A large multinational cohort study found no clear evidence that the use of smoking cessation pharmacotherapies during early pregnancy is associated with an increased risk of major congenital malformations.

Researchers evaluated three commonly used medications: nicotine replacement therapy (NRT), varenicline, and bupropion. Using data from more than 5.2 million births between 2001 and 2020 in Australia (New South Wales), New Zealand, Norway, and Sweden, the investigators analyzed outcomes among 135,284 pregnancies in which women either smoked during the first trimester or were dispensed one of these pharmacotherapies up to 90 days before conception or during early pregnancy.

Among these pregnancies, 9325 infants were exposed to NRT, 3031 to varenicline, and 1042 to bupropion. These groups were compared with over 120,000 infants born to women who smoked but did not use a smoking cessation medication during the relevant exposure window.

No significant increase in the prevalence of major congenital malformations (MCMs) was observed in the exposed groups:

• NRT: 37.6 per 1000 live births vs 34.4 per 1000 in the unexposed group; adjusted relative risk (aRR), 1.10; 95% confidence interval (CI), 0.98–1.22

• Varenicline: aRR, 0.90; 95% CI, 0.73–1.10

• Bupropion: aRR, 0.93; 95% CI, 0.67–1.29

The researchers also evaluated malformation subtypes by organ system. For NRT, no significant differences were observed in the risk of malformations affecting the heart, limbs, genital organs, kidney or urinary tract, respiratory system, or orofacial region. A higher rate of digestive system malformations was observed (3.8 vs 2.5 per 1000; aRR, 1.53; 95% CI, 1.05–2.23), but this association was no longer statistically significant after correction for multiple comparisons.

Among infants exposed to varenicline, a higher prevalence of kidney and urinary tract malformations was found (11.5 vs 4.2 per 1000; aRR, 2.75; 95% CI, 1.42–5.34). However, this finding was based on 11 exposed cases and was not statistically significant following correction for multiple comparisons. No differences were seen in the risks of cardiac, limb, or genital organ malformations.

For bupropion, data were limited due to smaller sample size. No increased risks were observed for overall or specific types of malformations. For example, the prevalence of cardiac malformations was lower in exposed vs unexposed infants (6.7 vs 11.6 per 1000; aRR, 0.55; 95% CI, 0.21–1.42), but this difference did not reach statistical significance.

Sensitivity analyses restricted to women who self-reported smoking or had multiple dispensings of pharmacotherapy supported the primary results. In addition, E values were calculated to evaluate whether unmeasured confounding could account for observed associations. These indicated that only a strong unmeasured confounder could explain the modest differences observed.

While larger studies may be needed to further assess rare outcomes and exposures to bupropion, the authors found no evidence of increased risk of major congenital malformations associated with NRT, varenicline, or bupropion use during early pregnancy.

Full disclosures are available in the published study.

Source: JAMA Internal Medicine