Electronic Nicotine Delivery Systems (ENDS) Use and Pregnancy II: Perinatal Outcomes Following ENDS Use During Pregnancy

Abstract

Purpose of Review:

This review examines the risk of adverse perinatal outcomes following electronic nicotine delivery system (ENDS) use during pregnancy, and considers whether there are sufficient data to support ENDS as a harm reduction approach during pregnancy.

Recent Findings:

Seven papers assessed perinatal outcomes following ENDS use during pregnancy. There was evidence that ENDS use was associated with increased risk for some adverse perinatal outcomes (e.g., small for gestational age). However, the repeated use of data sets, insufficient data (e.g., timing of ENDS use, type of ENDS products used), and limited samples size, contributed to mixed findings on the degree to which ENDS use (alone or in combination with combustible cigarettes (CC)) impacts the risk of adverse perinatal outcomes relative to CC smoking alone.

Summary:

The current data are still insufficient to support ENDS as a harm reduction approach, though findings do warrant concern and more detailed investigation of ENDS use during pregnancy. Future research directions, as well as implications for clinical recommendations and tobacco regulatory science are discussed.

1. INTRODUCTION

1.1. Overview and Focus of Review

There is a well-established link between combustible cigarette (CC) smoking during pregnancy and adverse perinatal outcomes [1]. In contrast, there is an emerging, yet still nascent, literature on the use of electronic nicotine delivery systems (ENDS) during pregnancy, and the relative risks of ENDS use for perinatal outcomes. This review will examine the extent to which the public perception that ENDS are safe during pregnancy (or, safer than CCs) [2–5] is justified by the current literature.

ENDS are a relatively new addition to the tobacco product (TP) marketplace (since 2007 in the US) and have since substantially expanded in terms of the variability of products [6]. The term ‘ENDS’ refers to a category of products which are electronic devices that heat a liquid to create an inhalable aerosol. Most notably, this category includes e-cigarettes, which are also known as vapes, vape pens, mods, pod mods, or Juul, among other names. Although the term includes the phrase ‘nicotine delivery system’, it is important to note that not all ENDS products contain nicotine. The nicotine levels in ENDS can be equivalent to or higher than the nicotine amounts contained within and/or delivered by CC smoking [7, 8]. Additionally, there are thousands of different flavor options and devices ranging from small closed-system disposable e-cigarettes that resemble traditional CCs all the way to large rechargeable and adjustable devices [8–10]. These product characteristics have the potential to impact the risk profile of ENDS devices.

1.2. A Historical Lesson: Risks of CC Smoking During Pregnancy

Although CC smoking during pregnancy is not the focus of this review, it provides a historical lesson. Furthermore, CC smoking is relevant to ENDS since the relative risks/benefits of ENDS use is often considered not only relative to abstinence from all TPs (where ENDS likely presents an increased risk) but also relative to CC smoking (where ENDS is often presumed to present a decreased risk (i.e., harm reduction)). It is well-established that CC smoking during pregnancy is related to increased risk for a range of adverse perinatal outcomes, including but not limited to: miscarriage [11], stillbirth [12], preterm premature rupture of membranes (PPROM) [13], placental abruption, placenta previa [14], preterm birth [15], congenital malformations [16], small for gestational age (SGA) [17], low birth weight (LBW) [18], Sudden Unexpected Infant Death/Sudden Infant Death Syndrome (SUID/SIDS) [19] as well as diabetes mellitus [20], postpartum depression, and diminished breastfeeding [1, 21, 22]. In utero CC exposure also has adverse impacts on health beyond infancy, with increased risk of a variety of long-term conditions into childhood and adulthood such as respiratory-related symptoms of allergies (e.g., wheezing) [23, 24], asthma [25], obesity [26], smoking [27], behavioral problems (e.g. attention deficit hyperactivity disorder, poor academic achievement) [28], and cardiovascular disease [29].

The risks of CC smoking during pregnancy are now widely accepted, but early research linking CC smoking during pregnancy to adverse outcomes faced skepticism, with critics suggesting that “low-birth-weight infants appear to be attributable to other individual characteristics rather than the smoking itself” [30], page 277). This skepticism is similar to earlier arguments disputing the link between smoking and lung cancer – positing that there are “differences in the genotypic composition of the smoking classes – non-smokers, cigarette smokers, pipe smokers, etc.” that is the “common cause” linking cigarette smoking and lung cancer and that “[the] theory that increased smoking is ‘the cause’ of the change in apparent incidence of lung cancer is not even tenable…” ([31] (pg. 298)). It is important to remember how delays in the recognition of the risk of smoking CC during pregnancy may have adversely impacted public health. Promptly assessing the risks of newer TPs, like ENDS, during pregnancy can minimize the chances that this mistake will be repeated.

1.3. Rationale for Considering Adverse Health Outcomes from ENDS Use in Pregnancy

A systematic review of the literature up to 2017 found no published human studies assessing pregnancy outcomes and ENDS use [32]. A more recent review, which covered the literature up to July 2019, identified only two studies which assessed ENDS use and perinatal outcomes in humans, and additionally considered important questions related to the potential harm (e.g., nicotine delivery) or harm reduction (e.g., use as cessation aid) and risk perception of ENDS during pregnancy during pregnancy, therefore underlining the clinical relevance of this topic [33]. Several lines of evidence lay the groundwork for the need to consider health outcomes for ENDS use during pregnancy.

