Intravenous Versus Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy

Pregnancy Clinical Trial

— IVIDA2  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05462704
• Other study ID #: Pro00060930
• Status: Recruiting
• Phase: Phase 3
• Start date: January 17, 2023
• Est. completion date: March 30, 2027

Study information

• Verified date: December 2023
• Source: Women and Infants Hospital of Rhode Island
• Contact: Crystal Ware, BSN, CCRP
• Phone: 401-274-1122
• Email: cware[@]wihri.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 13 - 30 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.

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=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 13 - 30 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 746
• Est. completion date: March 30, 2027
• Est. primary completion date: March 30, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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 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

Related Conditions & MeSH terms

• Anemia
• Anemia, Iron-Deficiency
• Deficiency Diseases
• Iron Deficiency Anemia
• Pregnancy

Intervention

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.
• Ferrous sulfate
325mg ferrous sulfate tablets (65 mg of elemental iron), 1 to 3 orally per day.

Locations

Country	Name	City	State
United States	Michigan University Medical Center	Ann Arbor	Michigan
United States	Hasbro Children's Hospital	Providence	Rhode Island
United States	Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	Washington University Medical Center	Saint Louis	Missouri

Sponsors (4)

Lead Sponsor	Collaborator
Women and Infants Hospital of Rhode Island	Hasbro Children's Hospital, University of Michigan, Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of peripartum blood transfusion	Maternal blood transfusion during delivery hospitalization and up to 7 days postpartum	Delivery to 7 days postpartum
Secondary	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
Secondary	Rate of maternal anemia presence 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	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
Secondary	Concentration of maternal hemoglobin postpartum day 1	Maternal hemoglobin on postpartum day 1	On day after participant delivered her infant; postpartum day 1
Secondary	Rate of cesarean delivery	Cesarean delivery for any indication in patients without prior cesarean deliveries	Once at infant delivery
Secondary	Rate of severe infusion adverse events	Safety and tolerability	2 days after intravenous iron or placebo infusion
Secondary	Rate of mild medication adverse events	Safety and tolerability	4 weeks after initiation of oral iron or placebo
Secondary	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
Secondary	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
Secondary	Rate of Maternal infection	Any infection diagnosed from initiation of treatment until 6 weeks postpartum	From initiation of treatment until 6 weeks postpartum
Secondary	Rate of Composite Maternal Complications	Maternal mortality or any one of several maternal morbidities	At 6 weeks postpartum
Secondary	Gestational age at delivery	Gestational age at delivery	At delivery
Secondary	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
Secondary	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
Secondary	Neonatal birth weight	Infant birth weight	At birth
Secondary	Concentration of umbilical artery pH	Concentration of umbilical artery pH from umbilical cord gases from infant umbilical cord segment at birth	At birth
Secondary	Concentration of umbilical artery bicarbonate	Concentration of umbilical artery bicarbonate from umbilical cord gases from infant umbilical cord segment at birth	At birth
Secondary	Concentration of umbilical artery base excess	Concentration of base excess from umbilical cord gases from infant umbilical cord segment at birth	At birth
Secondary	Concentration of umbilical artery lactate	Concentration of umbilical artery lactate from umbilical cord gases from infant umbilical cord segment at birth	At birth
Secondary	Concentration of neonatal hemoglobin	Concentration of neonatal hemoglobin from umbilical cord blood at birth or first neonatal complete blood count	At birth
Secondary	Concentration of neonatal ferritin	Concentration of neonatal ferritin from umbilical cord blood at birth or first neonatal blood draw	At birth
Secondary	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
Secondary	Rate of composite neonatal complication	Neonatal mortality or any one of several neonatal morbidities	Through 30 days from birth
Secondary	Concentration of child brain myelin	Concentration of infant brain myelin from magnetic resonance imaging	At an average of 6 months and 36 months
Secondary	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