Prenatal exposure to hypertensive disorders and adolescent brain white matter development

Hypertensive disorders of pregnancy (HDP) are associated with altered in utero neurodevelopment, yet long-term impact on adolescent white matter architecture remains unclear, particularly by HDP subtype and sex. While preeclampsia/eclampsia (P/E) is clinically more severe, pregnancy-related hypertension (PR-HTN) may involve longer in-utero exposure to hemodynamic stress. This study examined how distinct HDP exposures influence longitudinal white matter measures in adolescents.

Using a longitudinal cohort with two MRI timepoints (baseline ages 9-11 years; 2-year follow-up ages 11-13.8 years), we modeled fiber volume (FV) and fractional anisotropy (FA) using linear mixed-effects models. Analyses were sex-stratified and adjusted for prenatal exposures, maternal age, race/ethnicity, and income. False discovery rate (FDR) correction was applied.

In female adolescents, PR-HTN was significantly associated with lower FV across bilateral association, projection, and limbic pathways, alongside reduced FV and FA in the corpus callosum and forceps major/minor (q < 0.05). Conversely, P/E exposure showed no FDR-significant associations. No significant associations were observed in males for either HDP subtype.

Chronic in-utero exposure to PR-HTN, rather than acute P/E, is associated with widespread reductions in white matter structural integrity in females. These findings support subtype-specific and developmentally sensitive associations between HDP exposure and offspring brain development.

This study demonstrates that pregnancy-related hypertension, a traditionally "milder" disorder, has more pronounced long-term impacts on adolescent white matter scaffolding than preeclampsia/eclampsia. The results highlight a female-specific vulnerability to chronic prenatal hypertensive stress, manifesting as reduced volumetric and microstructural integrity in critical commissural and association white matter tracts. These findings shift the clinical focus toward the neurodevelopmental risks of chronic gestational hypertension, suggesting that maternal cardiovascular health throughout the entire pregnancy is a vital determinant of offspring brain development.