Data are increasingly clear that within non-pregnant samples, ENDS use presents health risks as compared to abstinence from all TPs. ENDS use results in exposure to toxicants that vary widely in composition and dose between products (and increase with power and heat delivered by the device), including carbonyl compounds (e.g., formaldehyde, diacetyl), volatile organic compounds (e.g., benzene), trace elements (e.g., lead), and reactive oxygen species [34]. An outbreak in 2019 of acute lung injury linked with ENDS use led to the identification of e-cigarette, or vaping, product use-associated lung injury (EVALI) [35]. EVALI has been linked with the use of e-liquids that contain vitamin E acetate (which is more commonly found in e-liquids that contain tetrahydrocannabinol (THC)), and black-market products or products purchased off the street. The contribution of other e-liquid components to EVALI cannot be ruled out at this time [35]. Rates of hospitalizations due to EVALI have declined since the initial peak [35], perhaps in part due to CDC monitoring, FDA oversight of problematic vendors, and the publicization of these risks which could have resulted in self-monitoring within the e-cigarette industry, and increased education of the general public on which products to avoid. However, in addition to EVALI, there is mounting evidence that indicates ENDS use adversely affects the respiratory system, including the lungs [36]. ENDS may also adversely affect extrapulmonary organ systems, but research is preliminary [37, 38]. Although most of this research excludes pregnant persons, the general risks of exposure to toxicants and organ damage would be expected to apply to pregnant persons who use ENDS as well. Moreover, there may be additional risk to the fetus as a number of these toxicants may pass through the placenta [39].

Most ENDS contain nicotine, and nicotine itself is a known developmental toxicant [1, 40–44] that may alter brain development [45]. It is important to note that while it is clear that nicotine presents a risk to fetal development [1, 40–44], there is some evidence that using non-combustible Nicotine Replacement Therapy (NRT) may be an acceptable harm reduction method for pregnant smokers [46–48]. However, consistent clinical guidelines on NTR and pregnancy in the US are lacking. For example, in 2020, the American College of Obstetrics and Gynecologists (ACOG) states that pregnant women may be advised to use NRT upon discussion of risks and with close supervision [49]. In contrast, in 2021, the US Preventive Services Task Force (USPSTF) concluded there were insufficient data to make a recommendation [50]. Moreover, international guidelines are also strikingly inconsistent [51]. The delivery of nicotine from ENDS differs from NRT in important ways: not only do the pharmacokinetics differ (with ENDS providing higher peaks and lower troughs while NRT delivers a more steady state), the amount of nicotine delivered with ENDS use also varies widely across products depending upon factors including the nicotine level of the e-liquid, device design, power setting, as well as use behavior (puff topography) [8]. As such, although some research on the first-generation of ENDS devices indicated that the levels of nicotine delivery were low, current research indicates ENDS can deliver nicotine levels equivalent to or greater than that typically delivered by CC smoking [8], and the average nicotine concentration in ENDS sold in the US has increased over time [52]. Users may be unaware of the nicotine content of their ENDS [53–56] or have difficulty understanding nicotine content labels [54, 57]. Therefore, even if other nicotine delivery systems (e.g., NRT) are deemed safe during pregnancy, it is not possible to extrapolate from those findings to establish the safety of ENDS [1, 40–44].

Preclinical research suggests that exposure to ENDS aerosol reduces fertility (impairs embryo implantation), and in-utero exposure to ENDS aerosol results in a wide range of adverse health outcomes in the offspring [32], such as acute respiratory effects, and long-term memory reduction [58–62]. A subset of studies considered both nicotine-containing ENDS and no-nicotine ENDS conditions [60–62] and results indicate that ENDS do not need to contain nicotine to adversely affect perinatal outcomes. For example, in-utero ENDS aerosol exposure with or without nicotine alters some fibroblast markers and matrix proteins in offspring [63], homeostatic control markers [62], immune markers [64], and neural (hippocampal) [65] gene expression [65].

Taken together, these lines of evidence indicate it is critically important to consider the potential adverse impacts of ENDS use on perinatal outcomes especially as data emerge from human studies of ENDS use during pregnancy.

1.4. Consideration of Harm Reduction Potential of ENDS Use During Pregnancy

Although the focus of this review is to consider whether ENDS use itself is associated with adverse perinatal outcomes, it is also important to acknowledge that many pregnant persons do use other TPs, including CC smoking. These individuals may consider the use of ENDS as a form of harm reduction.

The perceptions of ENDS as a low-risk behavior or as a means of harm-reduction, relative to CC smoking or other combustible TP use, may contribute to ENDS use during pregnancy. Pregnant women tend to report that they believe ENDS use is less harmful than CC smoking during pregnancy [2, 3, 66–70]. Non-pregnant and pregnant women also commonly endorse the belief that ENDS use could help them quitting CC smoking [70–72]. Whether ENDS are an effective harm reduction strategy depends on two criteria: (1) the degree to which they are safe (or not) during pregnancy, and (2) whether they effectively reduce CC smoking. A review of the literature on whether ENDS is effective at reducing CC smoking behavior is beyond the scope of this review, though we have reviewed ENDS use and transitions of use during pregnancy elsewhere [72].

1.5. Scope and Methods of Review

The goal of this review is to synthesize findings in pregnant persons from population-based or cohort-based samples related to the risk of adverse perinatal outcomes following ENDS use during pregnancy.

This narrative literature review utilized the following methods to identify manuscripts: As was done in [72], searches were limited to ‘Human’ (i.e., preclinical research not included), and written in the English language. Searches in PubMed database initially focused on two population-based datasets with information on ENDS and pregnancy: namely the Population Assessment of Tobacco and Health (PATH, [73]) and the Pregnancy Risk Assessment Monitoring System (PRAMS, [74]). Searches used search terms related to ENDS (e.g., “electronic nicotine delivery systems” or “ENDS” or “electronic cigarettes” or “e-cigarette” or “vaping”) and pregnancy (e.g., “pregnant” or “pregnancy” or “prenatal” or “antenatal” or “perinatal”) plus the study names (i.e., “Pregnancy Risk Assessment Monitoring System” or “PRAMS” or “Population Assessment of Tobacco and Health” or “PATH”). More general searches in PubMed, PsychInfo, and Google Scholar to capture other datasets were then performed using the terms related to ENDS and pregnancy detailed above. The references of the identified papers were then reviewed to determine whether any of the cited papers met inclusion criteria for this review.

