Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Compared to oral iron, intravenous iron reduced maternal anemia at delivery (40% vs. 85%, P = 0.039), and rates of maternal hemoglobin < 10 g/dL were lower with intravenous iron compared to oral iron (10% vs. 54%, P = 0.029). Rates of mild to moderate adverse events were similar between the two groups, and no severe adverse reactions were noted with intravenous iron.
SOURCE: Lewkowitz AK, Stout MJ, Cooke E, et al. Intravenous versus oral iron for iron deficiency anemia in pregnancy (IVIDA): A randomized controlled trial. Am J Perinatol 2021; Nov 28. doi: https://doi.org/ 10.1055/s-0041-1740003. [Online ahead of print].
Although, in several parts of the world, there is a wide variation in hemoglobin concentration during normal pregnancy, the World Health Organization (WHO) defines anemia in pregnancy as a hemoglobin concentration of < 11 g/dL.1 Although it particularly is prevalent in less-developed countries, anemia in pregnancy remains a significant problem in the developed world.2 Therefore, effective management is needed to prevent adverse maternal and pregnancy outcomes, including increased susceptibility to infections, intrauterine fetal growth restriction, preterm delivery, postpartum hemorrhage, and the need for red cell blood transfusion.
In iron-deficiency anemia, the amounts of stored iron (ferritin) and transport iron (transferrin) are reduced, but total iron binding capacity (TIBC) is increased.3 In addition, the physiologic anemia of pregnancy exacerbates iron-deficiency anemia as a result of expanded plasma volume in excess of red cell mass.4 When iron-deficiency anemia is diagnosed during pregnancy, initial therapeutic options include the use of oral or intravenous (IV) iron therapy. Although a few high-quality randomized trials have been conducted in developed countries comparing oral iron to IV iron, none have been conducted in the United States. In this study, Lewkowitz et al evaluated IV compared to oral iron for the treatment of iron-deficiency anemia in the United States.5
This study started as a single-center, randomized clinical trial at Barnes Jewish Hospital in St. Louis, but later expanded to a second site, Indiana University.5 Inclusion criteria included women with iron-deficiency anemia (serum ferritin < 30 ng/mL, hemoglobin < 30 ng/mL, and normal hemoglobin electrophoresis). Women were excluded if they had non-iron-deficiency anemia, multiple gestations, prenatal diagnosed major congenital anomalies or known aneuploidy, planned delivery at another hospital, or if there was inability to obtain informed consent.5
A computer-generated randomization sequence was used to randomize participants in a 1:1 ratio to study intervention (IV dextran or ferumoxytol, if dextran was unavailable) or control (oral ferrous sulfate). The iron infusion was 1,000 mg of IV low-molecular weight iron dextran given as a single dose. All iron infusions occurred on labor and delivery, the antepartum unit, or obstetric triage.5 No further oral iron supplementation during pregnancy or postpartum was given to those who received IV iron.5 The control arm received oral ferrous sulfate 325 mg tablets at doses of once to three times daily. All of the patients completed a survey that assessed mild/moderate medication reactions during their delivery hospitalization.
The primary endpoint was maternal anemia, defined as hemoglobin < 11 g/dL on admission to labor and delivery. Secondary outcomes included maternal hemoglobin < 10 g/dL on admission to labor and delivery, maternal ferritin, blood transfusion, or mode of delivery; neonatal outcomes, such as gestational age at delivery, birth weight, neonatal hemoglobin and ferritin obtained from cord blood, cord gas pH, Apgar scores, and admission to a neonatal intensive care unit.5 A total sample size of 120 participants was anticipated to detect a 60% or greater relative difference in anemia (from 38.5% baseline anemia in the oral iron group to 15.4% with IV iron), assuming 80% power, a 10% attrition rate, and a type 1 error rate of 5%. However, because of financial constraints, the study was stopped early.
Women were recruited between April 15, 2018, and Dec. 31, 2019. Fifty-five women were approached for the study and 38 consented. Of these 38 women, 15 did not follow their assigned intervention and were withdrawn (five desired to pursue IV iron infusion and declined to start oral iron; 10 were prescribed oral iron after declining to receive IV iron). As such, 23 women were included in the analysis, among whom 10 women received IV iron and 13 women received oral iron. The rate of the primary outcome (hemoglobin of less than 11 g/dL on admission to labor and delivery) was high in both groups. However, women randomized to IV iron were significantly less likely than those randomized to oral iron to have a hemoglobin < 11 g/dL at delivery (n = 4 [40.0%] vs. n = 11 [84.6%]; P = 0.039).5 Among the secondary outcomes, women randomized to IV iron were significantly less likely to have a hemoglobin < 10 g/dL at delivery (n = 1 [10.0%] vs. n = 7 [53.9%]; P = 0.029) and to have higher hemoglobin at time of delivery (mean = 11.0 g/dL [standard deviation (SD) = 0.7 g/dL] vs. mean = 9.9 g/dL [SD = 1.1 g/dL]; P = 0.19).5 In addition, the rate of maternal blood transfusion was 15% in the oral iron group compared with 0% in the IV iron group, but this difference was not statistically significant. There were no severe adverse reactions. Similar rates of mild/moderate reactions were noted between the two groups (n = 3 [23%] for oral vs. n = 3 [30%] for IV; P = 0.708).5 It is important to understand that this study was underpowered, so the results should be interpreted with caution.
