Response to article – Alternative interpretation of “There is reduced immunohistochemical staining of placental aromatase in severe neonatal opioid withdrawal syndrome”

Dear Editor,

We recently read a very interesting and important study in the Journal of Maternal-Fetal & Neonatal Medicine entitled: “There is reduced immunohistochemical staining of placental aromatase in severe neonatal opioid withdrawal syndrome [1].” In this study, the authors investigated the effects of opioid exposure during pregnancy on placental immunostaining intensity of aromatase (i.e., CYP19A1). Additionally, the authors related severity of neonatal opioid withdrawal syndrome (NOWS) to immunostaining intensity of aromatase in placentas from opioid-exposed pregnancies of women undergoing medication-assisted treatment for opioid use disorder with either methadone or buprenorphine. Aromatase plays a major role in placental metabolism of methadone [2] and buprenorphine [3]. This investigation is important because understanding the interplay between these opioids and placental aromatase will better inform us on the determinants of fetal opioid exposure and NOWS caused by methadone and buprenorphine.

The authors reported a reduction in aromatase immunostaining in opioid-exposed placenta compared to unexposed controls. We were particularly interested in their additional finding that babies with severe NOWS had lower placental aromatase immunostaining than babies with non-severe NOWS. Based on this finding, the authors hypothesized that “reduced aromatase immunostaining results in altered aromatase function within the placenta, leading to higher circulating active opioid transferring from the placenta to the fetal compartment,” and offered that this phenomenon may cause higher rates of severe NOWS. However, the increased NOWS is more likely explained by a greater representation of treatment with methadone than buprenorphine in the group that developed severe NOWS. Methadone induces more severe NOWS than buprenorphine [4], and this effect is thought to be mediated by the higher efficacy of methadone than buprenorphine to activate the mu opioid receptor. We acknowledge the possibility that methadone inhibits or downregulates placental aromatase to a greater degree than buprenorphine, which in turn may permit greater methadone distribution to the fetus, contributing to the greater severity of NOWS observed following methadone treatment. However, we think this is unlikely because buprenorphine has an approximately 10-fold lower K_i than methadone to inhibit aromatase activity [5]. We would be interested in a comparison of placental aromatase immunostaining as a function of pharmacotherapy (methadone vs. buprenorphine) to determine whether methadone downregulates aromatase to a greater degree than buprenorphine. The sample size of the dataset used in the study is likely large enough to power this analysis, and we encourage the authors to conduct the analysis and report their findings.

We feel it is important to highlight these alternative interpretations because we are concerned that a casual reader of this article may simply conclude that placental aromatase plays a protective role against NOWS. The reader should take care not to assume a causal relationship between low placental aromatase and severe NOWS based on this study.

Sincerely,

Julia Tobacyk, Ph.D.

Lisa Brents, Ph.D.