Stop Smoking Drugs Don’t Promote Congenital Malformations

The use of smoking cessation medications during the first trimester of pregnancy posed no greater risk for major congenital malformations (MCMs) in infants than smoking, based on a meta-analysis of approximately 400,000 infants. 

“Maternal smoking during pregnancy is the leading cause of harms to both mother and baby, contributing to outcomes such as preterm birth, low birthweight, fetal and neonatal death, birth defects, and long-term health consequences, and smoking cessation significantly reduces these risks,” said lead author Duong T. Tran, PhD, of the University of New South Wales, Sydney, Australia, in an interview.

“Although nicotine replacement therapy (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. Current guidelines advise against varenicline and bupropion during pregnancy and advise NRT with caution, she said.

In a study published in JAMA Internal Medicine, Tran and colleagues reviewed data from four countries (Norway, Sweden, New Zealand, and Australia) to examine overall risk for MCMs, risks in subgroups, and specific malformations associated with smoking cessation therapy use.

The study population included 267,522 women with a mean age of 27.2 years at the time of childbirth, and 391,474 singleton births, including 9325 infants exposed to NRT, 3031 to varenicline, and 1042 to bupropion. 

Overall prevalence of MCMs was not significantly different for infants exposed to NRT, varenicline, or bupropion compared with unexposed infants per 1000 live births (37.6 vs 34.4, 32.7 vs 36.6, and 35.5 vs 38.8, respectively). 

In subgroup analyses, NRT was associated with a higher risk for digestive organ MCMs compared with no exposure (3.8 vs 2.6 per 1000 live births) but no difference in risk for MCMs related to heart, limbs, genital organs, kidneys, urinary tract, respiratory system, or orofacial clefts. Varenicline was associated with a higher risk for kidney or urinary tract MCMs compared with no exposure (11.5 vs 4.2 per 1000 live births), but no difference appeared in the risk for heart, limb, or genital MCMs; data on risk for other MCMs were too imprecise, the researchers wrote. Bupropion data were too sparse for a subgroup analysis, the researchers noted. 

The findings were limited by several factors including the lack of data on adverse neurodevelopmental outcomes or other long-term functional defects and by a lack of data on whether women smoked during their entire first trimester, the researchers noted. However, the results suggest that the use of NRT, varenicline, and bupropion during pregnancy were not associated with an increased overall MCM risk compared with continued smoking, and that the data are reassuring given the detrimental impact of smoking on both maternal and child health, they concluded. 

Data May Guide Patient Discussions

The current study yielded results consistent with previous trials of NRT, which had been too small to provide definitive evidence of safety, Tran said. “As for varenicline, no clinical trials have assessed its safety during pregnancy. Our study found no increased risks of MCMs overall, nor specific malformations affecting the heart, limbs, and genital organs,” she said. The study is the first to examine the effects of bupropion on MCMs and found no risk for exposure overall, she added.

“Clinicians can use these findings to guide decision-making during consultations with pregnant women, weighing the potential benefits of these medicines against the possibility of smoking-related adverse outcomes,” said Tran.

“Future research should confirm the effectiveness of these medicines specifically for pregnant women,” Tran told Medscape Medical News. “While these pharmacologic smoking cessation aids like NRT, varenicline, and bupropion are effective in the broader population of people who smoke, physiological changes during pregnancy could alter medicine metabolism, and consequently their effectiveness,” she noted. Studies are needed to evaluate the effects of smoking cessation medications on other adverse outcomes as well, such as the likelihood of preterm birth, low birth weight, and any potential risks to the pregnant woman, Tran added. 

Study Size Supports Safety

“Robust pregnancy-related drug safety data are difficult to acquire, and this is particularly so for rare, life-altering conditions like MCMs,” wrote Tim Coleman, MD, of the University of Nottingham, Nottingham, England, and Sophie Orton, PhD, of the Society for the Study of Addiction, Northampton, England, in an accompanying editorial. 

The current study provides encouragement to clinicians to offer smoking cessation medications to pregnant women, especially given the even greater health risks associated with continuing to smoke while pregnant, the editorialists wrote. The data support previous evidence of the safety of NRT and increase comfort with other options. 

“Some who try but are unable to stop smoking with NRT might now consider trying varenicline or bupropion,” although with counseling that neither drug is recommended in guidelines or widely used for smoking cessation during pregnancy, they said. 

Ideally, the current study will prompt randomized, controlled trials of the effectiveness of varenicline and bupropion, they added. Meanwhile, motivation to stop smoking during pregnancy is often high, and clinicians should take advantage and consistently offer cessation support to all pregnant patients who smoke, they emphasized.

Data Augment Clinicians’ Comfort

Clinicians know the significant risk associated with smoking during pregnancy, but most do not routinely offer NRT when advocating smoking cessation, said Marissa Platner, MD, associate professor of maternal-fetal medicine at Emory University, Atlanta, in an interview. “This paper gives us the opportunity to be able to better counsel our patients on the possibility of quitting given the limited risk of fetal harm from medical options to assist with smoking cessation,” she said.

Platner was surprised by the association between kidney and urinary tract abnormalities and varenicline but noted that these abnormalities may not be severe. 

In clinical practice, the data are helpful in counseling patients toward smoking cessation and on more options for assistance, said Platner. “The findings overall are very reassuring, and I would recommend these medications to patients who are open to smoking cessation,” she said.

“The major limitation of the study is that it is based on population-level data and self- reported smoking status without any knowledge of how much women were smoking,” Platner told Medscape Medical News. “More research is needed to look at long-term outcomes and larger numbers of the specific associated anomalies with the medications and NRT,” she added.

This study was supported by an NHMRC Ideas Grant, the University of New South Wales Research Infrastructure Grant, University of New South Wales Scientia Program Award, the National Health and Medical Research Council Medicines Intelligence Centre of Research Excellence (1196900), the Research Council of Norway, and the Research Council of Norway Centers of Excellence. The researchers had no financial conflicts to disclose. Coleman disclosed grants from the National Institute for Health and Care Research paid to their institution. Orton disclosed grants from the Society for the Study of Addiction and the National Institute for Health and Care Research. Platner had no financial conflicts to disclose.