Maternal-fetal biodisposition of buprenorphine and its metabolites in opioid dependent pregnant individuals

To determine the concentration of buprenorphine (BUP) and its metabolites in maternal and fetal samples and investigate the relationship between BUP concentrations and neonatal opioid withdrawal syndrome (NOWS). Matched maternal and fetal samples were collected from 12 individuals maintained on BUP for opioid use disorder during pregnancy. All delivered at term (≥37 weeks gestation) via cesarean section. Samples were collected at delivery and included maternal plasma (PL), amniotic fluid (AF), and umbilical cord blood (CB). Concentrations of BUP, its biologically active metabolite norbuprenorphine (NBUP) and its inactive metabolites glucuronide forms of buprenorphine (BUP-Gluc) and norbuprenorphine (NBUP-Gluc) were determined by liquid chromatography-mass spectrometry. The concentrations of BUP and its metabolites were compared between neonates who developed NOWS, defined as withdrawal symptoms requiring pharmacologic treatment, and those who did not. Five (42%) of neonates born to mothers in the study developed NOWS. There was no difference in gestational age, birthweight or other baseline characteristics between the two groups. All individuals in the study were receiving 16 mg daily of BUP at delivery. BUP concentrations were higher in cord blood (0.65 v 0.31ng/mL, p=0.01) and amniotic fluid (0.64 v 0.0 ng/mL, p=0.04) in neonates who developed NOWS, compared to those who did not. The concentrations of NBUP were also higher in neonates who developed NOWS (2.01 v 0.0ng/mL, p=0.03). There were no differences in maternal plasma concentrations between the two groups. Despite similar maternal dosing and plasma concentrations, NBUP concentrations in AF and BUP concentrations in AF and CB were higher for infants later diagnosed with NOWS, suggesting accumulation of the drug in the fetal compartment. Further studies are needed to determine the mechanisms and whether analysis of these specimens at delivery may help predict NOWS in buprenorphine-exposed neonates.