BACKGROUND AND PURPOSE:

• Smoking cessation pharmacotherapies may be used by pregnant people who wish to quit smoking during pregnancy, but evidence on fetal safety is limited
• Tran et al. (JAMA Intern Med, 2025) assessed whether prenatal use of smoking cessation pharmacotherapies like nicotine replacement therapy (NRT), varenicline, and bupropion was associated with increased risks of major congenital malformations (MCMs)

METHODS:

• Retrospective cohort study
  • Common protocol in New South Wales (NSW, Australia), New Zealand (NZ), Norway, and Sweden
  • Data derived from national registers
  • Births between 2001 and 2020
• Population
  • All births to women who
    • Smoked during the first trimester or
    • Received smoking cessation pharmacotherapy
• Exposures
  • Receipt of smoking cessation pharmacotherapy 90 days before conception or during the first trimester
    • NRT | Varenicline | Bupropion
  • Unexposed: smoking during the first trimester, but no pharmacotherapy
• Study design
  • Propensity score matching used to match exposed infants to unexposed infants
• Primary outcome
  • Major congenital malformations

RESULTS:

• 267,522 women | 391,474 infants
  • Mean maternal age: 27.2 (SD, 6.0) years
  • Exposed to NRT: 9325 infants | Varenicline: 3031 | Bupropion: 1042
• Compared with unexposed infants, there were no differences in prevalence of MCMs overall following exposure to any of the pharmacotherapies
  • NRT
    • Exposed: 37.6 per 1000 live births | Unexposed: 34.4
    • Adjusted relative risk (aRR) 1.10 (95% CI, 0.98 to 1.22)
  • Varenicline
    • Exposed: 32.7 per 1000 live births | Unexposed: 36.6
    • aRR 0.90 (95% CI, 0.73 to 1.10)
  • Bupropion
    • Exposed: 35.5 per 1000 live births | Unexposed: 38.8
    • aRR 0.93 (95% CI, 0.67 to 1.29)
• For NRT, there was no difference in the risk of MCMs by most subtypes
  • Heart | Limbs | Genital organs | Kidney/urinary tract | Respiratory system | Orofacial clefts
• There was a higher risk of digestive organ MCMs with NRT but not statistically significant after multiple comparisons
  • Exposed: 3.8 per 1000 live births | Unexposed: 2.5
  • aRR 1.53 (95% CI, 1.05 to 2.23) | P=0.41
• For varenicline, there was also no difference in the risk of MCMs by most subtypes with enough data
  • Heart | Limbs | Genital organs
• There was a higher risk of kidney/urinary tract MCMs but not statistically significant after multiple comparisons (small sample set)
  • Exposed: 11.5 | Unexposed: 4.2 per 1000 live births
  • aRR 2.75 (95% CI, 1.42 to 5.34) | P=0.09
• For bupropion, data were too sparse to estimate the risk of MCM by subtype

CONCLUSION:

• Use of nicotine replacement therapy, varenicline, and bupropion was not associated with an increased risk of congenital malformations vs smoking
• The authors state

Overall, our findings are reassuring given the extensive detrimental effects of smoking on maternal and child health

Larger studies providing more robust estimates of risk for the remaining malformation subgroups are needed

Learn More – Primary Sources:

Risk of Major Congenital Malformations Following Prenatal Exposure to Smoking Cessation Medicines