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

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposures: 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). Main Outcomes and Measures: 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. Results: 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). These associations were robust to adjustment for diffusion image quality, and prenatal burden was not associated with baseline image quality. In repeated-measures models across four imaging timepoints, higher APE burden was associated with steeper FA increases across adolescence (positive APE x Age interaction in 5 of 11 tracts; positive across all 11), though these trajectory effects were attenuated after adjustment for image quality. Post hoc analyses indicated that pregnancy complications and prenatal cannabis exposure were the most consistent contributors to these associations. White matter FA partially mediated the association between prenatal APE burden and involuntary emotional dysregulation, with no association with voluntary emotion regulation strategies. Conclusions and Relevance: Cumulative prenatal APE burden was associated with lower fronto-limbic white matter FA at the start of adolescence, an association that was stable across development and robust to image-quality adjustment. Evidence for altered developmental trajectories was more sensitive to image quality and should be interpreted cautiously. These findings identify fronto-limbic white matter-- particularly the uncinate fasciculus and corpus callosum-- as a candidate neurobiological correlate of cumulative prenatal adversity, while underscoring that this pathway reflects a bounded set of prenatal exposures.