Iron interventions in pregnancy and better clinical outcomes: the jury is out
Authors: Jahnavi Daru
Journal: The Lancet Global Health (2019)

Maternal anaemia is a well recognised and serious problem in low-income and high-income countries.1Stevens GA Finucane MM De-Regil LM et al.Nutrition Impact Model Study GroupGlobal, 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.Lancet Glob Health. 2013; 1: e16-e25Summary Full Text Full Text PDF PubMed Scopus (1004) Google Scholar Anaemia is for all intents and purposes a laboratory diagnosis, characterised by a fall in haemoglobin concentration below a defined threshold. Adverse events related to anaemia are well known, and severe anaemia has been shown to increase risk of maternal and perinatal mortality.2Daru J Zamora J Fernández-Félix BM et al.Risk of maternal mortality in women with severe anaemia during pregnancy and post partum: a multilevel analysis.Lancet Glob Health. 2018; 6: e548-e554Summary Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 3Nair M Choudhury MK Choudhury SS et al.Association between maternal anaemia and pregnancy outcomes: a cohort study in Assam, India.BMJ Global Health. 2016; 1e000026Crossref PubMed Scopus (60) Google Scholar The most common cause of maternal anaemia is a deficiency of iron, which in theory is easily treated, with trials showing improvements in blood parameters following iron interventions.4Haider BA Olofin I Wang M et al.Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis.BMJ. 2013; 346f3443Crossref PubMed Scopus (448) Google Scholar However, in practice, anaemia persists as a problem in pregnancy worldwide. An improved understanding of the impact of anaemia on clinically meaningful outcomes is required.4Haider BA Olofin I Wang M et al.Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis.BMJ. 2013; 346f3443Crossref PubMed Scopus (448) Google Scholar In The Lancet Global Health, the trial by Sutapa Neogi and colleagues5Neogi SB Devasenapathy N Singh R et al.Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trial.Lancet Glob Health. 2019; 7: e1706-e1716Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar makes an important contribution to the field as a well conducted, large randomised study investigating the impact of intravenous iron sucrose versus standard oral iron therapy on clinical maternal and infant outcomes. The study recruited more than 2000 pregnant women between 20 and 32 weeks of gestation with a haemoglobin concentration between 5 g/dL and 9 g/dL across four government medical colleges in India. In the intervention group, participants received intravenous iron sucrose across five visits, compared with high-dose oral iron in the control group. The primary endpoint was a composite of postpartum haemorrhage, intrapartum or postpartum blood transfusion, puerperal sepsis, shock, prolonged hospital stay, and intensive care unit admission or referral to centres with additional facilities. The authors were advised to stop the trial early due to futility, and they concluded there was insufficient evidence to demonstrate effectiveness of intravenous iron in improving maternal outcomes. This study highlights several important points, the first of which was the decision to give oral iron preparations to women with haemoglobin concentrations between 5 and 9 g/dL. In practice, many women with severe anaemia (commonly defined as a haemoglobin concentration <7 g/dL) are offered blood transfusion or other parenteral iron treatment as a first-line therapy.6National Health Portal IndiaAnaemia during pregnancy (maternal anaemia).https://www.nhp.gov.in/disease/gynaecology-and-obstetrics/anaemia-during-pregnancy-maternal-anemiaDate accessed: October 17, 2019Google Scholar Second, the authors chose a composite of many clinically relevant outcomes as their primary endpoint. This choice is impressive because iron trials are rarely powered to a clinical endpoint, let alone multiple endpoints.4Haider BA Olofin I Wang M et al.Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis.BMJ. 2013; 346f3443Crossref PubMed Scopus (448) Google Scholar However, composite endpoints are not without challenges and controversy, as described in other medical specialities.7Cordoba G Schwartz L Woloshin S Bae H Gøtzsche PC Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review.BMJ. 2010; 341c3920Crossref PubMed Scopus (232) Google Scholar Interpretation is often difficult, especially when there are numerous clinical events. These events might occur sequentially and often to the same individual (eg, haemorrhage leading to a transfusion), which means that it is difficult to determine which factor is affecting the overall estimate. In this study, fewer women in the intravenous iron group needed blood transfusion than those in the oral iron group. Parenteral iron is well known to improve laboratory blood values,8Shi Q Leng W Wazir R et al.Intravenous iron sucrose versus oral iron in the treatment of pregnancy with iron deficiency anaemia: a systematic review.Gynecol Obst Invest. 2015; 80: 170-178Crossref PubMed Scopus (21) Google Scholar possibly reducing the need for transfusion. Finally, this trial was terminated early, with the data monitoring committee citing futility following a preplanned interim analysis of data from just over 2000 participants (50% of the target sample size of 4000) assessing safety and efficacy. Following this analysis, the conditional power was estimated at 1·14% for the null effect, 3·0% for the continued effect, and 44·83% for the hypothesised effect.5Neogi SB Devasenapathy N Singh R et al.Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trial.Lancet Glob Health. 2019; 7: e1706-e1716Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar This suggests that the authors and data monitoring committee felt that there was likely to be no difference between the intervention and control groups, should the trial have continued to recruit to the full sample size estimate. Decisions to stop trials early are rarely made lightly, largely because the type 2 error rate increases. When decisions are made, they are usually the consequence of clear benefit (or harm) of an intervention, safety concerns, or an inability to recruit to target. In this study, without any clear safety concerns, the data monitoring committee had to use the lack of a demonstratable difference between the intervention and control groups at the interim analysis (adjusted odds ratio 0·95, 95% CI 0·70–1·29 for composite adverse maternal outcome) to terminate the trial early. However, without prespecification of the definition of futility to be used, or clear a priori stopping criteria, such decisions are left to open to interpretation, making the activities of data monitoring committees increasingly challenging. Following on from the work by Neogi and colleagues, there remains an opportunity to investigate effects of intravenous iron on numerous clinically relevant outcomes, including length of stay in hospital and haemorrhage at delivery, among others. The need for more high-quality randomised data has long been identified by clinicians, policy makers, and pregnant women as important areas for future research.4Haider BA Olofin I Wang M et al.Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis.BMJ. 2013; 346f3443Crossref PubMed Scopus (448) Google Scholar, 9Pasricha SR Colman K Centeno-Tablante E Garcia-Casal MN Peña-Rosas JP Revisiting WHO haemoglobin thresholds to define anaemia in clinical medicine and public health.Lancet Haematol. 2018; 5: e60-e62Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar This is especially relevant given the existing uncertainty on the safety of iron at the extremes of haemoglobin values in pregnancy.10Young MF Oaks BM Tandon S Martorell R Dewey KG Wendt AS Maternal hemoglobin concentrations across pregnancy and maternal and child health: a systematic review and meta-analysis.Ann NY Acad Sci. 2019; 1450: 47-68Crossref PubMed Scopus (75) Google Scholar Neogi and colleagues conclude that there was insufficient evidence to demonstrate a difference in composite clinical outcomes following the administration of iron sucrose compared with oral iron. The impact of iron preparations on clinically meaningful outcomes for maternal and infant wellbeing remains unanswered. This important work will hopefully pave the way for further research to answer these questions definitively to guide future policy and practice. JD received an honorarium from Pharmacosmos in 2018 for attending a meeting to assess the side-effect profiles of intravenous iron products. Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trialThe study was stopped due to futility. There is insufficient evidence to show the effectiveness of intravenous iron sucrose in reducing clinical outcomes compared with standard oral iron therapy in pregnant women with moderate-to-severe anaemia. Full-Text PDF Open Access