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

Abstract

Background

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. CYP19A1 (aromatase) is the enzyme responsible for metabolizing methadone and buprenorphine in the human placenta.

Objective

We sought to determine if differences exist in CYP19A1 and efflux transporter immunostaining intensity and density within the syncytiotrophoblast in opioid-exposed and unexposed pregnancies. Additionally, we sought to investigate whether CYP19A1 and efflux transporter expression was different in placentas of infants who developed severe neonatal opioid withdrawal syndrome (NOWS) and those who did not.

Study design

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. p < .05 was considered significant.

Results

One hundred and ten opioid-exposed neonates were included in this analysis (51 opioid-exposed cases and 59 opioid-exposed controls), 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, p = .03). The median placental Allred scores for aromatase were significantly lower in opioid-exposed cases that developed severe NOWS compared to opioid-exposed controls (p = .03) that did not develop severe NOWS. There were no differences in P-gp and BCRP scores between groups.

Conclusions

Syncytiotrophoblast aromatase immunostaining scores were reduced in opioid-exposed cases compared to unexposed controls. Additionally, infants who developed severe NOWS had significantly lower placental aromatase in the apical syncytiotrophoblast compared with those without severe NOWS.

Keywords:

• Aromatase
• placenta
• neonatal opioid withdrawal syndrome

Acknowledgements

The authors would like to thank the University of Michigan Biorepository for Understanding Maternal and Pediatric Health (BUMP) for providing samples for analysis.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

Funding for this research was made available through Michigan Institute for Clinical & Health Research (MICHR) [UL1TR002240].