Association of Adverse Prenatal Exposure Burden with Persistent Psychopathology and Accelerated Cortical Thinning in Youth

ABSTRACT Importance Adverse prenatal exposures (APEs) often co-occur and independently associate with risk for childhood psychopathology. Whether exposure to multiple APEs associates with persistent clinical effects through adolescence or underlying changes in brain maturation remains uncertain. Objective To evaluate longitudinal associations among cumulative APE burden, risk for psychopathology, and age-related cortical thinning in adolescents. Design, Setting, and Participants This cohort study analyzed 4-year follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study, which enrolled 11,868 youth aged 9 to 10 years beginning in 2016. Sibling-comparison analysis was performed on 414 non-adopted sibling pairs with discordant APEs. Statistical analysis occurred from March to June 2025. Exposures Cumulative APE burden was calculated by summing six binary prenatal exposures that independently associated with psychopathology at baseline: unplanned pregnancy; early maternal prenatal alcohol, tobacco, or marijuana use; complicated pregnancy; and complicated birth. Main Outcomes and Measures Outcomes included annual Child Behavior Checklist (CBCL) scores of dimensional psychopathology, using both continuous and thresholded outcomes; and biennial cortical thickness measures from structural magnetic resonance imaging, analyzed using linear mixed-effects models. Results Of 8,515 singleton children (4,055 females [47.6%]), 78% were exposed to at least one APE. Multiple APEs persistently and dose-dependently associated with increased odds of clinically significant psychopathology (CBCL total problems: odds ratio=2.01-6.75; corrected P=.0065-1.31×10 -13 ). Associations of APEs with attention-deficit/hyperactivity disorder symptoms attenuated over time (interaction: F=13.51; corrected P=7.13×10 -8 ), while those with depressive symptoms potentiated (interaction: F=5.82; corrected P=.0019). Greater APE burden associated with accelerated age-related cortical thinning in 36 of 68 cortical regions (interactions: F=3.26–8.89; corrected P’s=0.039-4.86×10 -4 ). Siblings with more exposures demonstrated persistently higher CBCL total problems (T=2.25; P=0.025) and accelerated cortical thinning (interactions: T=-3.00–-2.10; P’s<.05) in 5 of the 36 regions implicated in the larger sample. Conclusions and Relevance Multiple prenatal adversities associated with altered developmental trajectories of psychopathology and cortical maturation into mid-adolescence. These findings highlight the importance of fetal programming to mental health across life course, and the need for additional study of risk and resiliency-conferring factors in utero. Key Points Question Is adverse prenatal exposure (APE) burden associated with long-term changes in psychopathology and underlying cortical maturation trajectories in children? Findings In this 4-year follow-up cohort study of 8,515 singleton children in the ABCD Study, exposure to multiple APEs associated with persistent, dose-dependent increases in the risk of clinically significant psychopathology and diffuse acceleration in age-associated cortical thinning during adolescence. Findings were further supported by within-family comparisons in 414 sibling pairs discordant for APEs. Meaning These findings associate multiple prenatal adversities with enduring and developmentally dynamic effects on both cortical development and mental health in adolescence. The results emphasize the need for early identification, longitudinal monitoring, and neurodevelopmentally informed prevention strategies for at-risk youth.