Use of electronic nicotine delivery systems (ENDS) by pregnant women I: Risk of small-for-gestational-age birth

INTRODUCTION The 2016 US Surgeon General’s Report suggests that the use of electronic nicotine delivery systems (ENDS) is a fetal risk factor. However, no previous study has estimated their effect on adverse pregnancy outcomes. We assessed the prevalence of current ENDS use in pregnant women and explored the effect on birth weight and smallness-for-gestational-age (SGA), correcting for misclassification from nondisclosure of smoking status. METHODS We conducted a cohort study with 248 pregnant women using questionnaire data and biomarkers (salivary cotinine, exhaled carbon monoxide, and hair nicotine). We evaluated the association between birth weight and the risk of SGA by applying multivariate linear and logbinomial regression to reproductive outcome data for 232 participants. Participants who did not disclose their smoking status were excluded from the referent group. Sensitivity analysis corrected for misclassification of smoking/ENDS use status. RESULTS The prevalence of current ENDS use among pregnant women was 6.8% (95% CI: 4.4-10.2%); most of these (75%) were concurrent smokers. Using self-reports, the estimated risk ratio of SGA for ENDS users was nearly two times the risk in the unexposed (RR=1.9, 95% CI: 0.6-5.5), and over three times that for ENDS-only users versus the unexposed (RR=3.1, 95% CI: 0.8-11.7). Excluding from the referent group smokers who did not disclose their smoking status, the risk of SGA for ENDS-only use was 5 times the risk in the unexposed (RR=5.1, 95% CI: 1.1- 22.2), and almost four times for all types of ENDS users (RR=3.8, 95% CI: 1.3-11.2). SGA risk ratios for ENDS users, corrected for misclassification due to self-report, were 6.5-8.5 times that of the unexposed. CONCLUSIONS Our data suggest that ENDS use is associated with an increased risk of SGA. For this pregnancy cohort study, we recruited volunteers among patients seen at a prenatal clinic serving low-risk pregnant women (i.e. those without underlying medical conditions or co-morbidities and without antenatal complications) and assessed their exposure to tobacco products by self-report and non-invasive biomarker assays. We also obtained permission to access their medical records to extract specific data on the reproductive outcomes described below. Our study population consisted of pregnant women seeking prenatal care at a low-risk pregnancy clinic of a University affiliated center in Little Rock, Arkansas. The clinic is a low-risk pregnancy clinic, i.e. it provides care to ‘singleton, term, vertex pregnancies, (without) any other medical or surgical conditions’34. Pregnant women were eligible if they were ≥18 years old, spoke English, and planned to deliver their babies at the University affiliated hospital. Patients from the teen pregnancy clinics and high-risk patient clinics were therefore not included. From April 2015 to May 2017, eligible pregnant women were queried to identify smokers and ENDS users. From November to December 2016, the recruitment was non-consecutive, instead we identified and enrolled an ENDS user first, followed by the next smoker, and then the next nonsmoker. The questions were previously developed by Mullen et al.35 to improve disclosure of smoking status among pregnant women. We added a similar question to identify ENDS users. Participants were asked to fill in a 10-minute self-administered questionnaire assisted with a tablet computer using an application developed with LimeSurvey (GmbH, Hamburg, Germany). The questionnaire collected data on ever and current cigarette smoking and use of other tobacco products, including ENDS, the time since their last use, and their exposure to secondhand smoke/ENDS aerosol. In 2016, we added a question about the number of cigarettes smoked in the 3 months before the current pregnancy; therefore, this information was limited to a subset of participants. We also asked the participants to provide a 2 mL sample of saliva through a funnel into a vial for on-site testing of salivary cotinine (NicAlert, Nymox, St. Laurent, Quebec). According to the manufacturer, the cutoff value of this test for tobacco use is ≥10 ng/mL. Exhaled CO levels were collected by asking the participants to take a deep breath, hold it for 10 seconds, and breathe out slowly through a cardboard mouthpiece into a babyCOmpact, Smokerlyzer unit (Bedford Scientific, Haddonfield, NJ). According to the manufacturer, the cutoff value of CO to identify smoking is ≥7 ppm. Because cotinine in fluids such as saliva has a short half-life (16 hours)26, and previous studies demonstrated that hair nicotine is a more reliable biomarker of long-term exposure27, particularly for reproductive outcomes from maternal exposure to tobacco, we measured hair nicotine levels as described in the companion manuscript36. Ever users of ENDS were defined as those who