Neuroimaging Ancillary Study

Neuroimaging Ancillary Study of the IV Iron RAPIDIRON Trial

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.

Study Overview

• Status: Completed
• Conditions: Iron Deficiency Anemia; Child Development; Iron Deficiency Anemia of Pregnancy; Iron Deficiency Anemia Treatment; Neurodevelopmental Disorder of Foetus; Fetal Neurodevelopmental Disorder
• Intervention / Treatment: Drug: Ferric carboxymaltose; Drug: Iron isomaltoside; Drug: Ferric Sulfate

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 184

Contacts and Locations

Study Locations

• India
  • Karnataka
    • Belgaum, Karnataka, India
      • Jawaharlal Nehru Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

For this ancillary study, only infants of randomized RAPIDIRON Trial (NCT05358509) participants recruited in Karnataka State will be eligible for participation.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
RAPIDIRON IV iron intervention arm 1; 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; 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.
RAPIDIRON IV iron intervention arm 2; 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; 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.; Other Names: Ferric derisomaltose
RAPIDIRON active comparator arm; 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; 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.; Other Names: Ferric sulphate

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Child auditory brain response (ABR) results	Results on auditory brain response test	Birth - 4 months of age
Hair cortisol results	Results from hair cortisol testing	Birth
Maternal depression	Maternal depression, measured via the Edinburgh Post-Natal Depression Scale	Measured from 32-35 weeks fetal gestational age - 24 months offspring age
Maternal anxiety	Maternal anxiety, measured via State-Trait Anxiety Inventory	Measured from 32-35 weeks fetal gestational age - 24 months offspring age
Maternal Perceived Stress	Maternal Perceived Stress, measured via the Perceived Stress Scale (PSS-10)	Measured from 32-35 weeks fetal gestational age - 24 months offspring age
Maternal Empowerment	Maternal empowerment, measured via the SWPER Global Survey	Measured from 32-35 weeks fetal gestational age - 24 months offspring age
Breastmilk micronutrient analysis	Breastmilk micronutrient analysis, measured via maternal breastmilk samples	4 months offspring age
Maternal iron status	Maternal iron status, measured via hemoglobin, ferritin and TSAT	32 - 35 weeks fetal gestational age

Collaborators and Investigators

• Sponsor: Thomas Jefferson University
• Collaborators: Jawaharlal Nehru Medical College
• Investigators: Principal Investigator: Richard Derman, MD, MPH, Thomas Jefferson University

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2023
• Primary Completion (Actual): February 14, 2024
• Study Completion (Actual): April 7, 2025

Study Registration Dates

• First Submitted: September 14, 2022
• First Submitted That Met QC Criteria: September 14, 2022
• First Posted (Actual): September 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 16, 2025
• Last Update Submitted That Met QC Criteria: April 11, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: MRI; Pediatrics; Neuroimaging; India; Intravenous iron
• Additional Relevant MeSH Terms: Urogenital Diseases; Mental Disorders; Nutrition Disorders; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Pregnancy Complications; Hematologic Diseases; Iron Metabolism Disorders; Anemia, Hypochromic; Malnutrition; Iron Deficiencies; Neurodevelopmental Disorders; Anemia; Anemia, Iron-Deficiency; Deficiency Diseases; Fetal Diseases; Hematinics; Ferric Compounds; Iron isomaltoside 1000
• Other Study ID Numbers: U32401

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No