There is reduced immunohistochemical staining of placental aromatase in severe neonatal opioid withdrawal syndrome

Placental cytochrome p450 (CYP450) enzymes and efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are critical for transfer of drugs from the placenta to maternal circulation. <i>CYP19A1</i> (aromatase) is the enzyme responsible for metabolizing methadone and buprenorphine in the human placenta. We sought to determine if differences exist in <i>CYP19A1</i> and efflux transporter immunostaining intensity and density within the syncytiotrophoblast in opioid-exposed and unexposed pregnancies. Additionally, we sought to investigate whether <i>CYP19A1</i> and efflux transporter expression was different in placentas of infants who developed severe neonatal opioid withdrawal syndrome (NOWS) and those who did not. This was a retrospective nested case control study from 2014 to 2019 at a single tertiary care center. The opioid-exposed cohort included pregnant women aged ≥18 years on maintenance methadone or buprenorphine with non-anomalous singleton fetuses and gestational age ≥33 weeks. Controls included pregnant women with no medication exposure delivering at ≥37 weeks. De-paraffinized placental sections, inclusive of the apical syncytiotrophoblast membrane, were labeled with monoclonal antibodies for aromatase, P-gp, and BCRP. Placentas were scored for the presence and intensity of staining using the Allred scoring schema. Data were analyzed using descriptive, parametric, and nonparametric statistics. <i>p</i> &lt; .05 was considered significant. One hundred and ten opioid-exposed neonates were included in this analysis (51 <i>opioid-exposed cases</i> and 59 <i>opioid-exposed controls</i>), with 68/110 delivering at term. Ten unexposed controls delivering at term were also included. The median placental Allred scores for aromatase were significantly lower in the opioid-exposed cohort compared with the unexposed controls (exposed 6.8 ± 1.4 vs. unexposed 7.5 ± 0.7, <i>p</i> = .03). The median placental Allred scores for aromatase were significantly lower in <i>opioid-exposed cases</i> that developed severe NOWS compared to <i>opioid-exposed controls</i> (<i>p</i> = .03) that did not develop severe NOWS. There were no differences in P-gp and BCRP scores between groups. Syncytiotrophoblast aromatase immunostaining scores were reduced in <i>opioid-exposed cases</i> compared to <i>unexposed controls</i>. Additionally, infants who developed severe NOWS had significantly lower placental aromatase in the apical syncytiotrophoblast compared with those without severe NOWS.