1. The use of opioid medications during the first trimester is not significantly associated with greater risk of congenital malformations.
2. Following adjustments, opioid use during the first trimester was associated with a greater relative risk of oral clefts.
Evidence Rating Level: 2 (Good)
Pregnant women experience pain to varying degrees, yet teratogenicity of opioids is still unclear in epidemiological studies. Approximately 14% of commercial insurance beneficiaries and 22% of Medicaid beneficiaries receive at least one opioid prescription during pregnancy. This nationwide population-based cohort study sought to investigate congenital malformations in the context of pregnant women who received at least two opioid prescriptions during their first trimesters. A total of 1,602,580 publicly-insured and 1,177,676 commercially-insured pregnant women were included in analyses, with insurance eligibility three months prior to pregnancy and one month after delivery. Through the use of the Medicaid Analytic eXtract (MAX) and the MarketScan Research Database (MarketScan), these women were matched to their liveborn infants. Approximately 4.4% of publicly-insured and 1.1% of commercially-insured pregnant women had at least two opioid prescriptions dispensed during the first trimester. The absolute risk of overall malformations was 41 (95% CI 39.5 to 42.5) per 1,000 pregnancies exposed to opioid medications, compared to 32 (95% CI 31.7 to 32.3) per 1,000 in the MAX cohort. Overall malformations risk was 42.6 (95% CI 39.0 to 46.1) compared to 37.3 (95% CI 37.0 to 37.7) per 1,000 in the MarketScan cohort. Unadjusted relative risk (RR) estimates were calculated for all outcomes: overall malformations (RR = 1.06, 95% CI 1.02 to 1.10), cardiovascular malformations (RR = 1.09, 95% CI 1.00 to 1.18), ventricular septal defect (RR = 1.07, 95% CI 0.95 to 1.21), atrial septal defect/patent foramen ovale (RR = 1.04, 95% CI 0.88 to 1.24), clubfoot (RR = 1.06, 95% CI 0.88 to 1.28), and neural tube defect (RR = 0.82, 95% CI 0.53 to 1.27). However, nearly all of these outcomes regressed to the null after adjustment. The RR of oral clefts remained relatively high after adjustment (RR = 1.21, 95% CI 0.98 to 1.50), including a high risk of cleft palate (RR = 1.62, 95% CI 1.23 to 2.14). Overall, this study found that opioid medications are not associated with a significant increase in risk of congenital malformations, though oral clefts may be more likely.
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