Iron Depletion in the Substantia Nigra of Children With Prenatal Alcohol Exposure.

Prenatal alcohol exposure (PAE) occurs in 10%-60% of pregnancies and can contribute to fetal alcohol spectrum disorders (FASD). FASD presents with diverse cognitive, behavioral, and motor impairments. Animal studies suggest PAE disrupts fetal iron homeostasis, but direct evidence in the human brain is lacking. Because iron is essential for neurodevelopmental processes including myelination, neurotransmitter synthesis, and energy metabolism, perturbations in iron deposition may represent a modifiable mechanism linking PAE to adverse outcomes. The aim of this study was to explore whether PAE is associated with brain iron levels at age 7 years, assessed using quantitative susceptibility mapping MRI. Children were recruited from the Asking Questions about Alcohol in Pregnancy (AQUA) prospective longitudinal cohort. Participants were categorized as unexposed (no PAE, n = 5), exposed in the first trimester only (PAE T1, n = 14), or exposed across the first to third trimester (PAE T1-3, n = 6). Quantitative susceptibility mapping (QSM), an MRI modality sensitive to iron, was used to estimate regional brain iron across 38 cortical and subcortical regions. Linear models assessed the effects of alcohol exposure and timing of exposure on brain iron, adjusting for age and sex. Compared with unexposed children, those with any PAE had significantly lower QSM in the substantia nigra (β = -18.93, p = 0.011). Stratified analyses revealed that substantia nigra QSM was lower even after first-trimester-restricted exposure (T1 β = -22.63 95% CI [-37.35, -7.91]; p = 0.004). Cortical analyses showed regionally variable alterations, with reductions in the superior parietal cortex (β = -1.33, p = 0.011), insula (β = -1.33, p = 0.051), and pars opercularis (β = -0.926, p = 0.078), and elevations in the postcentral gyrus (β = 2.82, p = 0.003) in those with any PAE compared with unexposed. PAE is associated with region-specific disruptions in brain iron, inferred by QSM, with early exposure particularly affecting the substantia nigra and extended exposure linked to broader cortical and subcortical changes. These exploratory findings provide the first evidence in humans that PAE alters brain iron homeostasis, highlighting iron metabolism as a potentially modifiable pathway contributing to the neurodevelopmental burden of FASD.