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Prenatal opioid analgesics and the risk of adverse birth outcomes

Brogly SB, Velez MP, Werler MM, Li W, Camden A, Guttmann A. Epidemiology. 2021; 32(3):448-56. Epub 2021 Feb 19. DOI:

Background — It is unclear whether confounding accounts for the increased risk of preterm birth and small for gestational age (SGA) birth in opioid analgesic exposed pregnancies.

Methods — Using universal coverage health data for Ontario, we assembled a cohort of mother-infant pairs without opioid use disorder (627,172 pregnancies, 509,522 women). We estimated risk ratios between opioid analgesics and preterm birth, SGA birth, and stillbirth; neonatal abstinence syndrome was a secondary outcome. We used high dimensional propensity scores and sensitivity analyses for confounding adjustment.

Results — 4% of pairs were exposed, mainly to codeine (2%), morphine (1%), and oxycodone (1%). Compared with unexposed, the adjusted risk of preterm birth was higher with any (1.3, 95% CI 1.2, 1.3), first- (RR 1.2, 95% CI:1.2, 1.3), and second-trimester (RR 1.3, 95% CI:1.2, 1.4) opioid analgesic exposure. Preterm birth risk was higher for first- and second-trimester codeine, morphine, and oxycodone exposure, and for third-trimester morphine. There was a small increase in SGA with first-trimester exposure to any opioid analgesic or to codeine. Exposed pregnancies had an elevated stillbirth risk with any (RR 1.6, 95% CI: 1.4, 1.8), first- and second-trimester exposure. Few infants had neonatal abstinence syndrome (N=143); the risk was higher in exposed (RR 3.6, 95% CI: 2.1, 6.0). In sensitivity analyses of unmeasured confounding, an elevated risk in exposed pregnancies persisted for preterm birth but not SGA.

Conclusions — Opioid analgesic exposed pregnancies had a small increased risk of preterm birth and possibly stillbirth after accounting for confounding by indication and sociodemographic factors.