Prenatal use of smoking cessation pharmacotherapies was not linked to increased risks of major congenital malformations (MCMs) compared with smoking during the first trimester.
Nicotine replacement therapy (NRT), varenicline, and bupropion were examined in a retrospective cohort study conducted in four countries.
There were no differences between groups in prevalence of MCMs following exposure to NRT, varenicline, or bupropion.
Prenatal use of smoking cessation therapies was not linked to increased risks of major congenital malformations (MCMs) compared with smoking during the first trimester, a retrospective cohort study suggested.
Compared with unexposed infants -- defined as those born to women who smoked but were not dispensed a pharmacotherapy -- there were no differences in prevalence of MCMs, overall, following exposure to nicotine replacement therapy (NRT; adjusted relative risk [aRR] 1.10, 95% CI 0.98-1.22), varenicline (Chantix; aRR 0.90, 95% CI 0.73-1.10), or bupropion (Zyban; aRR 0.93, 95% CI 0.67-1.29), reported Duong Tran, PhD, of the National Drug and Alcohol Research Center at the University of New South Wales in Sydney, and colleagues.
"To our knowledge, this cohort study was the largest to date that investigated the risk of MCMs following prenatal exposure to smoking cessation pharmacotherapies," the researchers wrote in JAMA Internal Medicine. "Overall, our findings are reassuring given the extensive detrimental effects of smoking on maternal and child health."
Maternal smoking during pregnancy is the leading cause of harm to both mother and baby, contributing to adverse pregnancy outcomes such as pre-term birth, low birthweight, fetal and neonatal death, birth defects, and long-term health consequences, Tran told MedPage Today in an email. "Smoking cessation significantly reduces these risks."
"Although NRT, varenicline, and bupropion are effective pharmacologic aids for smoking cessation in the general population, we don't have robust evidence regarding their safety during pregnancy," Tran said.
The new study increases confidence in varenicline and bupropion safety and should encourage randomized clinical trials examining their effectiveness in pregnancy, wrote Tim Coleman, MD, and Sophie Orton, PhD, MSc, both of the University of Nottingham in England, in a commentary accompanying the study. "However, clinicians must act now and cannot wait for more evidence. In pregnancy, motivation to quit is high, and half of those who smoke at conception try stopping."
"To maximize abstinence and minimize smoking-related harms, clinicians should systematically offer cessation support to all pregnant patients who smoke," they continued. "In many jurisdictions, resources already include NRT or e-cigarettes and the option of behavioral support. Now patients who do not quit with usual support can make more evidence-based decisions about varenicline or bupropion, and some may choose to use one of these treatments to help them permanently stop smoking."
The study was conducted in New South Wales, Australia; New Zealand; Norway; and Sweden. Researchers linked records of all births from 2001 to 2020 to prescribed medicine dispensings, hospital admission, outpatient, and death data. The base cohort consisted of 391,474 infants among 267,522 women who smoked during the first trimester or were dispensed a smoking cessation pharmacotherapy 90 days before conception or during the first trimester.
Mean maternal age at childbirth was 27.2 years. Analyses included 9,325 infants exposed to NRT (from New South Wales and New Zealand), 3,031 to varenicline (all four countries), and 1,042 to bupropion (New South Wales and New Zealand).
There was no difference for NRT in the risk of MCMs of the heart, limbs, genital organs, kidney/urinary tract, respiratory system, or orofacial clefts, but a higher risk of MCMs of the digestive system (3.8 vs 2.5 per 1,000 live births, aRR 1.53, 95% CI 1.05-2.23) was suggested. However, that association was "no longer statistically significant after adjustment for multiple comparisons, suggesting the possibility of a chance finding," Tran and colleagues noted.
For varenicline, there was no difference in the risk of MCMs of the heart, limbs, or genital organs. Analyses suggested a higher risk of MCMs of the kidney/urinary tract (11.5 vs 4.2 per 1,000 live births, aRR 2.75, 95% CI 1.42-5.34), but researchers noted this finding "should be interpreted cautiously because it was based on only 11 exposed and 40 unexposed infants, and the association was no longer statistically significant after adjustment for multiple comparisons."
Finally, for bupropion, data were "too sparse" to estimate the risk of MCM subgroups, Tran and colleagues noted.
Limitations included that the study did not examine long-term functional defects, such as adverse neurodevelopmental outcomes; that there was a lack of data on whether women smoked throughout the entire first trimester; that some infants of women without a pharmacotherapy dispensed might have been exposed to over-the-counter NRT, and that some women in exposed groups might have discontinued therapy when they realized they were pregnant.
Additionally, stillborn infants were excluded from the study due to their rarity in the study and concerns about the quality of malformation recording among stillbirths. There also was a lack of data on pregnancy terminations.
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Jennifer Henderson joined MedPage Today as an enterprise and investigative writer in Jan. 2021. She has covered the healthcare industry in NYC, life sciences and the business of law, among other areas.
Disclosures
The study received funding from a National Health and Medical Research Council (NHMRC) Ideas Grant, the University of New South Wales Research Infrastructure Grant, a University of New South Wales Scientia Program Award, the National Health and Medical Research Council Medicines Intelligence Center of Research Excellence, the Research Council of Norway, and the Research Council of Norway through its Centers of Excellence funding scheme. Also, the National Drug and Alcohol Research Center receives funding from the Australian Government Department of Health under the Drug and Alcohol Program.
Tran and co-authors reported receiving grants from government agencies, and several co-authors reported being involved with research funded by pharmaceutical companies outside the submitted work.
Editorialist Coleman reported grants from the National Institute for Health Research paid to their institution, and editorialist Orton reported grants from the Society for the Study of Addiction and the National Institute for Health Research.
Primary Source
JAMA Internal Medicine
Source Reference: Tran DT, et al "Risk of major congenital malformations following prenatal exposure to smoking cessation medicines" JAMA Intern Med 2025; DOI: 10.1001/jamainternmed.2025.0290.
Secondary Source
JAMA Internal Medicine
Source Reference: Coleman T, Orton S "Using pharmacologic smoking cessation treatments in pregnancy" JAMA Intern Med 2025; DOI: 10.1001/jamainternmed.2025.0278.