Papers met criteria for inclusion for this review if they were population-based or cohort studies (cross-sectional or longitudinal) which assessed rates (or relative rates) of perinatal outcomes following ENDS use during pregnancy (relative to any other TP use category and/or no TP use). Information extracted from each paper (see Table 1) included the 1) characteristics of the sample: N, inclusion criteria, years of data collection, timing within pregnancy (e.g., gestational age at study participation); 2) definition of TP use groups: which groups were compared, how group membership was defined; 3) perinatal outcomes considered in the analysis and whether any confounds were accounted for in the analysis; 4) summary of findings related to perinatal outcomes for ENDS use groups or other relevant comparisons.

TABLE 1.

ENDS USE AND PERINATAL OUTCOMES

Citation, Dataset, and Sample	TP Use Comparison Groups	Perinatal Outcomes and Confounds	Summary of Findings Relevant to ENDS and/or Pregnancy: prevalence reported as %; odds ratios (OR) or adjusted OR (aOR) or relative risk (RR) always followed by [95% Confidence Intervals (CI)]
Pregnancy Risk Assessment Monitoring System (PRAMS) Dataset
Cardenas et al 2020 [75] Dataset: PRAMS; Phase 8 of Arkansas PRAMS (2016–2017) Sample: Arkansan women who had a live singleton birth during the Phase 8 cycle time frame and had complete information on TP use and SGA (N=1,594). Location: United States (Arkansas)	TP Use Group (Based on use during 3 mo prior to pregnancy and last 3 mo of pregnancy): 1. ENDS only (n=18) 2. CC only (n=372) 3. Dual use (n=100) 4. Other TP only (no ENDS or CC) (hookah, chewing, snuff, snus, dip, cigars, cigarillos, or little cigars; n=42) 5. No TP use (n=1,062) Transition Groups (3 mo prior to pregnancy → last 3 mo of pregnancy): 1. Dual use → ENDS Only: (n=25) 2. CC only →No TP: (n=157) 3. No TP → No TP: (n= 1062)	Perinatal Outcome: Small for gestational age (SGA) ENDS exposure: defined by reporting ‘1 day per week or less’ or ‘more than 1 time a day’ use in 3 months prior to pregnancy and/or last 3 months of pregnancy. Consideration of Confounds: Analyses generally consistent with and without adjustment for maternal age, race/ethnicity, education, and alcohol intake (≥1 drink a week). Adjusted results (i.e., multivariate relative risk (RR)) reported here.	Percent (%) of each TP use group: No TP Use: SGA=9.3% ENDS only: SGA=0% (note small sample: n=18) Dual Use: SGA=20.7% CC Only: SGA=16.8% Other TP Only: SGA=14.1% Multivariate RR [95% CI] relative to No TP Use: ENDS only: RR not calculable (note small n) Dual Use: SGA=1.8 [1.0, 3.4] CC Only: SGA=1.6 [1.0, 2.6] Other TP Only: SGA=1.9 [0.6, 5.3] Transition Groups (multivariate RR [95% CI]): ‘Dual use → ENDS Only’ increased risk of SGA relative to ‘CC only → No TP’: SGA 2.9 [1.4, 6.3]  No TP → No TP : SGA= 3.2 [1.5, 6.6]
Kim and Oancea 2020 [76] Dataset: PRAMS; Phase 8 (2016–2018) Sample: Women who gave birth to singletons; had complete data on variables of interest (N=55,521) Location: United States (nationally representative sample)	Based on any use during the last 3 months of pregnancy: 1. ENDS only (n=337) 2. CC only (n=3,484) 3. No TP use (n=51,430) Note: Dual use group (ENDS and CC) was excluded from the analyses (n=395).	Perinatal Outcomes: SGA; low birth weight (LBW); Preterm birth (PB) Consideration of Confounds: Used propensity matching to match TP use groups on 7 variables: maternal (race/ethnicity, age, educational attainment, 1st trimester CC smoking, 2nd trimester CC smoking), familial (income), obstetrical (prenatal care).	Weighted Percentages (%) per TP Use Group No TP Use: SGA=8.62, LBW=5.37, PB=7.15 ENDS Only: SGA=14.00, LBW=7.34, PB=11.74 CC Only: SGA=21.86, LBW=11.96, PB=10.57 Weighted, adjusted Odds Ratio (aOR [95% CI]) ENDS only vs. No TP Use: statistically significant increase in odds of SGA (1.76 [1.04, 2.96], LBW (1.53 [1.06, 2.22]), and PB (1.86 [1.11, 3.12]. ENDS only vs. CC only: no statistically significant differences in the odds of SGA (0.67 [0.30, 1.47]), LBW (0.71 [0.37, 1.37]), or PB (1.06 [0.46, 2.48]).
Wang et al 2020 [77] Dataset: PRAMS; 2016 Sample: women participants who gave birth to singletons and have complete data on variables of interest (N=31,973) Location: United States (nationally representative sample)	Based on any use during the last 3 months of pregnancy: 1. ENDS only (n=215) 2. CC only (n=2,622) 3. Dual use (n=432) 4. No TP use (n=25,501)	Perinatal Outcomes: SGA, PB Consideration of Confounds: Two models run. Both adjusted for confounders (demographics, adequate prenatal care, pre-pregnancy alcohol use, parity, previous pre-term birth, pre-pregnancy BMI, gestational weight gain). Model 2 also adjusted for use of CC and/or ENDS use in the 3 months prior to pregnancy; Model 1 did not. Findings were consistent across both models. Model 2 data reported here.	Rates (%) per TP Use Group No TP Use: SGA=8.9, PB= 7.6 ENDS Only: SGA=16.5, PB=7.8 CC Only: SGA=20.8, PB=11.7 Dual Use: SGA=20.1, PB=7.9 Adjusted Odds Ratio (aOR [95% CI]) vs. No TP ENDS only vs. No TP: Statistically significant increase in odds of SGA (2.4 [1.0, 5.7]), no statistical difference for PB (1.2 [0.5, 2.7]). Dual use vs. No TP: Statistically significant increase in odds of SGA (2.3 [1.3, 4.1]), no statistical difference for PB (1.3 [0.8, 2.3]). CC only vs. No TP: Statistically significant increase in odds of SGA (2.4 [1.8, 2.9]) and PB (1.6 [1.2, 2.0])
