Single-dose intravenous iron vs oral iron for treatment of maternal iron deficiency anemia: a randomized clinical trial

Background

Maternal iron deficiency anemia is a persistent global health challenge with increased risk of adverse perinatal outcomes. Obstetric guidelines advocate for first-line treatment of moderate iron deficiency anemia with twice-daily oral iron; however, rates of iron deficiency anemia in pregnancy remain above global targets and are rising.

Objective

Determine whether single-dose intravenous iron for primary treatment of maternal iron deficiency anemia in the second trimester is superior to twice daily oral iron in reducing incidence of low birth weight infants and maternal anemia at delivery.

Study Design

This is a parallel, 3-arm, semiblind superiority randomized controlled multicenter trial across 4 sites in India from March 15, 2021–May 12, 2023. Participants were singleton pregnancies at 14 to 17 weeks with moderate iron deficiency anemia (hemoglobin 7.0–9.9 g/dL) who were randomized 1:1:1 to (1) 60 mg oral ferrous sulfate twice daily; or single-dose infusion of (2) intravenous ferric derisomaltose or (3) intravenous ferric carboxymaltose. Two intravenous arms were selected as these are the only 2 intravenous iron formulations publicly available in India. All participants received folic acid supplementation throughout pregnancy and antihelminthic therapy, as recommended by national guidelines. The dual primary outcomes were: (1) low birth weight (<2500 grams) and (2) attainment of a maternal nonanemic state (hemoglobin ≥11.0 g/dL at 30–34 weeks or delivery) for each intravenous iron arm vs oral iron; intravenous iron arms were not compared to each other. Secondary outcomes included safety measures, and other maternal and infant outcomes. Participants with hemoglobin <7 g/dL or <1 g/dL improvement on therapy received rescue treatment with intravenous iron or blood transfusion as determined by their provider. Sensitivity analyses included defining nonanemic state as achieving hemoglobin ≥11.0 without need for additional IV iron or transfusion. Comparison of each intravenous iron arm to oral iron was conducted with a 2-sided alpha set at 0.0005 for achieving nonanemic state and 0.0245 for low birth weight for each intravenous iron arm using a Cochran-Mantel-Haenszel chi-square test stratified by enrollment site.

Results

The oral iron, ferric derisomaltose, and ferric carboxymaltose arms included 1450, 1456, and 1462 participants respectively. There was a reduced rate of low birth weight with intravenous ferric carboxymaltose (25·2%, relative risk 0·87 [97·55% confidence interval 0.75, 0.99], P=.017), but not intravenous ferric derisomaltose (29.1%, relative risk 0.98 [97.55% confidence interval 0.86, 1.12], P=.71) vs oral iron (29.3%). Achievement of nonanemic state was not improved: intravenous ferric carboxymaltose (relative risk 1.05 [99.95% confidence interval 0.97–1.15]) and intravenous ferric derisomaltose (relative risk 1.06 [99.95% confidence interval 0.98, 1.16]) vs oral (69.7%). In sensitivity analysis, there was increased rate of achieving nonanemic state without use of additional IV iron or transfusion in both intravenous ferric derisomaltose (relative risk 1.25 (1.13–1.396), P<.0001) and intravenous ferric carboxymaltose (relative risk 1.24 (1.12–1.38), P<.0001) vs oral iron.

Conclusion

First-line treatment of moderate maternal iron deficiency anemia with single-dose infusion of intravenous iron results in a reduced incidence of low birth weight infants (intravenous ferric carboxymaltose vs oral) and a higher incidence of attaining maternal nonanemic state without use of additional iron or blood transfusion (intravenous ferric carboxymaltose and ferric derisomaltose vs oral). Clinical guidelines should address the potential benefit of single-dose intravenous iron as the primary treatment of moderate iron deficiency anemia in pregnancy.