Different prenatal substance exposures have distinct developmental impacts

Background Prenatal substance exposure (PSE) is linked to cognitive and behavioral deficits. Although animal models show that PSE timing, duration, and type differentially affect offspring outcomes, human studies often collapse exposure patterns. We examined associations between PSE patterns and neurobehavioral outcomes in two longitudinal infant cohorts. Among PSE infants, one subgroup experienced exposure during only the first and/or second trimesters with in utero PSE discontinuation (PSE-T1T2); another experienced sustained exposure across all three trimesters with discontinuation at birth (PSE-AllT). Methods In the primary cohort (n=175), multimodal data (rsfMRI, 0-12 months; neonatal diffusion MRI) were collected. In the replication cohort (n=140), neonatal rsfMRI data were collected. Behavioral outcomes included cognitive, language, and motor scores. Results Unexpectedly, rsfMRI revealed greater neonatal brain differences in PSE-T1T2 than PSE-AllT compared to substance-free controls, yet PSE-AllT showed worse 12-month behavioral outcomes. These patterns replicated in the replication cohort. Functional connectivity growth trajectories across the first year showed modest subgroup-specific differences. Multimodal analyses revealed converging patterns: distinct functional and structural connectivity profiles predicted poorer 12-month outcomes in PSE-AllT. Conclusions These findings demonstrate that PSE timing differentially affects neural and behavioral development. Sustained PSE was associated with adverse 12-month outcomes driven by pattern-specific brain disruption. Early cessation and exposure to fewer substances may confer behavioral benefits, but neural alterations in PSE-T1T2 warrant follow-up on long-term impacts. By moving beyond exposure-versus-no-exposure models to identify biologically meaningful PSE subtypes based on exposure timing, these findings provide mechanistic insight into how early-life exposures shape neurobehavioral development.