Association of Gestational Opioid Exposure and Risk of Major and Minor Congenital Malformations

Key Points Question Is there an association between prenatal prescription opioid exposure and the risk of major and minor congenital malformations? Findings In this cohort study of 12 424 pregnancies, 891 women were dispensed prescription opioids during pregnancy. Opioid exposure in trimester 1 was not associated with major birth defects, but women dispensed opioids in trimester 3 had higher risks of offspring with minor birth defects in the musculoskeletal system. Meaning The study findings suggest a higher risk of minor congenital malformations in the musculoskeletal system that is associated with prenatal prescription opioid exposure in the third trimester; this risk appears to be dose-dependent.
Importance The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. Objective To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations. Design, Setting, and Participants This retrospective population-based cohort study evaluated linked Rhode Island Medicaid claims and vital statistics data of live births from January 1, 2008, to December 31, 2016. Data analysis was conducted from May 1, 2019, to May 31, 2020. Women who had a live birth during the study period, but no cancer or opioid use disorder, were followed up from 3 months before pregnancy to the end of pregnancy. Exposures Data on the mother’s prescription opioid exposure were obtained through pharmacy claims and exposure was defined as dispensing of at least 1 prescription opioid during the first, second, or third trimester. Main Outcomes and Measures The primary outcome was overall major or minor congenital malformations, defined as 1 or more major or minor congenital malformation. Secondary outcomes were defined as 10 specific categories of congenital malformations classified by organ systems using International Classification of Diseases diagnosis codes. Results Of 12 424 included pregnancies, 891 mothers (7.2%) received prescription opioids during pregnancy and 3153 infants (25.4%) were diagnosed with major or minor congenital malformations. Comparing prescription opioid exposure vs nonexposure, no excess risk was observed for major birth defects in infants with opioid exposure in trimester 1 (adjusted relative risk [aRR], 1.40; 95% CI, 0.84-2.34), and higher risks were found for overall minor birth defects in trimester 3 (aRR, 1.26; 95% CI, 1.04-1.53) and minor birth defects in the musculoskeletal system in trimester 2 (aRR, 1.50; 95% CI, 1.10-2.03) and trimester 3 (aRR, 1.65; 95% CI, 1.23-2.22). Significant dose responses in selected minor malformations and effects of specific opioids were also identified. Hydrocodone in trimester 2 (aRR, 3.01; 95% CI, 1.80-5.03) and oxycodone in trimester 3 (aRR, 2.43; 95% CI, 1.37-4.02) were associated with plagiocephaly, polydactyly, and other specified congenital deformities of the hip. Conclusions and Relevance The findings of this study suggest a higher risk of minor congenital malformations associated with use of prenatal prescription opioids in trimester 3, which seems to be dose-dependent. Further investigation is needed to establish causality and explore the physiologic plausibility of the association.
This cohort study examines the incidence of major and minor congenital malformations in infants born to women who receive opioids for medical indications during pregnancy.