Cumulative Prenatal Adversity and Fronto-Limbic White Matter Development Across Adolescence

The prenatal period is a critical window for intergenerational transmission of adversity, yet the neural substrates through which cumulative prenatal stress becomes biologically embedded in offspring brain development remain poorly understood. White matter microstructure is a candidate mechanism linking prenatal adversity to downstream emotional dysregulation.

To examine associations between cumulative adverse prenatal exposure (APE) burden and fronto-limbic white matter fractional anisotropy (FA) at baseline and across adolescent developmental trajectories, and to test whether white matter FA mediates prenatal APE effects on emotional dysregulation.

Cohort study using data from the Adolescent Brain Cognitive Development (ABCD) Study, Release 7.0, a diverse longitudinal cohort of US children recruited at ages 9 to 10 years across 21 sites. After diffusion tensor imaging quality control exclusions and retention of one twin or triplet per family, the final cross-sectional analytic sample comprised 10 483 participants. Longitudinal analyses included participants with data at one or more follow-up timepoints across four imaging waves.

Cumulative APE burden, operationalized as a sum of six binary adverse prenatal exposures (unplanned pregnancy; early alcohol, tobacco, and cannabis use before pregnancy recognition; complicated pregnancy; complicated birth; range, 0-6) following Zhi et al. (2026).

Fractional anisotropy in 11 a priori fronto-limbic white matter tracts at baseline (ages approximately 10 years) and across four imaging timepoints (ages approximately 10, 12, 14, and 16 years). Exploratory outcomes included Child Behavior Checklist (CBCL) dysregulation profile and Emotion Regulation Questionnaire (ERQ) subscales.

Higher prenatal APE burden was associated with lower baseline FA in left uncinate fasciculus (b = -0.00096; 95% CI, -0.00151 to -0.00042; FDR-corrected P = .006), corpus callosum (b = -0.00079; 95% CI, -0.00125 to -0.00032; FDR-corrected P = .006), and right uncinate fasciculus (b = -0.00071; 95% CI, -0.00120 to -0.00021; FDR-corrected P = .019). This association was stable across visits and robust to stringent adjustment for two complementary image-quality metrics (framewise displacement and frame censoring); prenatal burden was itself unassociated with image quality. Higher APE burden was additionally associated with steeper FA increases across adolescence (positive APE × Age interaction in 5 of 11 tracts); positive across all 11), these trajectory effects were more sensitive to image quality, though the right uncinate fasciculus association survived stringent adjustment. Post hoc analyses indicated that pregnancy complications and prenatal cannabis exposure were the most consistent contributors. White matter FA partially mediated the association between prenatal APE burden and involuntary emotional dysregulation, with no association with voluntary emotion regulation strategies.

Cumulative prenatal APE burden was associated with lower fronto-limbic white matter FA -particularly in the uncinate fasciculus and corpus callosum-an enduring association that was stable across adolescence and robust to rigorous image-quality adjustment. Evidence for altered developmental trajectories was more sensitive to image quality and should be interpreted as a more tentative, complementary finding. These findings identify fronto-limbic white matter as a candidate neurobiological correlate of cumulative prenatal adversity, while underscoring that this pathway reflects a bounded set of prenatal exposures.

Question: Is cumulative adverse prenatal exposure burden associated with fronto-limbic white matter microstructure across adolescence?Findings: In this cohort study of 10 483 adolescents from the ABCD Study, higher adverse prenatal exposure burden was associated with lower fractional anisotropy in bilateral uncinate fasciculus and corpus callosum -a stable association across adolescence that was robust to rigorous image-quality adjustment. Higher burden was additionally associated with steeper fractional anisotropy increases in 5 of 11 tracts, and white matter partially mediated associations with involuntary emotional dysregulation.Meaning: These findings identify fronto-limbic white matter microstructure as a candidate neurobiological correlate of cumulative prenatal adversity, consistent with early biological embedding through prenatal programming.