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=300) to test the central hypothesis that IV iron in pregnant women with IDA (Hb<11 g/dL and ferritin<30 ng/mL) at 13 - 30 weeks will be effective, safe and cost-effective in reducing severe maternal morbidity-as measured by maternal anemia at delivery-and will also improve offspring neurodevelopment.

Study Overview

• Status: Recruiting
• Conditions: Pregnancy; Iron Deficiency Anemia
• Intervention / Treatment: Drug: Ferric derisomaltose; Drug: Ferrous sulfate

Detailed Description

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=300) to test the central hypothesis that IV iron in pregnant women with IDA (Hb<11 g/dL and ferritin<30 ng/mL) at 13 - 30 weeks will be effective, safe and cost-effective in reducing severe maternal morbidity-as measured by maternal anemia at delivery-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 anemia at delivery in pregnant women with IDA.

Secondary Aim 1: Estimate the cost-effectiveness of IV iron , compared with oral iron, in pregnant women with 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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Crystal Ware, BSN, CCRP; Phone Number: 401-274-1122; Email: cware@wihri.org

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35401
      • Recruiting
      • University of Alabama Medical Center
      • Contact: Carolyn Webster, MD
  • Florida
    • Miami, Florida, United States, 33143
      • Recruiting
      • GNP Research at Heme-on-Call
      • Contact: Steven Fein, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • Michigan University Medical Center
      • Contact: Molly Stout, MD, MSCI
  • Missouri
    • Saint Louis, Missouri, United States, 65105
      • Recruiting
      • Washington University Medical Center
      • Contact: Ebony Carter, MD, MPH
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health and Sciences Uiversity Medical Center
      • Contact: Ashley Benson, MD
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Recruiting
      • Women & Infants Hospital of Rhode Island
      • Contact: Methodius Tuuli, MD, MPH, MBA
    • Providence, Rhode Island, United States, 02905
      • Recruiting
      • Hasbro Children's Hospital
      • Contact: Viren D'sa, MD
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah Hospital
      • Contact: Ann Bruno, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pregnant women between the ages of 18-45
• Singleton gestation
• Iron-deficiency anemia (serum ferritin <30ng/mL and Hb<11 g/dL)
• At 13-30 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV Iron; 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.	Drug: Ferric derisomaltose; 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.; Other Names: Monoferric
Active Comparator: Oral Iron; 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.	Drug: Ferrous sulfate; 325mg ferrous sulfate tablets (65 mg of elemental iron), 1 to 3 orally per day.; Other Names: Ferosul

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of maternal anemia (hgb<11mg/dL) at delivery	Hemoglobin <11mg/dL on admission to inpatient obstetrics unit for labor and delivery	Within 24 hours of admission to inpatient obstetrics unit for delivery of infant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of maternal hemoglobin at delivery	Hemoglobin on admission to inpatient obstetrics unit for labor and delivery	Within 24 hours of admission to inpatient obstetrics unit for delivery of infant
Concentration of maternal ferritin at delivery	Maternal ferritin on admission to inpatient obstetrics unit for labor and delivery	Within 24 hours of admission to inpatient obstetrics unit for delivery of infant
Concentration of maternal hemoglobin postpartum day 1	Maternal hemoglobin on postpartum day 1	On day after participant delivered her infant; postpartum day 1
Rate of cesarean delivery	Cesarean delivery for any indication in patients without prior cesarean deliveries	Once at infant delivery
Rate of severe infusion adverse events	Safety and tolerability	2 days after intravenous iron or placebo infusion
Rate of mild medication adverse events	Safety and tolerability	4 weeks after initiation of oral iron or placebo
Edinburgh Perinatal Depression Scale score	Edinburgh Perinatal Depression Scale score. Minimum score 0, maximum score 30, higher scores indicate worse depressive symptoms.	At randomization (baseline) and at 4-6 weeks postpartum
Maternal EuroQol Group Quality-of-Life Questionnaire score	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.	At 6 weeks postpartum by phone or in person
Rate of Maternal infection	Any infection diagnosed from initiation of treatment until 6 weeks postpartum	From initiation of treatment until 6 weeks postpartum
Rate of Composite Maternal Complications	Maternal mortality or any one of several maternal morbidities	At 6 weeks postpartum
Gestational age at delivery	Gestational age at delivery	At delivery
Rate of preterm birth at less then 37 weeks	Preterm birth; gestational age at delivery at less than 37 weeks (spontaneous or indicated)	At delivery
Rate of Neonatal Intensive Care Unit Admission	Admission to the neonatal intensive care unit for any indication	At birth through through 30 days from birth
Neonatal birth weight	Infant birth weight	At birth
Concentration of umbilical artery pH	Concentration of umbilical artery pH from umbilical cord gases from infant umbilical cord segment at birth	At birth
Concentration of umbilical artery bicarbonate	Concentration of umbilical artery bicarbonate from umbilical cord gases from infant umbilical cord segment at birth	At birth
Concentration of umbilical artery base excess	Concentration of base excess from umbilical cord gases from infant umbilical cord segment at birth	At birth
Concentration of umbilical artery lactate	Concentration of umbilical artery lactate from umbilical cord gases from infant umbilical cord segment at birth	At birth
Concentration of neonatal hemoglobin	Concentration of neonatal hemoglobin from umbilical cord blood at birth or first neonatal complete blood count	At birth
Concentration of neonatal ferritin	Concentration of neonatal ferritin from umbilical cord blood at birth or first neonatal blood draw	At birth
Neonatal Apgar scores	Apgar scores at 1 and 5 minutes of life. Minimum score 0, maximum score 10, higher scores indicate better well being.	At 1 minute and 5 minutes of life
Rate of composite neonatal complication	Neonatal mortality or any one of several neonatal morbidities	Through 30 days from birth
Concentration of child brain myelin	Concentration of infant brain myelin from magnetic resonance imaging	At an average of 6 months and 36 months
Child Mullen Scale of Early Learning Score	Mullen Scale of Early Learning Score as percentile. Minimum score 1, maximum score 99, higher scores indicate better neurodevelopment.	At an average of 6 months and 36 months
Rate of maternal blood transfusion at delivery	Maternal blood transfusion from delivery to 7 days postpartum	Delivery to 7 days postpartum

Collaborators and Investigators

• Sponsor: Women and Infants Hospital of Rhode Island
• Collaborators: Washington University School of Medicine; University of Alabama at Birmingham; University of Michigan; Oregon Health and Science University; University of Utah; Hasbro Children's Hospital; GNP Research at Heme-on-Call
• Investigators: Principal Investigator: Methodius Tuuli, MD, MPH, MBA, Women and Infants Hospital of Rhode Island

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2023
• Primary Completion (Estimated): March 30, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: May 15, 2022
• First Submitted That Met QC Criteria: July 14, 2022
• First Posted (Actual): July 18, 2022

Study Record Updates

• Last Update Posted (Actual): June 10, 2025
• Last Update Submitted That Met QC Criteria: June 5, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Hematologic Diseases; Iron Metabolism Disorders; Anemia, Hypochromic; Malnutrition; Iron Deficiencies; Anemia; Anemia, Iron-Deficiency; Deficiency Diseases
• Other Study ID Numbers: Pro00060930

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: 5 years after completion of study
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No