A Multicenter Randomized Trial of IV vs Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy

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ABSTRACT Iron-deficiency anemia is a common, under-treated problem in pregnancy. The prevalence of iron-deficiency anemia (anemia plus iron deficiency) is estimated at 16.2% overall in pregnancy and up to 30% at delivery, and it is associated with significant adverse maternal and fetal outcomes. While treatment with iron supplementation is recommended during pregnancy, important questions remain about the optimal route of delivery. Oral iron therapy, the current standard, is often suboptimal: up to 70% of patients experience significant gastrointestinal side effects that prevent adherence to treatment, resulting in persistent anemia. In addition, the timing and frequency of oral iron can influence absorption. Intravenous (IV) iron is an attractive alternative because it mitigates the adherence and absorption challenges of oral iron. However, it costs more, and there are historical concerns about adverse reactions. The American College of Obstetricians and Gynecologists recommends oral iron for the treatment of iron-deficiency anemia in pregnancy, with IV iron reserved for the “rare patient who cannot tolerate or will not take oral iron.” Our preliminary data show that this approach leads to 30% of patients with persistent IDA at delivery and an associated 3 to 6-fold increased risk of peripartum blood transfusion, a metric within the Centers for Disease Control and Prevention’s severe maternal morbidity composite. This preferential recommendation of oral iron is based on paucity of data on the benefits and safety of IV iron, compared with oral iron, in pregnancy. Our published systematic review and meta-analysis showed that IV iron is associated with greater increase in maternal hemoglobin (Hb), but most of the primary trials were conducted in developing countries, included small sample sizes (50 – 252), and did not assess meaningful maternal and neonatal outcomes. The current Cochrane review noted that despite the high incidence and disease burden associated with IDA in pregnancy, there is paucity of quality trials assessing clinical maternal and neonatal effects of iron administration in women with anemia. The authors called for “large, good quality trials assessing clinical outcomes.” The only large randomized trial of IV versus oral iron, conducted in India, showed no difference in a maternal composite outcome but is limited by use of iron sucrose with a wide range of iron doses (200 – 1600 mg) in up to 5 infusions. In addition, the primary composite outcome included components not directly related to anemia. In contrast, our pilot trial of a single infusion of 1000 mg of IV low molecular weight dextran in pregnant women in the U.S. with moderate-to-severe IDA significantly reduced the rate of maternal anemia at delivery and showed promise for reducing rates of blood transfusion. We propose the first definitive double blind, placebo controlled, multicenter randomized trial in pregnant women in the U.S. (N=746) to test the central hypothesis that IV iron in pregnant women with moderate-to-severe IDA (Hb<10 g/dL and ferritin<30 ng/mL) at 24 – 28 weeks will be effective, safe and cost-effective in reducing peripartum blood transfusion and improve offspring neurodevelopment. A multidisciplinary team of investigators in the U.S., will pursue the following specific aims: 1) Evaluate the effectiveness and safety of IV iron, compared with oral iron, in reducing the rate of peripartum blood transfusion in pregnant women with moderate-to-severe IDA. (Primary Aim); 2) Estimate the cost- effectiveness of IV iron, compared with oral iron, in pregnant women with moderate-to-severe IDA as measured by incremental cost per Quality Adjusted Life-year (QALY). (Secondary Aim 1); and 3) Assess the effect of IV iron, compared with oral iron, on offspring brain myelin content and neurodevelopment. (Secondary Aim 2).