Neuroimaging Ancillary Study

Study Overview
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Brief Summary
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As a follow-up to the RAPIDIRON Trial (NCT05358509), and in combination with the RAPIDIRON-KIDS Study (NCT05504863), this study will involve infants of RAPIDIRON Trial participants recruited at one site in Karnataka and is designed to implement a magnetic resonance imaging (MRI) protocol and incorporate neuroimaging measures. Implementation of this study will promote an understanding of the effects on fetal and neonatal brain development, including iron deposition in brain tissues, when a woman is treated for iron deficiency anemia (IDA) by either (a) providing her oral iron tablets and instructions for use; or (b) administering a single-dose IV iron infusion for the treatment of IDA during pregnancy.

Detailed Description
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The hypothesis of this study is as follows: Reduced iron availability through fetal development impacts fundamental early neurodevelopmental processes, including neurogenesis of the hippocampus, amygdala, and other 'core' deep brain basal ganglia regions (e.g., globus pallidus); and myelination of the brain's white matter connecting these deep brain structures and higher-order cortical regions involved in motor, memory, and executive functioning. The specific aims of this Neuroimaging Ancillary Study are: To determine impact of the IV iron intervention compared to oral iron on specific markers of brain development; and As a secondary analysis, to explore whether infant sex acts as a moderator of treatment on these specific brain development markers. This study will recruit pregnant mothers currently participating in the parent RAPIDIRON Trial, who will be approached to give consent for themselves and their offspring for participation in this Neuroimaging Ancillary Study. Participation in this Ancillary Study will involve assessments at 32-35 weeks fetal gestational age, birth, 4 months, 12 months, and 24 months post-delivery. This will involve a fetal MRI and three post-birth MRIs conducted with the offspring to collect the main neuroimaging measures. In addition, we will collect various secondary offspring and maternal measures including child auditory brain response; maternal depression, anxiety, perceived stress, and empowerment; hair cortisol; and breastmilk micronutrient analysis. Please see the protocol for additional details.

Official Title
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Neuroimaging Ancillary Study of the IV Iron RAPIDIRON Trial

Conditions
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Iron Deficiency Anemia, Iron Deficiency Anemia of Pregnancy, Neurodevelopmental Disorder of Foetus, Iron Deficiency Anemia Treatment, Fetal Neurodevelopmental Disorder, Child Development

Intervention / Treatment
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* Drug: Ferric carboxymaltose
* Drug: Iron isomaltoside
* Drug: Ferric Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For the maternal participant in the parent RAPIDIRON Trial - a pregnancy that has not gone beyond the period for obtaining a fetal MRI (by scanning the mother at 32-35 weeks fetal gestational age) An indication of the pregnant woman's intent to deliver in the study area and to reside there so as to be available not only to complete RAPIDIRON participation but also to allow her and her offspring to participate in ancillary study visits; Informed consent of the pregnant RAPIDIRON participant for her participation and that of her offspring in this ancillary trial; and Concurrent participation in the RAPIDIRON-KIDS follow-up study (NCT05504863). Exclusion Criteria: If a fetal brain anomaly is found when the maternal participant undergoes an MRI at 32-35 weeks fetal gestational age, the dyad would be excluded from the ancillary study; If any of the following occur, this would result in dyad ineligibility for participation or continued participation in this ancillary study: maternal blood transfusion after enrollment, a pregnancy ending in stillbirth, neonatal death, diagnosis in the offspring of moderate to severe hypoxic-ischemic encephalopathy (or HIE), and/or blood transfusion to the offspring.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| RAPIDIRON IV iron intervention arm 1<br>Maternal participants in this arm were given a single dose of an IV iron formulation - ferric carboxymaltose - during pregnancy as part of their participation in the parent RAPIDIRON Trial. Participants weighing 50kg and over received a single dose having 1000mg of iron, with others receiving a lower dose as determined by a formula used by the manufacturer (20mg iron/kg body weight). This was given between 14 and 17 weeks fetal gestational age. | Drug: Ferric carboxymaltose<br>* As part of the RAPIDIRON Trial, maternal participants randomized to intervention arm 1 were given a single dose of ferric carboxymaltose between 14 and 17 weeks of pregnancy.<br>|
| RAPIDIRON IV iron intervention arm 2<br>Maternal participants in this arm were given a single dose of an IV iron formulation - iron isomaltoside - during pregnancy as part of their participation in the parent RAPIDIRON Trial. Participants weighing 50kg and over received a single dose having 1000mg of iron, with others receiving a lower dose as determined by a formula used by the manufacturer (20mg iron/kg body weight). This was given between 14 and 17 weeks fetal gestational age. | Drug: Iron isomaltoside<br>* As part of the RAPIDIRON Trial, maternal participants randomized to intervention arm 2 were given a single dose of iron isomaltoside between 14 and 17 weeks of pregnancy.<br>* Other names: Ferric derisomaltose;|
| RAPIDIRON active comparator arm<br>Maternal participants in this arm of the RAPIDIRON Trial were given ferrous sulfate tablets with 60mg elemental iron each and instructed to take two per day (one in the morning and one at night) throughout their pregnancy. | Drug: Ferric Sulfate<br>* As part of the RAPIDIRON Trial, maternal participants randomized to the active comparator arm were given 200 ferrous sulfate tablets immediately after randomization ( 12 weeks of pregnancy). Participants were instructed to take two tablets a day, with each tablet containing 60mg elemental iron.<br>* Other names: Ferric sulphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal hippocampal volume | Fetal hippocampus volume, measured via fetal MRI | 32-35 weeks fetal gestational age | 
| Fetal diffusion parameters: fractional anisotropy (FA) | Fetal white matter microstructure will be measured via FA at the posterior limb of internal capsule using fetal MRI | 32-35 weeks fetal gestational age | 
| Fetal diffusion parameters: mean diffusivity | Fetal white matter microstructure will be measured via MD at the posterior limb of internal capsule using fetal MRI | 32-35 weeks fetal gestational age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal sub-cortical gray matter structures | Fetal sub-cortical gray matter structures in the brain using fetal MRI | 32-35 weeks fetal gestational age | 
| Fetal white matter microstructure measures | Additional fetal white matter microstructure measures using fetal MRI, including qualitative T2 MRI measures and NODDI metrics | 32-35 weeks fetal gestational age | 
| Child hippocampal volume | Child hippocampal volume, measured via MRI | 4 - 24 months of age | 
| Child white matter volume | Child white matter volume, measured via MRI | 4 - 24 months of age | 
| Child white matter microstructure | Child white matter microstructure, including myelination, fiber coherence, and architecture, measured via MRI | 4 - 24 months of age | 
| Child white matter connectivity | Child white matter connectivity, measured via MRI | 4 - 24 months of age | 
| Child functional connectivity | Child functional connectivity, measured via MRI | 4 - 24 months of age | 
| Child cerebral metabolism | Child cerebral metabolism, including perfusion and spectroscopy, measured via MRI | 4 - 24 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroimaging, Intravenous iron, MRI, Pediatrics, India