Effects of codeine on pregnancy outcome: results from a large population-based cohort study

Guidelines on codeine safety during pregnancy rely on small studies with inconsistent results, and associations between codeine use during pregnancy and increased risk of congenital malformations remain unsubstantiated. Our objective was to analyze the effect of codeine on pregnancy outcome. Pregnancy outcomes of 2,666 women who used codeine during pregnancy were compared with 65,316 women who used no opioids during pregnancy. Information on maternal sociodemographic and medical characteristics, potential confounders, and pregnancy outcome was obtained from The Norwegian Mother and Child Cohort Study [den norske Mor & barn-undersokelsen (MoBa)] data set and the Medical Birth Registry of Norway (MBRN) data set. The data sets were linked via the maternal personal identification number. Associations between codeine therapy and pregnancy outcomes were identified using logistic regression analyses. No significant differences were found in the survival rate [adjusted odds ratio (OR) 0.9, 95% confidence interval (CI) 0.6-1.5] or the congenital malformation rate (adjusted OR 0.9, 95% CI 0.8-1.1) between codeine-exposed and unexposed infants. Codeine use anytime during pregnancy was associated with planned Cesarean delivery (adjusted OR 1.4, 95% CI 1.2-1.7; P < 0.0001). Third-trimester use was associated with acute Cesarean delivery (adjusted OR 1.5, 95% CI 1.3-1.8; P < 0.0001) and postpartum hemorrhage (adjusted OR 1.3, 95% CI 1.1-1.5; P < 0.0001). No significant associations with other adverse pregnancy outcomes were found. No effects of maternal codeine intake during pregnancy were observed on infant survival or congenital malformation rate. Our findings are reassuring; however, the association with acute Cesarean delivery and postpartum hemorrhage may justify a certain level of caution when administering codeine toward the end of pregnancy.