Stillbirth, ischemic placental disease, and neonatal opioid withdrawal syndrome following exposure to opioid analgesic medication during pregnancy
Embargo Date
2024-05-18
OA Version
Citation
Abstract
BACKGROUND: Opioid use has been associated with adverse pregnancy outcomes including neonatal opioid withdrawal syndrome (NOWS) and certain congenital malformations. Less intensively studied in relationship to prescription opioid exposure are stillbirth and ischemic placental disease (IPD), including preeclampsia, placental abruption, and intrauterine growth restriction (IUGR)/being born small for gestational age (SGA), which often result in preterm birth. Little is also known about how NOWS risk varies by the specific prescription opioid used.
Given the highly prevalent and growing use of prescription opioid analgesics during pregnancy, a better understanding of their impact on these less studied outcomes as well as the association between NOWS and specific opioid medications is needed.
METHODS: Three studies were performed using a cohort derived from the Medicaid Analytic eXtract (MAX), which contains administrative billing data for Medicaid enrollees in 46 states and Washington DC. These studies assessed (1) the association between prescription opioid use leading up to delivery and the risk of stillbirth, (2) the association between prescription opioid use and the risk of ischemic placental disease including pre-eclampsia, placental abruption, intrauterine growth restriction (IUGR) and preterm delivery, and (3) the association between properties of prescription opioid use and risk of NOWS. For Study 1, a case-control approach was utilized, with controls sampled from the cohort at risk to mirror the gestational age at stillbirth observed in the US population. Cases and controls were compared with respect to demographic and clinical characteristics, and odds ratios were calculated based on opioid exposure occurring within 4, 8, and 20 weeks prior to the stillbirth event of control sampling date. Study 2 used a cohort design in which risks of each component of ischemic placental disease were compared between opioid exposed and unexposed women according to timing of exposure during pregnancy (early, late and both early and late). Study 3 compared pregnancies exposed to opioids in the last 90 days before delivery based on characteristics of the opioid used. Relative risks were calculated for NOWS unadjusted, adjusted for characteristics of the medications used (including MMEs), and adjusted for confounding by demographic characteristics and medical history using fine stratification and reweighting of an exposure propensity score. Odds ratios of stillbirth, hazard ratios of ischemic placental disease, and relative risks of NOWS, with their 95% confidence intervals (CI) were estimated overall and within subgroups of interest. Because the analyses relied on administrative claims that require assumptions about timing of pregnancy and may not adequately capture illicit opioid use, other illicit drug use, smoking and obesity, probabilistic bias analyses were employed to estimate the impact of exposure misclassification and unmeasured confounding.
RESULTS:
Study 1:
Among eligible pregnancies in the MAX database, we identified 25,565 stillbirths and 255,650 controls. A small increased risk was observed for exposure in the four weeks prior to delivery (adjusted odds ratio 1.24, 95% CI 1.16 – 1.32), with attenuation of the effect when considering alternate exposure windows of 8 or 20 weeks prior to the stillbirth event or control sampling date. Some differences were observed by specific medication used, with no meaningful increase observed for codeine (aOR 1.09, 95% CI 0.98 – 1.22) and a modest increase for oxycodone (aOR 1.39, 95% CI 1.16 – 1.67). Exploration of the 1.24-fold increase for exposure to any opioid in the four weeks prior to delivery suggests potential for reverse causation whereby medication could have been dispensed after recognition of fetal death, with opioid dispensings in the week of pregnancy loss associated with an aOR of 1.48 (1.34 – 1.63) and dispensings in the 2nd – 4th weeks prior to pregnancy loss associated with an aOR of 1.09 (95% CI 0.97 – 1.23). This could also be compatible with a triggering effect with a specific etiologically relevant window.
Study 2:
Of 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled by 6.5%. We observed an early exposure aHR of 1.34 (95% CI 1.26–1.43) for placental abruption, 1.21 (1.18–1.23) for preterm delivery, 1.13 (1.09–1.17) for SGA, and 0.95 (0.91–0.98) for preeclampsia. Estimates for late exposure were attenuated for each ischemic placental disease outcome. Exposure both early and late was associated with higher aHRs for placental abruption (1.62, 1.47–1.78), preterm delivery (1.37, 1.33–1.42) and SGA (1.26, 1.19–1.33), but not preeclampsia (0.99, 0.93–1.05).
Study 3:
We compared 16,202 codeine, 1,244 tramadol, 4,540 oxycodone, 260 methadone, 90 hydromorphone, and 63 morphine users vs. 25,710 hydrocodone users. When compared to hydrocodone users, adjusted relative risk of NOWS was lower for use of weak agonists [codeine (RR 0.57, 95% CI 0.46–0.70) and tramadol (1.06, 0.73–1.56)] and higher for use of strong agonists [oxycodone (1.87, 1.66–2.11), hydromorphone (2.03, 1.09–3.78), morphine (2.84, 1.30–6.22), and methadone (3.02, 2.45–3.73)]. Long half-life opioids had a slightly increased risk compared to short half-life products (1.33, 1.12–1.56).
DISCUSSION: Opioid use proximate to delivery does not appear to be a major trigger of stillbirth, although a weak effect cannot be excluded. Prescription opioids may modestly increase risk of placental abruption, preterm birth, and SGA, but they do not appear to be associated with preeclampsia. The risk of NOWS in infants with exposed to opioids during the 90 days before delivery, however, was different based on the type of opioid used. This information may help prescribers with opioid analgesic selection for pain management in late pregnancy.