473 - A Pilot Study to Understand the Role of Inflammation in White Matter Injury in Opioid-Exposed Neonates

Poster Number: 473
Publication Number: 473.343

Elizabeth Yen, Tufts University School of Medicine, Boston, MA, United States; Neel Madan, Tufts Medical Center, Boston, MA, United States; Pooja Sikka, Tufts University School of Medicine, Boston, MA, United States; Tomo Tarui, Tufts Childrens Hospital, Boston, MA, United States; Kiran Singh, Tufts Childrens Hospital, Norwood, MA, United States; Tomoko Kaneko-Tarui, Tufts Medical Center, Boston, MA, United States; Juyeon Baik, Tufts University, Somerville, MA, United States; Jonathan M. Davis, Tufts Childrens Hospital, Boston, MA, United States; Jill Maron, Women & Infants Hospital of Rhode Island, Providence, RI, United States

Background: Opioid-exposed neonates are predisposed to white matter injury. The mechanism underlying this injury is unknown. Preliminary transcriptomic data in our laboratory showed that prenatal opioid exposure may be pro-inflammatory.

Objective: This pilot study examines if inflammation is linked with white matter injury in opioid-exposed neonates.

Design/Methods: Ten opioid-exposed and 10 sex- and age-matched non-exposed neonates (34-42 weeks’ gestational age) were enrolled. Saliva and brain magnetic resonance imaging (MRI) were obtained within 48 hours of birth and prior to pharmacotherapy for the exposed cohort. Expression of select inflammatory genes (Table 1) based on emerging pre-clinical studies were normalized as delta threshold cycle (∆Ct) values. Brain MRI was acquired without sedation. Diffusion tensor imaging (DTI) was acquired with a baseline image (b=0 s/mm2) and 15 different diffusion orientations (b=1,000 s/mm2). Single-subject and group-level DTI analyses were performed using voxel-wise whole tract analysis of the fractional anisotropy (FA) data with Tract Based Spatial Statistics and a pipeline optimized for neonatal DTI data, adjusted for sex and age. Gene expression and MRI results were compared by opioid exposure and the presence of white matter hyperintensity (WMH). Gene expression and FA data were correlated using Pearson’s correlation, continuous data were analyzed using a t-test, and categorical data using Chi-square. Significance was set at p ≤ 0.05.

Results:
Opioid-exposed neonates had a significantly higher incidence of WMH (Table 2). Qualitative reduction of FA was seen in multiple white matter tracts (Table 1, p >0.05, threshold-free cluster enhancement/ TCFE corrected). Gene expression did not differ significantly between exposed and non-exposed neonates, and between those with and without WMH. Correlation between FA and gene expression in the opioid-exposed cohort showed a trend of negative correlation for CXCL1 (p=0.11). Within those with WMH, FA significantly and negatively correlated with IL6 (p=0.01) and approached significance for TLR4, IL1B, and CXCL1 (p=0.06 to 0.11) (Table 3).
Conclusion(s): To our knowledge, this is the first clinical study to simultaneously assess inflammation and white matter changes in in utero opioid-exposed neonates. Exposure is associated with structural and microstructural changes in major white matter tracts, notably in the amygdala and cerebral cortex. While limited by a small sample size, our preliminary data suggest that these abnormal white matter changes may not be directly linked with higher inflammation.
Table 1. List of Inflammatory Genes and Areas with Reduced Fractional Anisotropy
Table 2. Demographics and Characteristics of Enrolled Subjects*Matched. NA: not available/applicable. Bold numbers indicate significance.
Data are presented as mean (standard deviation), median (interquartile ranges) for continuous measures and N (%) for categorical measures.