Intravenous Versus Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy (IVIDA2)

Double-blind Placebo-controlled Multicenter Randomized Trial of Intravenous Versus Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy

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 severe maternal morbidity-as measured by peripartum blood transfusion-and will also improve offspring neurodevelopment.

Iron-deficiency anemia (IDA) is a common, undertreated problem in pregnancy. According to data from the U.S. National Health and Nutrition Examination Survey (NHANES), 25% of pregnant women in the U.S. have iron deficiency, with rates of 7%, 24%, and 39% in the first, second, and third trimesters, respectively. The prevalence of IDA is estimated at 16.2% overall and up to 30% at delivery. Iron deficiency is associated with significant adverse maternal and fetal outcomes including blood transfusion, cesarean delivery, depression, preterm birth, and low birth weight. Moreover, iron-deficient mothers are at risk of delivering iron-deficient neonates who, despite iron repletion, remain at risk for delayed growth and development. While treatment with iron supplementation is recommended during pregnancy, 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 (nausea, constipation, diarrhea, indigestion, and metallic taste) that prevent adherence to treatment, resulting in persistent anemia. Intravenous (IV) iron is an attractive alternative because it mitigates the adherence and absorption challenges of oral iron. However, IV iron costs more, and there are historical concerns about adverse reactions. The American College of Obstetricians and Gynecologists (ACOG) recommends oral iron for the treatment of IDA in pregnancy, with IV iron reserved for the restricted group of patients. 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. ACOG's 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 it is limited by use of iron sucrose which required five infusions, resulting in a wide range of iron doses (200 - 1600 mg). In addition, the primary composite outcome included some components not directly related to anemia. In contrast, our pilot trial of a single infusion of 1000 mg of IV low molecular weight iron 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 improving maternal morbidity by reducing rates of blood transfusion. This is 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 severe maternal morbidity-as measured by peripartum blood transfusion-and will also improve offspring neurodevelopment. A multidisciplinary team of investigators in the U.S., will pursue the following specific aims: Primary Aim: 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. Secondary Aim 1: 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 2: Assess the effect of IV iron, compared with oral iron, on offspring brain myelin content and neurodevelopment.

Participants will receive matching ferrous sulfate or placebo formulate to appear and taste similar. They will also each receive an infusion of 1000mg ferric derisomaltose in 250ml of normal saline or 250ml of normal saline only, camouflaged in an opaque intravenous bag and tubing covers.

Participants assigned to the IV iron group will receive a single IV infusion of 1000 mg ferric derisomaltose (Monoferric, Pharmacosmos Therapeutics Inc., Morristown, NJ) in 250 mL given over 20 minutes and daily placebo tablets until delivery.

Participants assigned to the oral iron group will receive a single 250 mL IV normal saline infusion given over 20 minutes and 325mg tablets of ferrous sulfate (65 mg of elemental iron) to be taken until delivery.

Participants assigned to the IV iron group will receive a single IV infusion of 1000 mg ferric derisomaltose (Monoferric, Pharmacosmos Therapeutics Inc., Morristown, NJ) in 250 mL given over 20 minutes.

Edinburgh Perinatal Depression Scale score. Minimum score 0, maximum score 30, higher scores indicate worse depressive symptoms.

Maternal EuroQol Group Quality-of-Life Questionnaire (EQ-5D-5L). Minimum score 11111 (full health), maximum score 55555 (worst health), higher scores indicate worse quality of life.

Concentration of umbilical artery pH from umbilical cord gases from infant umbilical cord segment at birth

Concentration of umbilical artery bicarbonate from umbilical cord gases from infant umbilical cord segment at birth

Concentration of umbilical artery lactate from umbilical cord gases from infant umbilical cord segment at birth

Concentration of neonatal hemoglobin from umbilical cord blood at birth or first neonatal complete blood count

Apgar scores at 1 and 5 minutes of life. Minimum score 0, maximum score 10, higher scores indicate better well being.

Mullen Scale of Early Learning Score as percentile. Minimum score 1, maximum score 99, higher scores indicate better neurodevelopment.

Inclusion Criteria: Pregnant women between the ages of 18-45 Singleton gestation Iron-deficiency anemia (serum ferritin <30ng/mL and Hb<10 g/dL) At 24-28 weeks gestation Plan to deliver at participating hospital Exclusion Criteria: Non-iron-deficiency anemia e.g thalassemia, sickle cell disease, B12 or folate deficiency, hypersplenism. Malabsorptive syndrome, inflammatory bowel disease, gastric bypass, or sensitivity to oral or IV iron Multiple gestation Inability or unwillingness to provide informed consent Inability to communicate with members of the study team, despite the presence of an interpreter Planned delivery at a non-study affiliated hospital

Data will be collected from human subjects and will be shared according to NIH guidelines. The investigators are committed to the sharing of final data, being mindful that the rights and privacy of people who participate in research must be protected at all times. The investigators will make a complete study dataset available for sharing. The investigators will have a description of study dataset, including code books, meta-data related to the dataset, and documented programming code used for creating the final study population, for creating variables, and for conducting all outcomes analyses. The investigators will remain HIPAA compliant, and therefore any datasets resulting from participants will be free of any identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of individual subjects.

The investigators will make the data and associated documentation available to users under a data-sharing agreement that provides for commitment to: a) using the data only for research purposes and not to identify any individual participant; b) securing the data using appropriate computer technology; and c) destroying or returning the data after analyses are completed. Timelines for distribution of data will vary depending on any required restrictions as mentioned above. Data may be distributed by a number of electronic methods, including web-based databases, datasets, and spreadsheets, or via electronic media such as compact discs.