First-Trimester Prescription Opioids Not Linked to Most Developmental Malformations

The objective of this study was to evaluate the risks of first-trimester exposure to prescription opioids for major congenital malformations.

Use of prescription opioids during early pregnancy was not associated with higher risk for most developmental malformation. These findings from a population-based cohort study were published in The BMJ.

Data from pregnancies from 2000 to 2014 in the Medicaid Analytic eXtract (MAX) cohorts (n=1,602,580) and from 2003 to 2015 in the IBM Health MarketScan Research Database (n=1,177,676) were analyzed for this study. Opioid exposure was defined as the filling of 2 or more prescriptions during the first 90 days of pregnancy. Congenital malformations significantly associated with opioid exposure were assessed.

A total of 70,447 (4.4%) and 12,454 (1.1%) pregnancies in the MAX and MarketScan databases, respectively, had 2 or more opioid prescriptions filled during the first trimester. The most frequently filled opioid prescriptions were hydrocodone alone or with codeine.

Women exposed to opioids had more instances of chronic pain, had more comorbidities including psychiatric conditions, and were more likely to be prescribed other prescription drugs. In the MAX database, which included data on ethnicity, White women were more likely to be exposed to opioids (standardized difference, 0.6) than were women of other ethnicities.

All absolute risk estimates for malformations were increased among the infants born to exposed mothers. To correct for these baseline differences, the researchers applied propensity score stratification, balancing the exposed and unexposed women so that standardized differences were less than 0.10.

After propensity matching, absolute risk estimates for malformations did not suggest infants born to exposed mothers were more common (relative risk [RR], 1.06; 95% CI, 1.02-1.10).

Stratified by defect type, these malformations did not have risk scores that differed significantly from 0: neural tube defect (RR, 0.82; 95% CI, 0.53-1.27), cleft lip (RR, 1.02; 95% CI, 0.69-1.51), patent foramen ovale or atrial septal defect (RR, 1.04; 95% CI, 0.88-1.24), clubfoot (RR, 1.06; 95% CI, 0.88-1.28), ventricular septal defect (RR, 1.07; 95% CI, 0.95-1.21), cleft palate with cleft lip (RR, 1.02; 95% CI, 0.69-1.51), and cardiovascular malformations overall (RR, 1.09; 95% CI, 1.00-1.18).

The researchers found that infants born to exposed mothers had an increased risk (RR, 1.62; 95% CI, 1.23-2.14) for only cleft palate defects.

Stratified by the time when opioid prescriptions were filled, infants born to mothers who likely used opioids late in the first trimester were at increased risk for oral clefts (RR, 1.32; 95% CI, 1.03-1.68).

This study was limited by the assumption that women who filled opioid prescriptions actually used the medications, which may not be true in all cases.

These data indicated use of opioids during the first trimester did not substantially increase the risk for developmental malformations, although there was a small increase in the risk for cleft palate and oral clefts.

Disclosure: Several authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Bateman BT, Hernandez-Diaz S, Straub L, et al. Association of first trimester prescription opioid use with congenital malformations in the offspring: population-based cohort study. BMJ. 2021;372:n102. doi:10.1136/bmj.n102