Wang et al 2021 [78] Dataset: PRAMS; 2016–2018 Sample: Pregnant women who gave birth to a live singleton; had complete data on CC and ENDS use before and during pregnancy (N=99,201) Location: United States (nationally representative sample)	Use categories based on CC and ENDS use in the last 3-months of pregnancy. No TP Use (n=90,198; 92.0%) ENDS only use: O-ENDS (n=108; 0.1%) F-ENDS (n=131; 0.1%) Dual use: L-CC&O-ENDS (n=230; 0.2%) L-CC&F-ENDS (n=163; 0.1%) H-CC&O-ENDS (n=212; 0.2%) H-CC&F-ENDS (n=118; 0.1%) CC only use: L-CC (n=4,988; 4.2%) H-CC (n=3,176; 2.9%)	Perinatal Outcomes: SGA; PB Consideration of Confounds: Two models run. Both adjusted for confounders mother’s age, education level, race/ethnicity, marital status, previous preterm history, plurality, prenatal care, pre-pregnancy BMI, drinking alcohol before pregnancy, and birth year. Model B also adjusted for use of CC and/or ENDS use in the 3 months prior to pregnancy; Model A did not. Findings were consistent across both models. Model B data reported here. Frequency of TP Use Definitions Occasional ENDS (O-ENDS): < 1/day Frequent ENDS (F-ENDS): ≥ 1/day Light CC (L-CC): 1–5 CC/day Heavy CC (H-CC): ≥ 6 CC/day No TP Use: No ENDS or CC use	Prevalence (%) of SGA and PB No TP Use: PB: 7.6%; SGA: 8.9% ENDS Only O-ENDS: PB: 5.1%; SGA: 15% F-ENDS: PB: 10.0%; SGA: 10.1% Dual Use L-CC&O-ENDS: PB:5.5%; SGA: 18.7% L-CC&F-ENDS: PB: 8.7%; SGA: 27.0% H-CC&O-ENDS: PB: 11.3%; SGA: 25.3% H-CC&F-ENDS: PB: 8.5%; SGA: 20.8% CC Only L-CC: PB: 11.1%; SGA: 18.1% H-CC: PB: 11.7%; SGA: 21.5% Adjusted ORs [95% CI] for adverse outcomes: No TP Use: referent group ENDS Only O-ENDS: PB: 0.8 [0.3, 1.7], SGA: 1.4 [0.5, 3.9] F-ENDS: PB: 1.2 [0.7, 2.3], SGA: 1.1 [0.5, 2.5] Dual Use L-CC&O-ENDS: PB: 0.6 [0.3, 1.1], SGA:2.0 [1.1, 3.4] L-CC&F-ENDS: PB: 1.2 [0.6, 2.4], SGA: 3.4 [1.7, 6.6] H-CC&O-ENDS: PB: 1.5 [0.8, 2.9], SGA: 3.4 [2.0, 5.7] H-CC&F-ENDS: PB: 1.4 [0.8, 2.6], SGA: 3.1 [1.3, 7.1] CC Only L-CC: PB: 1.3 [1.1, 1.5], SGA: 2.1 [1.8, 2.5] H-CC: PB: 1.4 [1.2, 1.8], SGA: 3.1 [2.3, 3.3]
Other Datasets
Cardenas et al 2019 [80] Dataset: Pregnancy Cohort Study (same as Clemens 2019) Sample: Pregnant women age 18+; recruited from prenatal clinic serving low-risk pregnant women (i.e. those without underlying medical conditions or co-morbidities and without antenatal complications); (enrolled=248; N=232 in pregnancy outcome analysis). Location: United States (Arkansas)	Current (any past month) use: 1. ENDS Only (n=6) 2. CC Only (n=56) 3. Dual Use (n=17) 4. Other TP Use (n=11) 5. Secondhand exposure only (No Current TP Use but Exposed to secondhand smoke/ENDS-aerosols; n=45) 6. Unexposed (No current TP Use and No secondhand smoke/ENDSaerosol; n=97) Note: from total sample N=248, weeks of gestation at enrollment <20 weeks (n=84; 33.9%); 20+ weeks (n=162; 65.3%); missing data (n=2; 0.8%). Current ENDS Use (yes) by weeks of gestation at enrollment (<20 week: N=12 (14.3%); 20+ weeks: N=11 (6.8%); missing data: n=1 (50%))	Perinatal Outcome: SGA Among participants who reported current ENDS use (current=any past month use), frequency of ENDS use: daily to 10 times/month (20.8%); 3–9 times/month (29.2%), 1–2 times/month (50%). Consideration of Confounds: Multivariate relative risk (RR), adjusted for maternal age and race/ethnicity, are reported here; unadjusted findings (not shown) follow similar pattern.	Percent (%) of SGA in each TP use group: ENDS Only: SGA=33.3% Dual Users: SGA=23.5% CC Only: SGA=23.1% Secondhand exposure only: SGA=14.0% Unexposed: SGA=11.3% Multivariate relative risk (RR [95% CI]) of SGA vs. the Unexposed group: Unexposed: RR= referent group ENDS Only: 3.1 [0.8, 11.7] Dual Users: 1.9 [0.6, 5.5] CC Only: 1.9 [0.9, 4.3] Secondhand exposure only: 1.2 [0.5,3.0] Secondary analysis correcting for misclassification, using biomarker confirmation (hair nicotine ≥2.77 ng/mL as the standard), found association between ENDS use and the risk of SGA were 3 to 4 times the uncorrected estimates.
Clemens et al 2019 [79] Dataset: Pregnancy Cohort Study (same as Cardenas et al 2019) Sample: Pregnant women (≥18 years old) recruited from prenatal clinic serving low-risk pregnant women; who gave birth to singletons; had complete survey data; and provided hair specimens (N=76) Location: United States (Arkansas)	Current (any use within past month) of CC and/or ENDS By Self-Report (SR): 1. No TP Use (n=38) 2. Dual use(n=11) 3. CC only (n=27) Self-Report Confirmed by Biomarkers (SR+B): 1. No TP Use (n=25) 2. Dual use (n=9) 3. CC only (n=24) ENDS only user (n=1) excluded. Average gestational age for sample not reported.	Perinatal Outcome: SGA ENDS use defined as any past month use of electronic vapor product (e-cigarettes, e-cigs, electronic cigarettes, e-hookahs, mods, pods, cartomizers, clearomizers, or tanks). Consideration of Confounds: Adjusted relative risk (RR), adjusted for maternal age, are reported here; unadjusted findings (not shown) follow similar pattern.	TP Use groups defined by self-reported use (SR) or SR confirmed by biomarker (SR+B). Percent (%) of SGA in each TP use group: No TP Use: SR: 8%, SR+B: 4% Dual Use: SR:27%, SR+B: 33% CC Only: SR: 26%, SR+B: 29% Adjusted relative risk (RR [95% CI]) of SGA: No TP Use: referent group Dual Use: SR:3.9 [0.9,16.2], SR+B: 8.3[1.0,69.1] CC Only: SR:3.9 [1.1, 13.6], SR+B: 7.8[1.0,59.0] Adjusted RR of SGA by hair nicotine ≥2.77 ng/mg (vs < 2.77 ng/mg): 7.7 [1.1, 56.0]
McDonnell et al 2020 [81] Dataset: Prospective observational cohort study Sample: Pregnant women attending large urban maternity hospital for antenatal care. Prospectively identified based on clinical charts for ENDS use, CC use and no TP use. (N=620) Location: Ireland (Dublin)	Participants were asked about ‘current’ ENDS and CC use between 10–14 weeks of gestation: 1. ENDS only (n=218) 2. CC only use (n=99) (at least 1 CC/day) 3. Dual use (n=195) 4. Never TP use (n=108)	Perinatal Outcomes: Infant birthweight; LBW; gestational age at delivery; NICU admission; Mean Apgar scores; Breastfeeding at discharge Consideration of Confounds: Unadjusted results are reported here and in the paper. Age, ethnicity, parity, and socio-economic status determined (by multiple regression) not to influence birthweight comparisons between TP use groups.	Birthweight: ENDS only use (3470 ± 555 g) was similar to No TP use (3471 ± 504 g); and significantly greater than CC use (3166 ± 502 g) and Dual use (3140 ± 628 g). LBW: ENDS only use (11%) had a similar rate to No TP use (12.9%); and significantly lower rate than CC use (28%) and Dual use (30.7%). Average gestational age at delivery (M+SD): No statistically significant differences between ENDS use (39+3 weeks), dual use (39+0), CC use (39+2), and no TP use (39+4). NICU admission: ENDS only use (6.9%) did not differ from No TP use (4.6%), CC use (6%) or dual use (7.6%) groups. Apgar scores: did not differ between groups (9, 10). Breastfeeding: ENDS only use (48.6%) had significantly lower rates than No TP use (61.1%) and significantly higher rates than CC only (27.2%) or dual use (29.7%) groups.

