Antenatal Opioid Exposure and Global and Regional Brain Volumes in Newborns
Authors: Yao Wu, Stephanie L. Merhar, Carla M. Bann, Jamie E. Newman, Kushal Kapse, Josepheen De Asis-Cruz, Nicole Mack, Sara B. De Mauro, Namasivayam Ambalavanan, Jonathan M. Davis, Scott A. Lorch, Deanne Wilson-Costello, Brenda B. Poindexter, Myriam Peralta-Carcelen, Catherine Limperopoulos
Journal: JAMA Pediatrics (2025)

Importance Although antenatal opioid exposure is associated with impaired brain growth, previous studies are limited by small sample sizes and lack of controls. As a result, the impacts of opioid exposure on the developing brain remain poorly understood. Objective To compare global, regional, and tissue-specific brain volumes in opioid-exposed newborns vs unexposed controls. Design, Setting, and Participants In the OBOE (Outcomes of Babies with Opioid Exposure) study, term newborns with antenatal opioid exposure and unexposed controls were recruited at 4 sites in the US from August 2020 to December 2023. Data analysis was performed from August 2020 to December 2024. Main Outcomes and Measures The primary outcome was brain volumes in both groups, assessed via unsedated 3-dimensional (3-D) volumetric magnetic resonance imaging (MRI) in opioid-exposed and unexposed newborns prior to 8 weeks of age. T2-weighted MRI data were acquired on Siemens and Philips 3T scanners and harmonized across sites. Brains were segmented using DrawEM- and 3D U-Net–based pipelines and manual corrections. Brain volumes were compared between groups using analysis of covariance, adjusting for postmenstrual age at MRI, sex, birth weight, maternal smoking, and maternal education. Results A total of 173 newborns with antenatal opioid exposure and 96 unexposed controls were studied. MRIs were performed at a mean (SD) age of 42.84 (2.11) postmenstrual weeks, and 117 newborns (43.5%) were female. The opioid-exposed group had significantly smaller total brain volume (387.51 vs 407.06 cm 3 ; difference, 19.55; 95% CI, 8.75-30.35) and cortical (167.07 vs 176.35 cm 3 ; difference, 9.28; 95% CI, 3.86-14.70), deep gray matter (27.22 vs 28.76 cm 3 ; difference, 1.54; 95% CI, 0.66-2.43), white matter (159.90 vs 166.65 cm 3 ; difference, 6.76; 95% CI, 1.71-11.81), cerebellar (23.47 vs 24.99 cm 3 ; difference, 1.52; 95% CI, 0.67-2.36), brainstem (6.80 vs 7.18 cm 3 ; difference, 0.38; 95% CI, 0.19-0.57), and amygdala volumes (left: 0.48 vs 0.51 cm 3 ; difference, 0.03; 95% CI, 0.004-0.05; right: 0.51 vs 0.55 cm 3 ; difference, 0.04; 95% CI, 0.08-0.07) compared to controls. Methadone-exposed newborns showed significantly smaller white matter volume compared to controls, while buprenorphine-exposed newborns showed significantly smaller right amygdala volume than controls. Compared to controls, newborns exposed to opioids only and those exposed to opioids plus other substances both showed significant reductions in volumes of cortical and deep gray matter, cerebellum, brainstem, right amygdala, and total brain. Polysubstance-exposed newborns additionally showed smaller volumes in white matter and the left amygdala compared to controls. Conclusions and Relevance In a large cohort of antenatally opioid-exposed newborns, there were significant reductions in global and regional brain volumes compared to unexposed controls. These data suggest vulnerability of the developing brain to antenatal opioid exposure, with varying effects depending on the type and number of substances. Trial Registration ClinicalTrials.gov Identifier: NCT04149509