First trimester prescription opioid use linked to small increase in risk of oral clefts

Use of prescription opioids in early pregnancy does not appear to significantly increase the risk of certain congenital malformations, a recent study has found. However, an association is observed with a slightly elevated risk of oral clefts.

“Overall, our findings suggest that prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although clinicians should be aware of the potential for a small increase in the risk of oral clefts and counsel patients about this risk,” the researchers said.

This population-based cohort study identified 1,602,580 publicly insured (MAX) and 1,177,676 commercially insured (MarketScan) pregnant women with eligibility from at least 3 months before pregnancy to 1 month after delivery, as well as infants with eligibility for at least 3 months after birth.

The researchers determined the use of prescription opioids by requiring two or more dispensations of any opioid during the first trimester.

Overall, 70,447 (4.4 percent) publicly insured and 12,454 (1.1 percent) commercially insured pregnant women had two or more dispensations of an opioid during the first trimester.

In the MAX cohort, the absolute risk of malformations overall was 41.0 (95 percent confidence interval [CI], 39.5–42.5) per 1,000 pregnancies exposed to opioids relative to 32.0 (95 percent CI, 31.7–32.3) per 1,000 unexposed pregnancies. The absolute risk estimates in the MarketScan cohort were 42.6 (95 percent CI, 39–46.1) and 37.3 (95 percent CI, 37.0–37.7), respectively. [BMJ 2021;372:n102]

Pooled unadjusted relative risk (RR) estimates were elevated for all outcomes but shifted substantially toward the null after adjustment: for malformations overall (RR, 1.06, 95 percent CI, 1.02–1.10), cardiovascular malformations (RR, 1.09, 95 percent CI, 1.00–1.18), ventricular septal defect (RR, 1.07, 95 percent CI, 0.95–1.21), atrial septal defect/patent foramen ovale (RR, 1.04, 95 percent CI, 0.88–1.24), neural tube defect (RR, 0.82, 95 percent CI, 0.53–1.27), and clubfoot (RR, 1.06, 95 percent CI, 0.88–1.28).

Notably, the heightened risk for oral clefts persisted after adjustment (RR, 1.21, 95 percent CI, 0.98–1.50), with a higher risk of cleft palate (RR, 1.62, 95 percent CI, 1.23–2.14).

“Our analyses expand the available evidence for the safety of opioids in pregnancy,” the researchers said. “Based on a systematic review, 12 case-control and 18 cohort studies have previously measured the association between opioid exposure in pregnancy and congenital malformations.”

Seventeen of these studies reported significant associations with at least one type of malformation. However, the possibility of confounding bias, outcome and exposure misclassification, and recall bias could not be excluded for some studies and, combined with limited power, resulted in uncertainty about the teratogenic potential of opioids. [Pediatrics 2017;139:e20164131]

“[These] results inform the selection of analgesic drugs for women who are pregnant and women of reproductive age who might inadvertently become pregnant,” the researchers said.

The current study was limited by its design, potential residual confounding, null or near null associations, and possible selection bias due to the analysis based on pregnancies resulting in live births.