Abbreviations and Terms: TOBACCO-RELATED: TP=tobacco product (includes CC and ENDS and other tobacco products); ENDS=Electronic Nicotine Delivery Systems (note: ENDS refers to a category which includes e-cigarettes; although nicotine is in the name, we are using this term generally and products assessed in each study CANNOT be presumed to include nicotine just because they are referred to as ENDS); CC=Combustible cigarette; Dual Use= ENDS and CC use; “smoking” refers to use of combustible tobacco products (e.g., CC), “vaping” refers to use of ENDS product. PREGNANCY OUTCOMES: SGA = Small for Gestational Age; LBW = Low Birth Weight; PB=preterm birth. STATISTICS: OR= Odds Ratio; aOR= Adjusted Odds Ratio; RR = Risk Ratio; M=mean, SD=Standard Deviation; CI=Confidence Interval. OTHER: BMI= Body Mass Index; PRAMS= Pregnancy Risk Assessment Monitoring System.

As specific factors related to ENDS described above (e.g., nicotine, flavor, device characteristics) have the potential to impact the risk profile of ENDS devices, this review included details on the characteristics of the product(s) used in each study. This information was included wherever possible, but was often not available in detail.

2. RESULTS

Seven papers were identified that addressed adverse pregnancy outcomes within individuals who used ENDS during pregnancy; these papers are summarized in Table 1.

