Article: Peter Hajek et al., “Electronic cigarettes versus nicotine patches for smoking cessation in pregnancy: a randomized controlled trial,” Nature Medicine 28:5 (May 2022), pp. 958-964.

Reviewed by: Stacey McKenna

More than 480,000 people die in the United States every year due to combustible cigarettes and more than 16 million Americans are living with a smoking-related disease. It is well established that the habit increases the risk of developing a wide range of health problems, from emphysema and cardiovascular disorders to cancer. For pregnant smokers, the potential dangers extend to negative birth outcomes, including low birthweight, miscarriage and stillbirth. Despite these risks, about 13.5 percent of women in the United States smoke combustible cigarettes, and about 7.2 percent of those who become pregnant report smoking at some point during their pregnancy.

Given that it is notoriously difficult to quit smoking, the quest to find more effective tobacco cessation tools as well as safer alternatives to combustible cigarettes is key for empowering individuals—including pregnant smokers—to improve their health. In recent years, studies conducted with nonpregnant smokers have begun to indicate that e-cigarettes may serve such a purpose. While not risk-free, electronic nicotine delivery systems (ENDS) are safer than combustible cigarettes and may be more effective quit tools than nicotine replacement therapies (NRT) such as patches or chewing gum. Furthermore, although animal studies indicate that nicotine use is not risk-free during pregnancy, a small body of emerging research demonstrates that NRT is associated with fewer negative birth outcomes than smoking combustible cigarettes. Less is known about the efficacy of alternatives to combustible cigarettes in helping people reduce tobacco-related harms during pregnancy, and this dearth of high-quality research gives clinicians few evidence-based pathways by which to help pregnant smokers who want to quit.

To advance this conversation, Peter Hajek and his colleagues conducted a clinical trial evaluating the relative efficacy and safety of e-cigarettes and NRT as alternatives to combustibles during pregnancy. To do this, the research team recruited and randomly assigned 1,140 United Kingdom-based pregnant smokers to either an e-cigarette group (569) or an NRT (571) group. The study provided the allocated products for up to eight weeks and then compared smoking and birth outcomes. The outcomes measured included: smoking and other nicotine use during pregnancy; biological validation of those self-reported responses; and key pregnancy-related serious adverse events, adverse events, and adverse reactions including birthweight, congenital abnormalities, and stillbirth.

Hajek et al. found no significant difference between validated end-of-pregnancy prolonged quit rates among participants in the e-cigarette arm compared to those in the NRT arm. However, because some participants who were assigned NRT also used e-cigarettes, the authors conducted an additional statistical test—a “pre-specified sensitivity analysis”—that excluded all abstinent participants who used “unallocated products.” This analysis indicated that participants in the e-cigarette arm were significantly more likely to report abstinence from combustible cigarettes than those assigned to nicotine patches at four weeks after proposed quit dates (15.4 percent compared to 8.6 percent, P = 0.001). In addition, the e-cigarette group was more likely to refrain from cigarette smoking at the end of pregnancy according to self-reported prolonged abstinence (10.7 percent versus 5.6 percent, P = 0.002), validated abstinence (9.8 percent versus 5.2 percent, P = 0.004) and self-reported point prevalence abstinence (19.8 percent versus 9.7 percent, P < 0.001). Thus, the authors concluded that e-cigarettes may be at least as effective as NRT in helping pregnant women quit smoking combustible cigarettes.

Regarding safety and tolerability, the two product categories were similar. The overall incidence of adverse events, as well as maternal and birth outcomes, were not significantly different, with 476 serious adverse events or adverse events reported in the e-cigarette arm and 479 in the NRT arm. However, low birthweight was more common in the NRT arm (14.8 percent) than in the e-cigarette arm (9.6 percent, P = 0.01). Both groups reported some undesirable reactions to the products, such as skin irritation and nausea among NRT-assigned participants and cough and throat irritation among e-cigarette-assigned participants.

Overall, Hajek et al.’s findings support the potential of ENDS products as a reduced-risk alternative for pregnant smokers of combustible cigarettes through this well-designed research. Their use of a randomized controlled model—the gold standard for clinical trials—ensured that causal conclusions could be drawn. In addition, the researchers used data from previous research to predict the number of “quitters” they could expect in each intervention. Based on this, they sampled enough participants to achieve 90 percent statistical power—which is well above the recommended minimum of 80 percent—across groups. Furthermore, the statistical assumptions and adjustments they made in response to the small but important proportion of participants who used “nonallocated” products (i.e., individuals in the NRT arm who used e-cigarettes or vice versa) ensured that if they did create bias, it would be toward the null hypothesis, so it did not weaken the strength of the authors’ conclusions. Importantly, the study also demonstrated that it is possible to conduct high-quality trials among groups that are typically deemed “vulnerable” and often excluded from clinical research.

The researchers acknowledged several limitations of the study, including timing (it coincided with the widely covered 2019 “e-cigarette or vaping product use-associated lung injury” outbreak in the United States); low overall rates of treatment uptake and abstinence; and participants’ potential expectations regarding assigned products. Issues around participant expectations and the broader social context in which smoking cessation and harm reduction aids are studied cannot be perfectly controlled and, in some cases, may reflect real-world challenges to uptake. The persistently low rates of treatment uptake and abstinence in smoking studies suggest that researchers should continue to seek larger sample sizes. Hajek et al.’s findings provide sufficient data on the safety of e-cigarettes and NRT during pregnancy to give other scholars the confidence to build studies with larger participant pools.

In addition, it is important to note that Hajek et al.’s efforts to validate participants’ self-reported abstinence from either combustible cigarettes or all nicotine using carbon monoxide or salivary levels of cotinine and anabasine were largely unsuccessful. Only 108 of 193 participants who reported abstinence returned saliva samples, and only 20 provided carbon monoxide readings. Although this does not undermine Hajek et al.’s findings—return rates did not differ significantly between the two study arms—it does suggest that there is a need for lower-barrier ways to collect this information.

Taken as a whole, this study presents strong evidence that e-cigarettes are at least as safe and effective as NRT for pregnant women seeking to quit smoking combustible cigarettes and provides data on which future research can build.