COMMENTARY
Treatment of iron deficiency anemia is critically important during pregnancy to prevent adverse maternal and neonatal outcomes.2 Although routine iron supplementation for all women in pregnancy is not recommended in the United States, the general practice is a trial of oral iron as first-line therapy after diagnosis of iron-deficiency anemia, with an appropriate rise being an increase of approximately 2 g/dL over three to four weeks.3,6 In the United States, IV iron therapy usually is indicated if patients are diagnosed with moderate to severe anemia in late gestation, if there is an inappropriate rise in hemoglobin concentrations after the trial of oral iron, if there are adverse effects to oral iron, or if there is medication nonadherence. The rationale for the use of IV iron in these circumstances is that IV iron circumvents the natural gastrointestinal regulatory mechanisms to deliver non-protein-bound iron directly to the red blood cells.3 Therefore, to maximize oral iron absorption, supplementation should be taken on an empty stomach, one hour before meals, with a source of vitamin C (ascorbic acid, orange juice).3 A history of severe allergic reaction to iron (anaphylaxis), active acute or chronic systemic infections, and chronic liver diseases should be ruled out before IV iron therapy is used during pregnancy. In addition, facilities and staff trained in the management of anaphylaxis from iron infusions should be available in the event of an anaphylactic reaction.3
Since free iron may lead to the production of hydroxyl radicals with potential toxicity to tissues, iron deficiency should be confirmed by ferritin levels before the use of parenteral preparations.3 Serum ferritin concentration is the best test to assess iron deficiency, and the single best indicator of storage-iron during pregnancy, since it is the first laboratory test to become abnormal in iron-deficiency anemia during pregnancy. Even though the ferritin level may be influenced by the plasma dilution later in pregnancy, a concentration below 15 mcg/L indicates iron depletion in all stages of pregnancy.3 Serum iron, transferrin, and TIBC are unreliable indicators of iron-deficiency anemia because of the wide fluctuation in levels caused by the recent ingestion of iron, diurnal rhythm, and other factors, such as infection.7 Screening for anemia during pregnancy in the United States involves assessing complete blood count at the initial prenatal visit and during the third trimester of pregnancy, with a workup for iron-deficiency anemia in women who screen positive.
In summary, all women diagnosed with iron-deficiency anemia should be given dietary advice on how to maximize iron intake during pregnancy in accordance with the American College of Obstetricians and Gynecologists’ (ACOG) recommendations.2 ACOG continues to recommend oral iron supplementation for iron-deficiency anemia in pregnancy, with IV iron indicated in patients who cannot tolerate or will not take oral iron.2 Anemic women may require additional precautions for delivery, including delivery in a hospital setting with facilities for blood transfusion.
REFERENCES
- Agarwal AM, Rets A. Laboratory approach to investigation of anemia in pregnancy. Int J Lab Hematol 2021;43 (Suppl 1):65-70.
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins – Obstetrics. Anemia in Pregnancy: ACOG Practice Bulletin, Number 233. Obstet Gynecol 2021;138:e55-e64.
- Pavord S, Myers B, Robinson S, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2012;156:588-600.
- Eke AC. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics. J Basic Clin Physiol Pharmacol 2021; Dec 8. doi:10.1515/jbcpp-2021-0312. [Online ahead of print].
- Lewkowitz AK, Stout MJ, Cooke E, et al. Intravenous versus oral iron for iron-deficiency anemia in pregnancy (IVIDA): A randomized controlled trial. Am J Perinatol 2021; Nov 28. doi:10.1055/s-0041-1740003. [Online ahead of print].
- Jimenez K, Kulnigg-Dabsch S, Gasche C. Management of iron deficiency anemia. Gastroenterol Hepatol (N Y) 2015;11:241-250.
- Montoro-Huguet MA, Santolaria-Piedrafita S, Cañamares-Orbis P, García-Erce JA. Iron deficiency in celiac disease: Prevalence, health impact, and clinical management. Nutrients 2021;13:3437.
Compared to oral iron, intravenous iron reduced maternal anemia at delivery (40% vs. 85%, P = 0.039), and rates of maternal hemoglobin < 10 g/dL were lower with intravenous iron compared to oral iron (10% vs. 54%, P = 0.029). Rates of mild to moderate adverse events were similar between the two groups, and no severe adverse reactions were noted with intravenous iron.
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