particularly in light of this response rate; as with any survey, those that have greater interest or more strongly held views on a topic may be more inclined to complete the survey. Another perceived limitation may be that this survey failed to capture the views of other health care professionals involved in antenatal care, particularly general practitioners who are responsible for up to 50% of intravenous iron prescribing for women of reproductive age [12]. However, although Australian national prescribing data does not provide a breakdown on intravenous iron prescribing in pregnancy versus non-pregnant reproductive-age women, our observational experience is that general practitioners are reluctant to administer intravenous iron in pregnancy outside the hospital setting, and so likely represent a small proportion of intravenous iron prescribers in pregnancy. Obstetric physicians in tertiary centres are another important prescribing group not captured by this survey, although this speciality group has few practicing members in Australia. That being said, the rationale for restricting the survey population to FRANZCOGs alone was to establish the consensus among obstetricians regarding ID treatment, as those most likely to influence local policy and to be involved in a potential trial.
