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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intravenous iron dextran infusion | Experimental | 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 |
|
| Oral ferrous sulfate supplementation | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Iron dextran | Drug | Single intravenous infusion of iron dextran 1000mg. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maternal Anemia at Delivery | Number of participants with maternal hemoglobin <11g/dl at delivery | At delivery |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
Patients must be pregnant in order to participate
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| Name | Affiliation | Role |
|---|---|---|
| Method Tuuli, MD | Indiana University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Indiana University School of Medicine | Indianapolis | Indiana | 46202 | United States | ||
| Center for Outpatient Health, Washington University in St. Louis |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18591330 | Background | 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. | |
| 22512001 | Background | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 Iron dextran: Single intravenous infusion of iron dextran 1000mg. |
| FG001 | 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. Ferrous sulfate 325mg: Oral iron supplementation with ferrous sulfate 325mg one to three times daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 Iron dextran: Single intravenous infusion of iron dextran 1000mg. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maternal Anemia at Delivery | Number of participants with maternal hemoglobin <11g/dl at delivery | Posted | Count of Participants | Participants | At delivery |
|
2 - 3 days after the single intravenous iron infusion or initiation of oral iron
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 Iron dextran: Single intravenous infusion of iron dextran 1000mg. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Methodius Tuuli | Brown University | 401-430-1575 | MTuuli@wihri.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 18, 2019 | Mar 6, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 27, 2018 | Mar 6, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D007505 | Iron-Dextran Complex |
| C020748 | ferrous sulfate |
| ID | Term |
|---|---|
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D003911 | Dextrans |
| D005936 | Glucans |
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All participants at less than 28 weeks gestation will have an anemia evaluation and work up per standard prenatal care. Those who meet a clinical diagnosis of iron-deficiency anemia will initiate oral iron and have their Complete Blood Count rechecked between 24 and 28 weeks gestation. If their hemoglobin is less than 10 mg/dL, they will be randomized to either continue their oral iron supplementation or receive a single intravenous dextran iron transfusion. If the patient is enrolled after 28 weeks and receives a diagnosis of iron deficiency anemia, she will be randomized at that time.
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The research team will be blinded to the patients' treatment arm. A team of resident physicians who are unfamiliar with the study aims will provide standard obstetric care to all participants.
| Ferrous sulfate 325mg | Drug | Oral iron supplementation with ferrous sulfate 325mg one to three times daily |
|
|
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 |
| St Louis |
| Missouri |
| 63110 |
| United States |
| 21975735 | Background | Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2011 Oct 5;2011(10):CD003094. doi: 10.1002/14651858.CD003094.pub3. |
| 34839481 | Derived | 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. |
| BG001 | 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. Ferrous sulfate 325mg: Oral iron supplementation with ferrous sulfate 325mg one to three times daily |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Chronic hypertension | Count of Participants | Participants |
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| Prepregnancy diabetes | Count of Participants | Participants |
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| Nulliparous | Patients having first birth | Count of Participants | Participants |
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| Prior preterm birth (<37 weeks' gestation) | Count of Participants | Participants |
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| Secondary | Maternal Hemoglobin at Delivery | Maternal hemoglobin on admission to inpatient obstetrics unit for delivery | Posted | Mean | Standard Deviation | g/dL | On admission to inpatient obstetrics unit for delivery |
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| Secondary | 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 | Posted | Count of Participants | Participants | 2 - 3 days after single intravenous iron infusion or initiation of oral iron |
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| Secondary | Maternal Hemoglobin Below 10g/dl at Delivery | Number of participants with hemoglobin below 10g/dl at delivery | Posted | Count of Participants | Participants | At delivery |
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| Secondary | Maternal Ferritin at Delivery | Maternal serum ferritin level in μg/L at delivery | Posted | Mean | Standard Deviation | μg/L | At delivery |
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| Secondary | 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. | Posted | Count of Participants | Participants | During inpatient admission for delivery of neonate |
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| Secondary | Mode of Delivery | Whether infant was delivered vaginally or via cesarean section | Posted | Count of Participants | Participants | Once, at infant delivery |
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| Secondary | Gestational Age at Delivery | Gestational age in weeks at delivery | Posted | Mean | Standard Deviation | weeks | Once, at infant delivery |
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| Secondary | Birth Weight | Neonatal weight at delivery | Posted | Mean | Standard Deviation | grams | Obtained once, at infant delivery |
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| Secondary | Umbilical Cord Arterial pH | Umbilical cord arterial pH obtained at delivery | Posted | Mean | Standard Deviation | Unitless | Drawn once from umbilical cord segment at delivery |
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| Secondary | 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). | Posted | Median | Inter-Quartile Range | score on a scale | Obtained at 1 minute of life |
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| Secondary | Neonatal Hemoglobin | Neonatal hemoglobin in g/dl at delivery | Posted | Mean | Standard Deviation | g/dL | Drawn once from umbilical cord segment at birth |
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| Secondary | 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). | Posted | Count of Participants | Participants | At birth |
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| Secondary | Neonatal Ferritin | Neonatal ferritin in ug/L at delivery | Posted | Mean | Standard Deviation | ug/L | Drawn once from umbilical cord segment at birth |
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| 0 |
| 10 |
| 0 |
| 10 |
| 3 |
| 10 |
| EG001 | 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. Ferrous sulfate 325mg: Oral iron supplementation with ferrous sulfate 325mg one to three times daily | 0 | 13 | 0 | 13 | 3 | 13 |
| Nausea/vomiting | Gastrointestinal disorders | Systematic Assessment |
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| D011134 |
| Polysaccharides |
| D002241 | Carbohydrates |