Intravenous Iron for Iron-deficiency Anemia in Pregnancy: a Randomized Controlled Trial (IVIDA)

Iron deficiency is the most common cause of anemia in pregnancy worldwide, and, when severe, can have serious consequences for mothers and babies. While treatment of iron-deficiency anemia with iron supplementation is recommended, treatment strategies remain controversial: the American College of Obstetrics and Gynecology recommends oral iron supplementation with parental iron reserved for the rare patient who cannot tolerate or will not take oral iron, while United Kingdom professional organizations recommend a more liberal use of parenteral iron. The reason for these disparate recommendations is that few high-quality studies comparing oral to parenteral iron have been conducted in developed countries, and the potential impact of parental iron treatment on obstetric and perinatal outcomes remains unclear. We propose the first randomized-controlled trial in the United States describing the effectiveness and safety of treating pregnant women with iron-deficiency anemia with a protocol including parenteral iron compared with a protocol based on oral iron.

Study Overview

• Status: Completed
• Conditions: Iron Deficiency Anemia of Pregnancy; Iron Malabsorption
• Intervention / Treatment: Drug: Iron dextran; Drug: Ferrous sulfate 325mg

Detailed Description

Iron deficiency is the most common cause of anemia in pregnancy worldwide, and, when severe, can have serious consequences for mothers and babies. In the United States, anemia affects nearly 20% of pregnancies and the majority is iron-deficiency anemia. Therefore, treatment of iron-deficiency anemia with iron supplementation is recommended.1 However, there is controversy about the treatment strategies.

The American College of Obstetrics and Gynecology recommends oral iron supplementation for iron-deficiency anemia in pregnancy, with parental iron reserved only for the "rare patient who cannot tolerate or will not take oral iron" (1) Conversely, guidelines from the United Kingdom. are more liberal on the use of parental iron for the treatment of iron-deficiency anemia in pregnancy (2). Both treatment guidelines are based on limited data regarding the risks and benefits of parental iron for treatment of iron-deficiency anemia in pregnancy. The majority of randomized trials were conducted in developing country settings. In fact, few high-quality studies have been conducted in developed countries, and none has been conducted in the United States Moreover, there is limited data from prior studies on the impact of parental iron treatment on perinatal outcomes. The most recent Cochrane review including mostly from trials conducted in low-income countries found that, although parenteral iron improved hemoglobin levels and iron stores than the oral route, no clinical outcomes were assessed and there were insufficient data on adverse effects (3). The authors concluded that "large, good quality trials, assessing clinical outcomes including adverse effects … are required" (3).

This randomized controlled trial aims to assess the effectiveness and safety of treating pregnant women with iron-deficiency anemia with a protocol including parenteral iron compared with a protocol based on oral iron. We hypothesize that treating iron-deficiency anemia with parental iron is associated with improved maternal and neonatal outcomes compared with a protocol based on oral iron. To increase generalizability of the findings, we will use broad inclusion criteria and analyze data using the intention-to-treat principle.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Center for Outpatient Health, Washington University in St. Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Iron-deficiency anemia (serum ferritin <30 micrograms, normal hemoglobin electrophoresis, and hemoglobin <10 mg/dL), planned delivery at Barnes-Jewish Hospital

Exclusion Criteria:

