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

摘要 缺铁性贫血是妊娠期常见的、未得到充分治疗的问题。缺铁的患病率 据估计，怀孕期间贫血(贫血加缺铁)的总比例为16.2%，分娩时高达30%。 它与严重的不良母婴结局有关。在补铁治疗的同时 虽然在怀孕期间被推荐，但关于最佳分娩途径的重要问题仍然存在。口服铁 目前的标准治疗往往是次优的：高达70%的患者出现明显的胃肠道症状 副作用，阻碍坚持治疗，导致持续性贫血。此外，时间和 口服铁质的频率会影响吸收。静脉注射(IV)铁是一种有吸引力的替代品，因为它 缓解口服铁质的黏附和吸收挑战。然而，它的成本更高，而且有历史上的 对不良反应的担忧。美国妇产科医师学会建议口服 铁用于治疗妊娠期缺铁性贫血，静脉注射铁保留给“罕见病患者” 不能忍受或不会服用口服铁。我们的初步数据显示，这种方法导致30%的患者 在分娩时持续存在IDA，围产期输血的风险增加3至6倍， 在疾病控制和预防中心的严重孕产妇发病率综合指标中。这 口服铁的优先推荐是基于缺乏静脉注射铁的益处和安全性的数据， 与口服铁相比，在怀孕期间。我们发表的系统综述和荟萃分析表明，静脉注射铁 与母体血红蛋白(Hb)的较大增加有关，但大多数初步试验都是进行的 在发展中国家，包括小样本量(50-252)，没有评估有意义的母亲和 新生儿结局。目前的Cochrane审查指出，尽管发病率和疾病负担很高 与妊娠期缺铁性贫血有关，缺乏评估临床母婴影响的高质量试验。 贫血妇女的铁剂使用情况。作者呼吁进行“大规模、高质量的临床评估试验”。 结果。“在印度进行的唯一一项静脉注射与口服铁的大型随机试验显示，在 产妇的综合结局，但受到使用蔗糖铁和大范围铁剂量(200-1600)的限制 Mg)，最多5次输液。此外，主要的综合结果包括与以下内容没有直接关系的成分 贫血。相比之下，我们的试点试验是在怀孕期间单次输注1000 mg静脉注射低分子葡聚糖 在美国，患有中到重度缺铁性贫血的妇女在分娩时显著降低了母亲贫血率 并显示出降低输血率的希望。我们提出了第一种权威的双盲安慰剂 在美国孕妇中进行的对照多中心随机试验(n=746)以检验中心假说 24-28岁中重度缺铁性贫血孕妇静脉注射铁(Hb和铁蛋白分别为10g/dL和30 ng/ml) 在减少围产期输血和改善后代方面，几周将是有效、安全和经济的 神经发育。美国的一个由多学科调查人员组成的团队将追求以下具体目标： 1)评价静脉注射铁剂与口服铁剂在降低围产期死亡率方面的有效性和安全性 中重度缺铁性贫血孕妇的输血。(主要目标)；2)估算成本- 静脉补铁与口服补铁对中重度缺铁性贫血孕妇的疗效比较 按每质量调整寿命年的增量成本(QALY)计算。(次要目标1)；和3)评估IV的效果 铁与口服铁相比，对子代大脑髓鞘含量和神经发育的影响。(次要目标2)。

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).