594 - Association of placental DNA methylation in stress-related and opioid receptor genes with neonatal opioid withdrawal syndrome severity

Publication Number: 4582.594

Samuel Francois, Boston University School of Medicine, Milford, MA, United States; Audrey Cantillon, Boston Medical Center, Brighton, MA, United States; Aneya L. Sousa, Boston University School of Medicine, Roxbury, MA, United States; Elizabeth Taglauer, Boston University School of Medicine, Boston, MA, United States; Sorraya Jaiprasert, Boston Medical Center, Boston, MA, United States; Huiping Zhang, Boston University School of Medicine, Boston, MA, United States; Elisha Wachman, Boston Medical Center, Newton, MA, United States

Background: Neonatal opioid withdrawal syndrome (NOWS) is a heterogenous condition influenced by multiple clinical and biological factors. Epigenetic mechanisms, such as DNA methylation, may contribute to differences in NOWS severity and neurobehavioral outcomes.

Objective: To investigate whether placental DNA methylation in stress-related and opioid receptor genes is associated with NOWS severity.

Design/Methods: Placental tissue was collected from 39 opioid-exposed pregnancies, including 24 infants who required pharmacologic treatment for NOWS (NOWS Rx) and 15 who did not (NOWS No Rx). Maternal and infant characteristics were compared between the two groups. Placental DNA methylation at 175 CpG sites across 11 stress- and opioid-related genes was assessed using a custom panel and compared between the two groups.

Results: Mothers in the NOWS Rx group reported significantly higher levels of stress, trauma, and psychiatric symptoms compared to the NOWS No Rx group. There were no significant differences in gestational age, birth weight, race, or ethnicity (Table 1). Hospital length of stay (LOS) was significantly longer in the NOWS Rx group [18.38 (SD 10.25) vs 7.00 (SD 5.10) days, p< 0.0001] (Table 2). Point-wise comparisons revealed higher mean methylation levels at eight CpG sites within HSD11B2, HTR1A, HTR1B, or OXTR in the NOWS Rx group (p < 0.05); however, these associations did not remain significant after correction for multiple comparisons (Table 3).

Conclusion(s): These findings suggest that differential placental DNA methylation in stress-related genes may contribute to variability in NOWS severity. Larger studies are warranted to validate these associations and explore their implications for long-term neurodevelopmental outcomes in opioid-exposed infants.

Table 1: Maternal and Infant Demographics and Birth Outcomes
Abbreviations: ACES = Adverse Childhood Experiences Scale; HADS = Hospital Anxiety and Depression Scale; ASI = Addiction Severity Index; GA = gestational age; NICU = neonatal intensive care unit; MOUD = medication for opioid use disorder; SSRIs = selective serotonin reuptake inhibitors

Table 2: Infant NOWS Outcomes
Abbreviations: PRN = as needed; NOWS = neonatal opioid withdrawal syndrome

Table 3: Top CpG associations comparing NOWS pharmacologically treated versus non-treated groups
Abbreviations: CpG = cytosine guanine dinucleotide; MD = mean difference; CI = confidence interval
*The non-treated group was used as the reference group; adjusted for benzodiazepine exposure and infant sex