• Non-iron-deficiency anemia, multiple gestation, prenatally diagnosed major fetal anomalies, known aneuploidy, planned delivery at other hospital, inability to obtain consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous iron dextran infusion; Women randomized to receive intravenous iron infusion will receive a single infusion of dextran 1000mg IV as an inpatient on the antepartum or Labor & Delivery Unit. They will receive continuous fetal monitoring for 30 minutes before and after the infusion as well for the duration of the infusion	Drug: Iron dextran; Single intravenous infusion of iron dextran 1000mg.; Other Names: Experimental
Active Comparator: Oral ferrous sulfate supplementation; Women randomized to continue oral iron will continue to take ferrous sulfate 325mg one to three tablets daily, with the final dose at the discretion of the patient's obstetric provider.	Drug: Ferrous sulfate 325mg; Oral iron supplementation with ferrous sulfate 325mg one to three times daily; Other Names: Active comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Anemia at Delivery	Number of participants with maternal hemoglobin <11g/dl at delivery	At delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Hemoglobin at Delivery	Maternal hemoglobin on admission to inpatient obstetrics unit for delivery	On admission to inpatient obstetrics unit for delivery
Number of Participants With Medication Adverse Events	Participants reporting symptoms when contacted by via telephone 2 - 3 days after their infusion of intravenous iron or initiation of oral iron	2 - 3 days after single intravenous iron infusion or initiation of oral iron
Maternal Hemoglobin Below 10g/dl at Delivery	Number of participants with hemoglobin below 10g/dl at delivery	At delivery
Maternal Ferritin at Delivery	Maternal serum ferritin level in μg/L at delivery	At delivery
Number of Participants Who Received Blood Transfusion	Participant receiving transfusion of packed red blood cells during admission for delivery of infant obtained via medical chart review.	During inpatient admission for delivery of neonate
Mode of Delivery	Whether infant was delivered vaginally or via cesarean section	Once, at infant delivery
Gestational Age at Delivery	Gestational age in weeks at delivery	Once, at infant delivery
Birth Weight	Neonatal weight at delivery	Obtained once, at infant delivery
Umbilical Cord Arterial pH	Umbilical cord arterial pH obtained at delivery	Drawn once from umbilical cord segment at delivery
APGAR Scores at 1 Minutes of Life	The APGAR score, named after the Virginia Apgar, pediatrician who came up with it, measures the physical condition of a newborn infant on a scale ranging from a minimum of 0 (worsts) to a maximum of 10 (best).	Obtained at 1 minute of life
Neonatal Hemoglobin	Neonatal hemoglobin in g/dl at delivery	Drawn once from umbilical cord segment at birth
Composite Neonatal Morbidity (Defined by the Occurrence of One or More of 10 Neonatal Morbidities.	Neonatal morbidity composite, defined by the occurrence of one or more of the following neonatal morbidities: neonatal seizures (diagnosed by clinician), intraventricular hemorrhage (diagnosed by clinician on brain MRI or Ultrasound), hypoxic-ischemic encephalopathy (diagnosed by clinician), neonatal hypothermic therapy (brain cooling as documented on inpatient record, sepsis (diagnosed by blood culture), respiratory distress syndrome (diagnosed by clinician), hyperbilirubinemia requiring photo therapy (diagnosed by clinician), birth injury (diagnosed by clinician), or meconium aspiration syndrome (diagnosed by clinician), neonatal intensive care unit admission (documented in the inpatient record).	At birth
Neonatal Ferritin	Neonatal ferritin in ug/L at delivery	Drawn once from umbilical cord segment at birth

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Method Tuuli, MD, Indiana University

Publications and helpful links

General Publications

• American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 95: anemia in pregnancy. Obstet Gynecol. 2008 Jul;112(1):201-7. doi: 10.1097/AOG.0b013e3181809c0d. Erratum In: Obstet Gynecol. 2020 Jan;135(1):222.
• Pavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C; British Committee for Standards in Haematology. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2012 Mar;156(5):588-600. doi: 10.1111/j.1365-2141.2011.09012.x. Erratum In: Br J Haematol. 2012 Aug;158(4):559.
• Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD003094. doi: 10.1002/14651858.CD003094.pub3.
• Lewkowitz AK, Stout MJ, Cooke E, Deoni SC, D'Sa V, Rouse DJ, Carter EB, Tuuli MG. Intravenous versus Oral Iron for Iron-Deficiency Anemia in Pregnancy (IVIDA): A Randomized Controlled Trial. Am J Perinatol. 2022 Jun;39(8):808-815. doi: 10.1055/s-0041-1740003. Epub 2021 Nov 28.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2018
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: February 15, 2018
• First Posted (Actual): February 19, 2018

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: May 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Iron Deficiency Anemia of Pregnancy; oral iron supplementation; parenteral iron supplementation; maternal anemia
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Hematologic Diseases; Gastrointestinal Diseases; Nutrition Disorders; Intestinal Diseases; Anemia, Hypochromic; Iron Metabolism Disorders; Malnutrition; Anemia, Iron-Deficiency; Anemia; Malabsorption Syndromes; Deficiency Diseases; Iron Deficiencies; Anticoagulants; Hematinics; Plasma Substitutes; Blood Substitutes; Dextrans; Iron-Dextran Complex
• Other Study ID Numbers: 1809251633

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No