Clinical trial NCT05462704: Intravenous Versus Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy
Official title: Double-blind Placebo-controlled Multicenter Randomized Trial of Intravenous Versus Oral Iron for Treating Iron-Deficiency Anemia in Pregnancy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Iron Deficiency Anemia
Pregnancy
Lead sponsor: Women and Infants Hospital of Rhode Island
Sponsor class: OTHER
Collaborators: name: Hasbro Children's Hospital
name: University of Michigan
name: Washington University School of Medicine
name: University of Utah
name: University of Alabama at Birmingham
name: Oregon Health and Science University
name: GNP Research at Heme-on-Call
First posted: 2022-07-18
Enrollment: 300
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of maternal anemia (hgb<11mg/dL) at delivery
timeFrame: Within 24 hours of admission to inpatient obstetrics unit for delivery of infant
Secondary outcomes:
measure: Concentration of maternal hemoglobin at delivery
timeFrame: Within 24 hours of admission to inpatient obstetrics unit for delivery of infant
measure: Rate of maternal blood transfusion at delivery
timeFrame: Delivery to 7 days postpartum
measure: Concentration of maternal ferritin at delivery
timeFrame: Within 24 hours of admission to inpatient obstetrics unit for delivery of infant
measure: Concentration of maternal hemoglobin postpartum day 1
timeFrame: On day after participant delivered her infant; postpartum day 1
measure: Rate of cesarean delivery
timeFrame: Once at infant delivery
measure: Rate of severe infusion adverse events
timeFrame: 2 days after intravenous iron or placebo infusion
measure: Rate of mild medication adverse events
timeFrame: 4 weeks after initiation of oral iron or placebo
measure: Edinburgh Perinatal Depression Scale score
timeFrame: At randomization (baseline) and at 4-6 weeks postpartum
measure: Maternal EuroQol Group Quality-of-Life Questionnaire score
timeFrame: At 6 weeks postpartum by phone or in person
measure: Rate of Maternal infection
timeFrame: From initiation of treatment until 6 weeks postpartum
measure: Rate of Composite Maternal Complications
timeFrame: At 6 weeks postpartum
measure: Gestational age at delivery
timeFrame: At delivery
measure: Rate of preterm birth at less then 37 weeks
timeFrame: At delivery
measure: Rate of Neonatal Intensive Care Unit Admission
timeFrame: At birth through through 30 days from birth
measure: Neonatal birth weight
timeFrame: At birth
measure: Concentration of umbilical artery pH
timeFrame: At birth
measure: Concentration of umbilical artery bicarbonate
timeFrame: At birth
measure: Concentration of umbilical artery base excess
timeFrame: At birth
measure: Concentration of umbilical artery lactate
timeFrame: At birth
measure: Concentration of neonatal hemoglobin
timeFrame: At birth
measure: Concentration of neonatal ferritin
timeFrame: At birth
measure: Neonatal Apgar scores
timeFrame: At 1 minute and 5 minutes of life
measure: Rate of composite neonatal complication
timeFrame: Through 30 days from birth
measure: Concentration of child brain myelin
timeFrame: At an average of 6 months and 36 months
measure: Child Mullen Scale of Early Learning Score
timeFrame: At an average of 6 months and 36 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Medical Center
state: Alabama
city: Miami
country: United States
facility: GNP Research at Heme-on-Call
state: Florida
city: Ann Arbor
country: United States
facility: Michigan University Medical Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University Medical Center
state: Missouri
city: Portland
country: United States
facility: Oregon Health and Sciences Uiversity Medical Center
state: Oregon
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Providence
country: United States
facility: Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
Study officials:
affiliation: Women and Infants Hospital of Rhode Island
name: Methodius Tuuli, MD, MPH, MBA
role: PRINCIPAL_INVESTIGATOR
References: