Placental epigenetic regulation in opioid exposed pregnancies

Neonatal opioid withdrawal syndrome (NOWS) results from chronic in utero opioid exposure and its severity is unpredictable. Inter-individual variability in placental opioid metabolism and transfer mediated by epigenetic changes may impact fetal opioid exposure and NOWS severity. We assessed DNA methylation in placental metabolizing enzymes and transporters on in utero opioid exposure and NOWS severity. Prospective multicenter cohort study of mother-baby dyads on medication for opioid use disorder (MOUD) in pregnancy. Inclusion: >18yo, on MOUD (methadone or buprenorphine), ≥34 weeks, singleton. Exclusion: major fetal anomalies, no biospecimen collection. Placental biopsies from all four quadrants inclusive of the syncytiotrophoblast collected within 1 hour of delivery. Placental DNA methylation levels of genes (ABCG1, ABCG2, CYP19A1 and HSD11B2) were quantified across many sites per gene via pyrosequencing following bisulfite conversion. CYP19A1 mRNA levels were determined by rtPCR. Umbilical cord drug levels were determined by LC-MS. Maternal and neonatal characteristics were abstracted from the electronic medical record. Severe NOWS was diagnosed when Finnegan scores exceeded 24 in a 12-hour period. P-value < 0.05 was deemed significant. Thirty-eight dyads on chronic MOUD were enrolled (Table 1). Promoter region methylation for placental transporter ABCB1 was lower in severe NOWS (non-severe NOWS 4.93 ±1.66 vs severe NOWS 3.62 ±1.73, p< 0.05). There were no methylation differences between groups for placental CYP19A1, ABCG2 and HSD11. Placental CYP19A1 methylation was inversely correlated with CYP19A1 mRNA levels (r= -0.30, p< 0.05) and umbilical cord norbuprenorphine levels across multiple loci (r= 0.82- 0.98, p=0.004). ABCB1, ABCG2 and HSD11B2 methylation was not associated with umbilical cord drug levels. Lower placental ABCB1 methylation was associated with severe NOWS. Higher placental CYP19A1 methylation correlated with lower CYP19A1 mRNA expression and higher umbilical cord norbuprenorphine levels in severe NOWS cases.View Large Image Figure ViewerDownload Hi-res image Download (PPT)