682 - White Matter Development Following Maternal Iron Supplementation: A Diffusion MRI Study of Intravenous versus Oral Iron

Publication Number: 2665.682

Douglas Dean, University of Wisconsin–Madison, Madison, WI, United States; Virupaxi V. Hattiholi, KAHER University Jawaharlal Nehru Medical College, Belagavi, Karnataka, India; Mahesh Kamate, J N Medical College, Belagavi, Karnataka, India; Moriah E. Thomason, Hassenfeld Children's Hospital at NYU Langone, New York, NY, United States; Kiran S. Talekar, Sidney Kimmel Medical College at Thomas Jefferson University, Media, PA, United States; Anmol Patted, Thomas Jefferson University, Philadelphia, PA, United States; Simal Thind, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States; Jesse Bradford-Rogers, Thomas Jefferson University, Philadelphia, PA, United States; Danielle DeSantis, Sidney Kimmel Medical College at Thomas Jefferson University, Point Pleasant Boro, NJ, United States; Umesh s. Charantimath, J N Medical College, KAHER, Belagavi, Karnataka, India; Manjunath S. Somannavar, J N Medical College, KLE Academy of Higher Education and Research Belagavi, Belagavi, Karnataka, India; S Yogeshkumar, Jawaharlal Nehru Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University)), Belagavi, Karnataka, India; Rebecca Hartman, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States; Benjamin E. Leiby, Thomas Jefferson University, Philadelphia, PA, United States; Roopa M. Bellad, Jawaharal Nehru Medical college,KL E Academy of Higher Education & Reserach ,Belagavi, Belagavi, Karnataka, India; Zubair Aghai, Nemours Children's Hospital, Philadelphia, PA, United States; Michael K. Georgieff, University of Minnesota, Saint Paul, MN, United States; Shivaprasad S. Goudar, J N Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University) Belgaum, Belgaum, Karnataka, India; Mrutyunjaya B. Bellad, KAHER's J N medical College Belagavi, Belagavi, Karnataka, India; Richard Derman, Sidney Kimmel Medical College at Thomas Jefferson University, Greenville, DE, United States

Background: Iron is essential for normal brain development, while iron deficiency (ID) can result in persistent neurodevelopmental deficits. White matter is particularly sensitive to iron availability, as iron is required for oligodendrocyte function and myelin lipid synthesis. While maternal iron supplementation during pregnancy is standard practice, optimal formulation and dosing strategies remain uncertain, and whether different supplementation approaches differentially impact offspring brain development is largely unexplored.

Objective: We examined the effects of iron supplementation strategies on early postnatal white matter development using diffusion MRI (dMRI).

Design/Methods: Participants were recruited from the RAPIDIRON and RAPIDIRON-KIDS trials. Participants were randomized to 1 of 3 trial arms at 14 weeks gestation: two different single dose 1 gram Fe IV iron formulations (IV-A, IV-B) or an 60 mg BID oral iron control through pregnancy. MRI scans were performed at 4 and 12 months of age during natural, non-sedated sleep. Diffusion MRI were acquired and fit to the DTI model. White matter regions were compared across the three treatment groups using the non-parametric Kruskal-Wallis test. Post-hoc pairwise comparisons were performed when significant differences were observed. Longitudinal linear mixed effects models were used to compare developmental trajectories between the three groups.

Results: Fig. 1 shows a representative axial slice of structural T1w, T2w, and FA map from a single subject, highlighting overall high image quality. At 4 months, an overall difference in MD and RD was observed across groups, with the IV-A group having lower values in the right and left thalamic radiations (Fig. 2). Across white matter regions, FA was observed to significantly increase with age, while MD and RD decreased. FA trajectories from the superior longitudinal fasciculus and anterior limb of the internal capsule were observed to differ between the groups, with IV-A having a greater rate of development (Fig. 3).

Conclusion(s): Our results indicate that iron supplementation during pregnancy impacts postnatal white matter development in offspring. The finding that one IV iron formulation conferred advantages over alternatives may suggest underlying pharmacokinetic differences-including maternal absorption, placental transfer efficiency, and sustained iron availability. Follow-up neurodevelopmental assessments is essential to determine whether neuroimaging biomarkers predict functional outcomes and to establish optimal iron supplementation strategies for supporting healthy brain development in at-risk populations.

Figure 1
Representative axial slices of T1-weighted, T2-weighted and DTI FA map at 4 (top) and 12 (bottom) month child.

Figure 2: Comparisons of MD (left) and RD (right) across three trial arms at 4 months.
MD and RD were observed to be significantly lower in the IV-A group, compared to IV-B and oral iron groups.

Figure 3: Age related changes of FA at 4 and 12 months of age.
Using longitudinal linear mixed effects models, we observed a significant group effect such that FA of the superior longitudinal fasciculus and anterior limb of the internal capsule showed a greater rate of development in IV-A.