Limited population-based cross-sectional data is emerging on infant outcomes indicating that perinatal ENDS use increases the risk for adverse infant outcomes. Four separate PRAMS analyses are available on this topic [75–78]. They primarily categorize TP use based on the last 3 months of pregnancy, and differed in the TP groups assessed, confounds accounted for in analyses (e.g., demographics, TP use at other time periods) and whether the full or partial PRAMS dataset was included (see Table 1 for details). Cardenas et al (2020) assessed relative risk of small for gestational age (SGA) in dual use, CC only, or other TP use groups, each relative to no TP use; relative risk could not be calculated for the ENDS only group due to a small sample (n=18) and no incidence of SGA [75]. Relative to no TP use, dual use and CC only use groups each had a similarly increased risk of SGA [75]. In addition, they considered SGA rates between transition groups. Those who reported dual use prior to pregnancy and then switched to ENDS only by the final trimester of pregnancy continued to show increased risk of SGA relative to those who smoked CCs prior to pregnancy who quit smoking (and did not use ENDS) by the final trimester of pregnancy and relative to those with no TP use at both timepoints [75]. Kim and Oancea (2020) [76] compared ENDS only with no TP use and separately with CC only use on three outcomes: SGA, low birth weight (LBW), and preterm birth (PB); the dual use group was excluded from analyses. Compared to no TP use, ENDS only group showed significantly increased odds of SGA, LBW, and PB; and no statistically significant differences in odds of SGA, LBW, or PB between ENDS only versus CC smoking only groups (although these latter analyses may have been somewhat underpowered to detect clinically-meaningful differences) [76]. Wang et al (2020) [77] assessed odds of SGA or PB in ENDS only, dual use, or CC only groups, each relative to no TP use. While ENDS only, dual use, and CC only groups all showed significantly increased odds of SGA relative to the no TP use group, only the CC only group also showed significantly increased odds for PB [77]. Wang et al (2021) considered odds of SGA and PB by TP product and frequency of use: TP groups (ENDS only, dual, CC only) were split into subgroups based on the frequency of ENDS (< or ≥ 1/day) and/or CC (1–5 or ≥6/day) and each subgroup was compared with no TP use group [78]. The dual use groups had the highest incidence of SGA, at least twice the odds of SGA relative to no TP use, regardless of whether they were in the higher or lower frequency CC or ENDS subcategories [78]. However, this study found no evidence that ENDS use alone (< or ≥ 1/day) increased the odds for SGA relative to no TP use [78]. Odds of PB was statistically significantly increased in the CC only, relative to no TP use, but not in the ENDS only or dual groups (although prevalence rates were similar between dual use group with more frequent use and CC only groups) [78]. The pattern of findings for PB and SGA was consistent whether or not pre-pregnancy CC smoking and ENDS use was included in the model [78].

Data from two separate cohorts – one from a prenatal clinic for women with low-risk pregnancies [79, 80], and one from an urban maternity hospital in Dublin, Ireland [81], also considered perinatal outcomes. TP use was either assessed as self-reported past month use (nicotine biomarkers collected) and not restricted to a specific time period within pregnancy [79, 80], or as ‘current’ use between 10–14 weeks of gestation [81]. Cardenas et al (2019) [80] assessed SGA in ENDS only, dual, CC only, or secondhand smoke/ENDS aerosol exposure groups, each relative to an unexposed group (no TP use or regular secondhand smoke/ENDS aerosol exposure). The risk of SGA, relative to unexposed group, was twice as high for the dual use and CC only groups, and three times as high for the ENDS only group; and after adjusting the analysis to exclude individuals from the non-exposure group with nicotine biomarker levels inconsistent with non-exposure, the relative risks were further increased for ENDS use groups to 6.5–8.5 higher than non-exposed group [80]. Clemens et al (2019) used a subset of that cohort with additional biomarker data available, to assess SGA in dual and CC only groups, each compared with no TP use [79]. Dual and CC only groups each had approximately 4 times higher risk of SGA relative to no TP use when TP groups were defined by self-report only, and each had approximately 8 times higher risk than no TP when groups were defined by self-report plus nicotine-biomarker-confirmation [79]. When based only on hair nicotine biomarkers (without consideration of CC or ENDS use), higher nicotine exposure was associated with 7.7 times higher risk of SGA [79]. Biomarkers indicated similar levels of nicotine exposure in dual use and CC use only groups [79, 80]. McDonnell et al 2020 [81] considered LBW, birthweight, gestational age at birth, NICU admission, mean Apgar scores, and breastfeeding at discharge in ENDS only relative to dual, CC only, and no TP use groups. Birthweight and incidence of LBW did not significantly differ between ENDS only and no TP use groups; ENDS only had higher average birthweight and lower rates of LBW than dual or CC only groups; rates of LBW were similar between dual and CC only groups but they were not formally compared [81]. ENDS only had lower rates of breastfeeding than the no TP use group, but higher than CC only and dual use groups [81]. Average gestational age, Apgar scores, or NICU admissions did not significantly differ between ENDS only and any other groups [81].

Taken together, although there are some mixed findings, these data suggest that ENDS use may be associated with some adverse perinatal outcomes, relative to no TP use. However, it is important to note that these findings were not fully independent of each other, since several of these analyses used the same dataset (e.g., PRAMS, Pregnancy Cohort Study). However, of the analyses that considered rates of SGA, three out of four ([76, 77, 80] but see also [78]) found increased SGA in ENDS only relative to no TP use, five out of five ([75, 77–80]) found increased SGA in dual use relative to no TP use. There was limited evidence for PB: one of three analyses found increased rates in ENDS only versus no TP use ([76] but see also [77, 78], and neither analysis that considered it found increased rates in dual use versus no TP use ([77, 78]). One of two analyses found increased rates of LBW in ENDS only versus no TP use ([76] but see also [81]). The only analysis that considered average birthweight, gestational age at birth, NICU admission, or Apgar scores did not find differences between ENDS only and no TP use, but did find diminished rates of breastfeeding in ENDS only relative to no TP use [81].

