Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study

BMJ. 2021 Feb 10;372:n102. doi: 10.1136/bmj.n102.


Objective: To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure.

Design: Population based cohort study.

Setting: Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15).

Participants: 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth.

Interventions: Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester.

Main outcomes measures: Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis.

Results: 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14).

Conclusions: Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology*
  • Abnormalities, Drug-Induced / etiology
  • Adult
  • Analgesics, Opioid / adverse effects*
  • Case-Control Studies
  • Cohort Studies
  • Cross-Sectional Studies
  • Databases, Factual
  • Female
  • Humans
  • Infant, Newborn
  • Pain Management / methods
  • Pain Management / statistics & numerical data
  • Practice Patterns, Physicians' / statistics & numerical data
  • Pregnancy
  • Pregnancy Complications / drug therapy*
  • Pregnancy Complications / epidemiology
  • Pregnancy Trimester, First
  • Risk


  • Analgesics, Opioid