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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Iron Deficiency Anemia, Pregnancy

Intervention / Treatment
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* Drug: Ferric derisomaltose
* Drug: Ferrous sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV Iron<br>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<br>* 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.<br>* Other names: Monoferric;|
| Active Comparator: Oral Iron<br>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<br>* 325mg ferrous sulfate tablets (65 mg of elemental iron), 1 to 3 orally per day.<br>* Other names: Ferosul;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of peripartum blood transfusion | Maternal blood transfusion during delivery hospitalization and up to 7 days postpartum | Delivery to 7 days postpartum | 

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 | 
| 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 | 
| 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 |