While there is indirect evidence of diminished risk (i.e., harm reduction) related to ENDS use compared to CC only use, there is very little direct evidence to support this claim. For example, while several analyses report adverse outcomes that occurred at higher rates in the CC only group but not the ENDS only group, only two studies formally compared ENDS only vs. CC use groups; a large nationally-representative US study [76] found the ENDS only group had equivalent rates of adverse outcomes as the CC only group (SGA, LBW, PB), while a smaller cohort study out of Ireland found lower rates of adverse outcomes in the ENDS only versus CC only or dual use groups (average birthweight, LBW, breastfeeding rates) [81]. None of the studies formally compared dual use with CC only in terms of perinatal outcomes. Therefore, the data addressing the question of whether ENDS use diminishes risk relative to CC smoking is mixed and limited.

Information on the frequency/heaviness of ENDS use in terms of perinatal outcomes is lacking. In some cases ENDS frequency was reported in the sample but not adjusted for in the analyses (e.g., [80]). Wang et al (2021) [78] considered heaviness/frequency of use of ENDS and CCs (alone or as dual use) and found that not only the number and type of products used (ENDS only, CC only, or dual) but also the frequency/heaviness of use of each product may impact odds of adverse perinatal outcomes. Although Wang et al [78] concluded that, in general, “higher levels of exposure tended to confer more risk”, this pattern held with regards to ENDS use for some but not all outcomes. So even though there may be a dose-response relationship, many studies fail to take the heaviness of use into account and this has not yet been clearly demonstrated with ENDS use and perinatal outcomes. None of the perinatal outcome papers considered the relationship of other ENDS product characteristics (e.g., nicotine level, flavor, ENDS device type) to pregnancy outcomes.

3. CONCLUSIONS

3.1. Summary of Key Findings

Although gaps in the literature remain and there are some conflicting findings, the body of currently available literature suggests that ENDS use (alone or dual use) during pregnancy may increase the risk of adverse perinatal outcomes relative to no TP use. Furthermore, the current body of evidence does not provide clear support for ENDS as an effective harm reduction strategy for pregnant persons who smoke CCs. However, in addition to comparing categories of use versus no use, a more nuanced evaluation of the impact of ENDS by timing of use (i.e., first vs. second vs. third trimester), frequency of use, nicotine level, and other product characteristics (e.g., flavor, device type) as well as the impact of ENDS on other outcomes (e.g., stillbirth, abnormal placentation) is needed to accurately quantify the risk of ENDS use during pregnancy on adverse perinatal outcomes.

3.2. Discussion of Risk of Adverse Perinatal Outcomes Following ENDS Use

Although the literature on ENDS use and perinatal outcomes is only emerging within the past year and some findings are mixed, an important subset of findings points to reason for concern that there are higher risks associated with ENDS only or dual use relative to no TP use. There is thus far little data directly addressing the question of whether dual use or ENDS only use reduces risk relative to CC only, and the available data is equivocal. Important gaps in the literature remain.

Overall, the data indicated increased odds of the adverse perinatal outcome of SGA following ENDS use only or dual use during pregnancy, relative to no TP use. Other perinatal outcomes (e.g., PB) were assessed in fewer analyses and the findings were mixed. Inconsistencies in the findings could reflect differences in pregnant persons included in each sample, how TP use groups were defined, which additional confounds were controlled for in the analyses, differences in power due to variable sample sizes, or regulatory differences across different states or countries. The fact that several analyses used data from the same datasets (e.g., PRAMS, Pregnancy Cohort Study) also likely inflates the consistency across findings.

It is important to consider whether ENDS may be a harm reduction strategy that could improve outcomes in pregnant women who smoke CCs. Although this is widely accepted to be true, existing evidence is insufficient to make this determination, and some of this evidence suggests this is not true. Most analyses did not formally compare ENDS only or dual use with CC only groups; within two that do make this direct comparison, findings are inconsistent [76, 81]. So, the degree to which adding ENDS to CC use (dual use) or switching to ENDS only in place of CC only use meaningfully reduces the risk of adverse perinatal outcomes is not clear. The limited direct evidence for harm reduction in terms of perinatal outcomes, alongside the cumulating evidence for potential perinatal risks from ENDS only or dual use (relative to no TP use), suggests a conservative approach aiming for total TP abstinence during pregnancy is still warranted, unless and until substantial harm reduction is demonstrated for dual or ENDS only use relative to CC only use.

Many of the adverse perinatal outcomes associated with CC use [1] have not yet been assessed in relation to ENDS use, including but not limited to miscarriage, stillbirth, placenta previa, congenital malformations, SUID/SIDS, diabetes, depression, and allergies, asthma, obesity, behavioral problems, and cardiovascular disease. The possibility remains that ENDS use may protect against some adverse outcomes (relative to CC use) but not others, which would present more challenges in terms of clinical decision-making.

Furthermore, the current data on ENDS and pregnancy outcomes provide very little information on the characteristics of ENDS products being used by pregnant women (e.g., nicotine levels, flavors, device types) and the frequency/heaviness of use. Many existing studies have a low level of use as a requirement to be categorized into the ENDS use group in their analyses. This may indicate that even limited exposure to ENDS during pregnancy may be sufficient to increase risk of adverse outcomes; alternatively, it is also possible that heavier ENDS use could be driving some of the risk outcome findings. While findings from Wang et al (2021) found some evidence that frequency/heaviness of use impacted outcomes, the pattern of increasing risk with increased ENDS exposure was not as consistently clear as it is with CC exposure [78]. This may have been due to limitations in how frequency/heaviness was conceptualized, with more nuanced measures and higher threshold required for minimal inclusion for CC (1–5 cc/day, ≥6 cc/day) than ENDS (<1/day, ≥1/day) in those analyses.

There is also very limited data on the relative impact of ENDS use on perinatal outcomes in relation to the timing of ENDS use during pregnancy. The PRAMS studies focused on TP use in the last 3 months of pregnancy [75–78] and one cohort study focused on weeks 10–14 of pregnancy [81], while the other cohort study collected gestational age information but did not define TP use groups based on use during a specific pregnancy time period [79, 80]. As additional perinatal outcomes are considered, a broader assessment of exposure across pregnancy time points is needed, as timing of exposure may influence the impact on adverse outcomes.