reported that they had tried ENDS, and current users were defined as those who reported ENDS use within the previous month. Similarly, ever cigarette smokers were defined as those who reported smoking at least 100 cigarettes in their lifetime, current cigarette smokers were defined as those who reported smoking in the previous month. Thus, we classified the participants according to self-report into one of the following six groups: 1) current ENDS dual users including concurrent cigarette smokers, 2) current ENDS-only users, 3) current cigarette smokers who currently did not use ENDS, 4) non-current smokers/non-current ENDS users not exposed to secondhand smoke or ENDS aerosols or other tobacco products, 5) non-users of tobacco products but exposed to secondhand smoke or ENDS aerosols, and 6) users of tobacco products other than cigarettes or ENDS. Among the non-current smokers there were only two ever smokers who reportedly stopped smoking more than a year before. Because the most likely threat to the validity of our study would be a measurement error introduced by misclassification due to nondisclosure of smoking status, we used data from salivary cotinine or CO tests to exclude undisclosed active tobacco users from the referent group (i.e. the fourth group listed above). We obtained each neonate’s estimated gestational age at birth and birth weight from medical records. We then used the US National Center for Health Statistics birth data as referent37, obtaining gender- and gestational age-adjusted z-score for birth weight for each singleton birth in our study population. Furthermore, we used the 10th percentile of the gender-specific and gestational age-specific birth weight38 to identify SGA. The protocol was approved by the Institutional Review Board (Protocol Number 203805) of the authors’ University. Participants who reported using tobacco and wanted to quit were provided with a flyer with a toll-free number to a smoking-cessation resource. We obtained written informed consent from the participants to: collect questionnaire data, breath, saliva, and hair specimens for markers of tobacco use; access the participants’ personal prenatal medical records; and retrieve specific data from their medical and birth records. The association of ENDS use with age, income, education, occupation, weeks of gestation (if known at baseline) and cigarette smoking was assessed using the entire set of observations. We compared the self-reported levels of smoking and ENDS use along with the distribution of hair nicotine, salivary cotinine, and CO, in each of the six comparison groups. We used the z-score of the birth weight of the participants’ neonates as a continuous outcome variable, while SGA was treated as a dichotomous outcome variable. Confidence intervals (CIs) around proportions were calculated using the Wilson score method39. Stratified analyses were used to adjust the risk ratio (RR) using the Mantel-Haenszel estimator of the common RR40. Multiple regression analyses were conducted for birth-weight data, while multiple logistic regression analysis was performed for SGA using the log-binomial model to estimate the RR and its 95% CI41, as the outcome (SGA) was common (>10%) in the study population. We conducted sensitivity analyses to correct the estimate of the size of the association between tobacco use and the risk of SGA for misclassification by self-report of smoking/ENDS use. Specifically, we used two approaches for this. First, we excluded from the referent group those self-reported non-users of tobacco not exposed to secondhand smoke or ENDS aerosols who had salivary cotinine or CO levels consistent with active smoking/ENDS use. Second, we used the estimates of sensitivity and specificity for self-report of smoking using hair nicotine as the gold-standard, both from our own study population and from estimates published in the literature29, which were then applied for correction of misclassification of self-report, using the formula described elsewhere42. We also considered other pregnancy outcomes such as preterm delivery (PTD, i.e. a neonate delivered at less than 37 weeks of gestation) and admissions to the neonatal intensive care unit. However, in this low-risk pregnancy clinic study population, there were few PTDs and other adverse reproductive outcomes (Supplementary Table 1), and we focused our assessment on the adjusted z-score for birth weight and SGA. The sample size estimates were based only on the estimation of the prevalence of ENDS use and were deemed exploratory for the remaining study objectives. All of these analyses used complete case analysis and were conducted with SAS v9.4 (SAS Institute, Cary, NC). Frequency of current use* of electronic nicotine delivery systems (ENDS) among pregnant women by age, weeks of gestational age at enrollment, parity, race/ethnicity, education, income, and current cigarette smoking in Little Rock, Arkansas, 2015–2017 (N=248)