Ischemic Placental Disease, Preterm Delivery, and Their Association With Opioid Use During Pregnancy

Am J Epidemiol. 2022 Mar 24;191(5):759-768. doi: 10.1093/aje/kwab132.


Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000-2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia.

Keywords: intrauterine growth restriction; opioids; placental abruption; preeclampsia; preterm delivery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abruptio Placentae* / epidemiology
  • Abruptio Placentae* / etiology
  • Analgesics, Opioid / adverse effects
  • Female
  • Fetal Growth Retardation
  • Humans
  • Infant, Newborn
  • Infant, Small for Gestational Age
  • Placenta
  • Placenta Diseases* / chemically induced
  • Placenta Diseases* / epidemiology
  • Pre-Eclampsia* / chemically induced
  • Pre-Eclampsia* / epidemiology
  • Pregnancy
  • Premature Birth* / chemically induced
  • Premature Birth* / epidemiology
  • Risk Factors


  • Analgesics, Opioid