3.3. Implications for Clinical Recommendations and Tobacco Regulatory Science

Determination of the risks and/or harm reduction potential of ENDS could impact public health through several mechanisms. This information could inform public understanding, clinicians’ guidance, and the FDA’s regulation of ENDS. In turn, these effects could impact the decision-making of pregnant persons regarding ENDS use and change the ENDS marketplace. This information is particularly important as it relates to pregnancy, a time of increased vulnerability to tobacco-related harms, and a time of potential behavioral change.

3.3.1. Clinical Implications

Some pregnant women believe that ENDS use does not pose significant harm during pregnancy or presents a harm reduction relative to CC smoking during pregnancy [2, 3, 66–70, 72]. ENDS use during pregnancy may pose a clinically significant risk. While it may be the case that ENDS may function as a harm reduction aid relative to CC smoking, the current data are still insufficient to support ENDS as a harm reduction approach as a clinical recommendation for women who smoke CCs. As reviewed above, there are not yet clear data to show the degree to which ENDS use diminishes risk relative to CC smoking (if one switches from CC to ENDS only) or whether dual use of ENDS alongside CC (e.g., replacing a subset of one’s CCs per day with ENDS) reduces or increases risks during pregnancy. The actual relative risks of these behaviors likely relate to the ways in which the products are used (frequency of use, characteristics of the products used), so the notion that any use of ENDS (alone or alongside CCs) could be seen as a harm reduction option relative to CC is most likely an oversimplification. The one clinical message that can be clearly discerned from the existing data is that fully quitting ENDS use, CC smoking, and other TP use during pregnancy is optimal. Of course, many women would like to fully quit TPs during pregnancy but struggle to do so. Pregnant women should be encouraged to follow current clinical guidelines and try evidenced-based cessation treatments approved for use during pregnancy (e.g.,[47, 49, 82]) prior to relying on ENDS as a harm reduction approach. Further, as more research on ENDS use during pregnancy emerges, these findings can be used to inform clinical guidelines related specifically to ENDS use in pregnancy.

3.3.2. Tobacco Regulatory Implications

The US Food and Drug Administration (FDA) has the ability to regulate TPs, including ENDS, following the passing of the ‘Tobacco Control Act’ in 2009 (Family Smoking Prevention and Tobacco Control Act §§ 901–910, Pub. L. No.111–31, 123 Stat. 1776 (June 22, 2009)) [83], and determination in 2016 that this regulatory authority extends to ENDS products ([Pub. L. No., 81 FR 28973 (August 8, 2016)). The ability for the FDA to make evidence-based regulatory decisions about ENDS products provides an opportunity to shape public health more proactively than was possible when the field first acknowledged the risks of CC smoking during pregnancy.

Although the data on ENDS use in pregnancy are still emerging and more research is needed to guide regulations, some future regulatory directions that may have an impact on public health are suggested below.

Public education campaigns and warning labels may be helpful to align beliefs surrounding ENDS risks and harm reduction potential with the available data and state of the field. Warning labels have been successful in reducing the prevalence of CC smoking in pregnant persons [84–86]. One challenge for regulators may be the dearth of information on the types of product characteristics used by pregnant persons and how that relates to adverse outcomes. For example, preclinical data indicate that ENDS aerosol exposure – with or without nicotine - can have adverse impacts on perinatal outcomes, but the current clinical data are not able to parse out the degree to which nicotine accounts for, or simply exacerbates, the risks of ENDS use. Until this is clear, warning labels or public education campaigns may need to focus on ENDS more generally, while separately also pointing out the risks of nicotine itself during pregnancy.

Many individuals who use ENDS indicate difficulty understanding the nicotine content and other characteristics of products (e.g., [53–57]), making it difficult to get accurate survey information on these topics. Clear package labels that unambiguously report the amount of nicotine in the product and/or delivered to users, especially in relation to CC, would give consumers the opportunity to make informed self-administration choices, with the potential to titrate down their own nicotine doses. Standardization of this reporting across brands and devices would improve consumer knowledge. Incorporation of this information into public education campaigns may improve general knowledge of these topics and, in turn, lead to more precise clinical data on product characteristics used in pregnancy. Although less commonly reported, some studies found pregnant women cited lower price as a reason for using ENDS; taxation may address this concern [69, 87, 88], since taxes have been an effective tool in reducing CC smoking prevalence [89, 90].

3.4. Next Steps and Future Directions

It would be valuable for future studies assessing how ENDS impact perinatal outcomes to collect more refined information on ENDS use behavior in terms of frequency/heaviness of ENDS use, and ENDS product characteristics (e.g., flavors, nicotine levels, and devices) used during pregnancy. Relatedly, there is a need to continue conducting research, with comprehensive assessments, as new ENDS products emerge, as they may pose different risk profiles.

In addition to the key pregnancy outcomes presented in the existing literature, it is crucial to examine additional adverse outcomes that have been associated with TP use, such as maternal outcomes, and longer-term outcomes in the offspring (e.g., into childhood).

Most of the available research is in US samples. Research comparing outcomes across countries with different population-level ENDS use or products available (due to differing ENDS regulations; [91]) could shed light on the full scope of possibility of ENDS not only as a potential risk, but also their potential as a harm reduction approach, during pregnancy.

Finally, given the indications that ENDS use during pregnancy is associated with adverse outcomes, clinical trials on TP cessation during pregnancy should consider ENDS cessation as endpoint of interest as well, alongside CC smoking cessation endpoints.

Continued research in this area is of high priority. Prompt and thorough assessment of risks of newer TPs, such as ENDS, may have significant public health impacts by increasing pregnant persons’ and clinicians’ knowledge as well as informing tobacco regulatory actions, all of which may influence behavior, ultimately sparing adverse health effects for parents and infants.