title: Delayed villous maturation in term placentas exposed to opioid maintenance therapy: a retrospective cohort study.
abstract: Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy.
  
  
  
  This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone.
  
  
  
  This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone.
  
  
  
  Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20-2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52-3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64-3.31). Results were similar after accounting for smoking.
  
  
  
  Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone).
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA. Electronic address: serraae@upmc.edu.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Serra
authors.affiliation: School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Lemon
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Neggin B
authors.initials: NB
authors.lastname: Mokhtari
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: W Tony
authors.initials: WT
authors.lastname: Parks
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Catov
authors.affiliation: School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Steve N
authors.initials: SN
authors.lastname: Caritis
mesh_terms: D000328:Adult; D002047:Buprenorphine / Q000009:adverse effects; D016022:Case-Control Studies; D002824:Chorionic Villi / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008691:Methadone / Q000009:adverse effects; D058850:Opiate Substitution Treatment / Q000009:adverse effects*; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000453:epidemiology; D010414:Pennsylvania / Q000453:epidemiology; D010922:Placenta Diseases / Q000473:pathology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000453:epidemiology; D012189:Retrospective Studies
chemical_list: D002047:Buprenorphine; D008691:Methadone
keywords: buprenorphine; delayed villous maturation; methadone; opioid; opioid maintenance therapy; placenta; stillbirth