Antenatal Opioid Exposure and Cerebral Cortical Maturation in Newborns

Importance: Antenatal opioid exposure is associated with adverse neurodevelopmental outcomes and smaller brain volumes, but the effects of opioids on newborn cortical folding maturation have not been defined. The Advancing Clinical Trials in Neonatal Opioid Withdrawal Outcomes of Babies With Opioid Exposure (OBOE) Study is a multisite prospective longitudinal cohort study examining the association of antenatal opioid exposure with brain maturation and outcomes in newborns. Objective: To compare cerebral cortical folding in newborns exposed to opioids vs nonexposed controls. Design, Setting, and Participants: In this cohort study, full-term newborns from the OBOE study with antenatal opioid exposure and nonexposed controls were recruited at 4 US sites, including obstetric clinics, maternal substance use treatment programs, and birth hospitals, from August 5, 2020, to December 28, 2023. Data analysis was performed from August 19, 2020, to March 25, 2026. Exposure: Newborn opioid exposure, including opioid-only and polysubstance exposure as well as exposure to specific opioids. Main Outcomes and Measures: Nonsedated T2-weighted magnetic resonance imaging (MRI) data were acquired via harmonized protocols, and 3D brain images were segmented and parcellated using the Developing Brain Region Annotation With Expectation-Maximization pipeline. The inner cortical gray matter surface was used to measure cortical folding across the frontal, parietal, temporal, and occipital lobes. Group differences between opioid-exposed and nonexposed newborns were compared via analysis of covariance, adjusting for postmenstrual age at MRI, sex, birth weight, maternal age, smoking status, and education level. Results: A total of 259 newborns (mean [SD] gestational age at birth, 39.1 [1.0] weeks; 145 [56.0%] male) were included in the analysis, of whom 164 had antenatal exposure to opioids and 95 were nonexposed controls (mean [SD] postmenstrual age at MRI, 42.8 [2.2] and 42.9 [2.0] weeks, respectively). Compared with nonexposed controls, newborns who had been exposed to opioids had significantly decreased sulcal depth in the frontal (difference, -0.11 mm [95% CI, -0.20 to -0.02 mm]), parietal (difference, -0.19 mm [95% CI, -0.31 to -0.07 mm]), and global (difference, -0.09 mm [95% CI, -0.18 to -0.01 mm]) regions, as well as decreased surface area in the frontal (difference, -1048 mm2 [95% CI, -1497 to -598 mm2]), parietal (difference, -501 mm2 [95% CI, -834 to -168 mm2]), temporal (difference, -422 mm2 [95% CI, -682 to -162 mm2]), occipital (difference, -232 mm2 [95% CI, -439 to -26 mm2]), and global (difference, -2185 mm2 [95% CI, -3327 to -1043 mm2]) surfaces. Compared with controls, newborns exposed to methadone showed larger reductions in frontal, parietal, and global surface areas than those exposed to buprenorphine, with parietal surface area significantly reduced only in the methadone-exposed group (difference, -656 mm2 [95% CI, -1111 to -202 mm2]). Newborns with polysubstance exposure had significantly reduced sulcal depth in the frontal, parietal, and global surfaces, as well as reduced surface area across all lobes compared with controls, whereas opioid-only exposed newborns showed fewer significant differences from controls, with reduced parietal sulcal depth and decreased frontal and global surface areas. Conclusions and Relevance: In this cohort study, newborns with antenatal exposure to opioids had reduced cerebral cortical sulcal depth and surface area compared with nonexposed controls, with greater reductions among newborns exposed to methadone compared with those exposed to buprenorphine, and in newborns with polysubstance exposure compared with those with opioid exposure only. Ongoing serial MRI and long-term follow-up are under way to assess the impact of these early cortical maturational differences on later neurodevelopment and behavior.