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13 Developmental and Reproductive Effects Potential effects of e-cigarette use during pregnancy are of great inter- est for a number of reasons. The increasing prevalence of use among young women in the reproductive age range, combined with the known hazards of combustible tobacco cigarette smoking and the heightened awareness of health issues in relation to pregnancy, naturally raises the question of the nature of how e-cigarettes may affect the pregnancy. Although there is little evidence to draw on in response to that con- cern, there are a range of opinions regarding its impact, as summarized recently. A review examining perception and use of electronic cigarettes during pregnancy found that the most common perceptions of e-cigarette use during pregnancy were that they posed some risk to maternal and child health, but were safer than combustible tobacco cigarettes for both mother and baby and that they may be used as a tool for smoking cessa- tion (McCubbin et al., 2017). The physiological challenges of pregnancy make this a time of vulner- ability to other stressors, particularly those associated with cardiovascular health, and thus a time of particular concern regarding potential health effects of e-cigarettes. Changes in blood flow, blood pressure, and glucose tolerance associated with normal pregnancy have been noted to constitute a âstress testâ that results in a sizable proportion of women becoming temporarily diabetic or hypertensive. In addition, there may be changes in renal function, immunological responses, and other potentially relevant concerns. Short-term effects of e-cigarette use on maternal physiology 461
462 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES would be feasible to assess using non-invasive markers, such as Doppler ultrasound to assess blood flow to the fetus. The fetus undergoes rapid organ development and tissue growth prior to birth. Many toxins, including nicotine, can cross the maternal pla- cental barrier. In addition, gestational age of the fetus greatly influences susceptibility to a particular toxicant. For example, during embryonic life certain chemical exposures can be teratogenic while at a later gestational age, these same toxins can impair tissue and organ growth. Observational studies of offspring born of mothers who used e-cigarettes during preg- nancy are needed to examine the impact of in utero e-cigarette exposure on congenital malformations and fetal growth. Additional observational studies are needed to determine the impact of in utero e-cigarette expo- sure on postnatal lung function and behavior of offspring in later life. Although some potential adverse effects of nicotine on fetal development and growth are known, nothing is known about the effects of aerosols that contain flavorings. CHARACTERIZATION OF DISEASE ENDPOINTS AND INTERMEDIATE OUTCOMES The potential for e-cigarettes to affect the course and outcome of preg- nancy is plausible, given the range and magnitude of known effects of combustible tobacco cigarette smoking, which includes placental abrup- tion, ectopic pregnancy, preterm birth, fetal growth restriction, stillbirth, infant mortality, sudden infant death syndrome (SIDS), and orofacial clefts (HHS, 2014). While the specific constituents of tobacco smoke responsible for the harm to the mother and fetus are incompletely understood, nico- tine is likely to be one of the sources of risk to the fetus, which would be pertinent to potential effects of e-cigarettes. The harm from other tobacco constituents, including carbon monoxide and tobacco-Âpecific s n Â itrosamines, for example, which pose threats to reproductive health, would not be pertinent or would be far less of a concern. It is possible that chemicals unique to e-cigarettes would affect fetal and neonatal develop- ment, but there is little or no direct evidence to guide such inferences. Broadly, there is the potential for nicotine effects on pregnancy com- plications and fetal development. Pregnancy complications of concern based on tobacco include an increased risk of placental abruption and a potential protective effect for hypertensive disorders. Fetal and neoÂ natal outcomes of concern include stillbirth, reduced growth, and preterm birth, extending into infant mortality, neurodevelopmental deficits, and increased risk for lower respiratory tract infections and asthma develop- ment. The most sensitive neonatal response to nicotine exposure might be a reduction in birth weight (Hayes et al., 2016), which is markedly affected
DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 463 by tobacco use. The most severe, though non-specific, neonatal outcome associated with tobacco use is infant mortality. In a study from Sweden, infant mortality was decreased in subsequent pregnancies in mothers who quit smoking (Johansson et al., 2009). No epidemiological studies or biological studies have yet been performed to examine potential links between maternal e-cigarette use during pregnancy and reduction in birth weight or increased infant mortality. In utero and early postnatal nicotine exposure through e-cigarette use may adversely affect the immune system and lung function of exposed infants. A study from South Africa found that infants had a fivefold greater risk of acquiring bacterial pneumonia if they had a primary caregiver who smoked (Verani et al., 2016). Other studies reported that young children exposed to tobacco smoke in utero were more likely to have impaired lung function (Dezateux et al., 2001; Gray et al., 2017). The most directly relevant analogy to e-cigarettes would be nicotine replacement therapy (NRT), which is another form of nicotine delivery through means other than inhalation (i.e., ingestion or dermal absorp- tion). However, the epidemiological evidence on NRT and pregnancy is quite limited. An evaluation of the use of NRT versus placebo among pregnant combustible tobacco cigarette smokers resulted in more favor- able birthweights for the NRT group despite similar cotinine levels (pre- sumably reflecting similar levels of nicotine intake) in one study (Wisborg et al., 2000). This suggests that constituents of tobacco other than nicotine are the source of harm, though a more recent trial showed no benefit (Coleman et al., 2012), which would be consistent with nicotine being responsible for tobaccoâs effects. The advisability of using NRT during pregnancy remains unresolved (Osadchy et al., 2009). Nonetheless, the use of NRT and possibly the use of e-cigarettes as a substitute for tobacco would likely reduce the potential for harm given the absence of carbon monoxide and other toxicants present in tobacco smoke. Despite the lack of direct evidence, e-cigarettes are generally per- ceived to be less harmful than combustible tobacco by pregnant women who smoke combustible tobacco cigarettes (Baeza-Loya et al., 2014; Mark et al., 2015). Perspectives of clinical experts vary widely, including argu- ments that e-cigarettes are likely to be just as harmful as combustible tobacco cigarettes during pregnancy (Farquhar et al., 2015) and others advocating for a role for e-cigarettes in harm reduction for pregnant women (Bryce and Robson, 2015). Obstetricians who were surveyed indi- cated that 13.5 percent judged e-cigarettes to be free of harm, 29.0 percent believed e-cigarettes had adverse effects but were less harmful than com- bustible tobacco cigarettes, 13.5 percent indicated that e-cigarettes and combustible tobacco cigarettes were equally harmful, and 36.5 percent indicated that they did not know (England et al., 2016).
464 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES OPTIMAL STUDY DESIGN The optimal study design would be a randomized trial in which pregnant women are assigned to smoke combustible tobacco cigarettes or e-cigarettes, or not use either product, which is ethically unacceptable and infeasible to implement. Approximating that, calls for observational designs that attempt to isolate the impact of e-cigarettes on the course and outcome of pregnancy and subsequent neonatal development are warranted. This would require accurate assessment of e-cigarette use throughout the course of pregnancy, recognition of different potential impacts depending on timing during gestation, thorough consideration of potential confounding factors that could introduce bias into the com- parisons across exposure groups, and rigorous, objective assessment of the spectrum of endpoints from pregnancy complications through birth outcomes and infant health and development. As is the case for other health endpoints, there is a need to compare e-cigarette users with (1) non-users of any nicotine-containing products and (2) specifically combustible tobacco cigarette users, with careful control for correlated behaviors such as alcohol and marijuana use given their association with smoking (Agrawal et al., 2012; Metz and Stickrath, 2015). This is especially relevant to pregnancy because women are often motivated to take measures to improve the health of their pregnancy and may be more motivated to stop smoking combustible tobacco cigarettes than at other times of their life. It would be important to recognize the potential for effects on the fetus to become manifest over the course of early life and perhaps beyond, given the growing evidence that the prenatal environ- ment influences health outcomes such as neurobehavioral development, cardiovascular and pulmonary disease risks, and mental health through the life course. QUESTIONS ADDRESSED BY THE LITERATURE Other than public and clinical perceptions of the relative safety or harm from e-cigarettes, there is almost no directly relevant research in humans to inform an assessment. Laboratory research on toxicity of e-cigarettes in pregnancy has begun, as described below, but there are no clinical or epidemiological studies thus far. EPIDEMIOLOGY No studies are currently available that directly assess the impact of e-cigarette use on the health of pregnancy. Not only have clinical end- points not been examined, but to the committeeâs knowledge, there are no
DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 465 studies of markers of maternal or child health related to exposure during pregnancy. CASE REPORTS AND OTHER CLINICAL STUDIES No case reports or other clinical studies of e-cigarettes in relation to pregnancy were identified. IN VIVO ANIMAL AND IN VITRO/MECHANISTIC STUDIES A study by Parker and Rayburn (2017) examined the effects of regular, menthol, and electronic cigarette butt (ECB) leachates on Xeonopus laevis embryos and found that all leachates were teratogenic, but the ECB were less toxic and teratogenic than the other two in their model. Another study by Palpant and colleagues (2015), using zebrafish and human embryonic stem cells, found negative health effects on heart development from both combustible tobacco cigarette and e-cigarette exposure of similar nicotine levels, but that combustible tobacco cigarette smoke exposure was more toxic. STUDIES ON COMBUSTIBLE TOBACCO AND NICOTINE The scarcity of studies examining the impact of e-cigarettes on fetal and postnatal development and reproductive health during pregnancy presents a significant limitation in predicting health effects of e-cigarette emissions on the fetus and pregnant mother. Consequently, the committee considered research on the effects of combustible tobacco cigarettes and NRT on developmental and reproductive outcomes, which may or may not reflect the real risk of e-cigarette aerosols to fetal and reproductive health, but which the committee could draw on in their assessment of the health risk of e-cigarettes to these outcomes. For example, although there are currently no studies in humans evaluating the effects of nicotine- containing or non-nicotine e-cigarettes on fetal and childhood develop- ment and reproductive health, because e-cigarettes often contain nicotine, data examining the effects of nicotine exposure on the fetus and young child may estimate risk of nicotine exposure. Epidemiological Studies Nicotinic acetylcholine receptors (nACHRs) are present in the fetal brain and lungs of humans, and nicotine is a nACHR agonist (Smith et al., 2010; Wang et al., 2001). Exposure of the fetus to nicotine through maternal e-cigarette use or combustible tobacco cigarette smoking has the
466 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES potential to activate nACHRs in the brain and lung prematurely, causing disruption of normal development. Children of mothers who smoked combustible tobacco cigarettes during pregnancy have been reported to have an increased likeli- hood of developing behavioral difficulties including attention-deficit/Â hyperactivity disorder (e.g., Abbott and Winzer-Serhan, 2012), possi- bly caused by prenatal exposure to constituents of combustible tobacco cigarette smoke. Maternal combustible tobacco cigarette smoking dur- ing pregnancy also has been associated with a significant increase in wheezing during childhood in several studies (Gilliland et al., 2001, 2003; Moritsugu, 2007). Whether children exposed to e-cigarette aerosols when in utero are also at increased risk for similar adverse outcomes remains unknown. Very high nicotine levels have been detected in dried blood spots of neonates of mothers who smoked combustible tobacco cigarettes during pregnancy, indicating the ease with which nicotine can cross the placen- tal barrier (Murphy et al., 2013; Spector et al., 2014). In addition, because drug metabolism of nicotine has been reported to be slower in the fetus and infant compared with the adult (Dempsey et al., 2000), greater cumu- lative exposure to nicotine may occur in the fetus and infant exposed to nicotine. The consequences of slower drug metabolism could result in greater toxicity to the fetus and neonate when compared with similar nicotine exposure in more mature children and adults. The observation that combustible tobacco cigarette smoke exposure is causally related to an increased risk of SIDS has been noted (Moritsugu, 2007). Reduction in the number of SIDS cases in European countries in which combustible tobacco cigarette smoking rates declined over a period of years further suggests an association (Boldo et al., 2010). The role of nicotine in SIDS is unclear; however, Lavezzi and colleagues (2014) found that among subjects who died of sudden intrauterine unexpected death syndrome or of SIDS, those whose mothers smoked combustible tobacco cigarettes during pregnancy were more likely to have greater Î±7 nACHR immunostaining in lung epithelial cells and lung vessel walls compared with those whose mothers did not smoke combustible tobacco cigarettes. In a study examining the risk of major congenital abnormalities in children of mothers who smoked combustible tobacco cigarettes or used NRT, there were no differences between the two groups with the excep- tion (OR = 4.65; 99% CI = 1.76â12.25) that children of NRT users had an increased risk of respiratory anomalies (Dhalwani et al., 2015). The adverse effect of nicotine on in utero lung development has been suggested to be caused by an increase in oxidative stress (Maritz and van Wyk, 1997). If nicotine is the primary component in combustible tobacco cigarette smoke that alters lung and brain development in the children
DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 467 of mothers who smoke those cigarettes during pregnancy, then exposure to the nicotine from e-cigarette aerosols may also present an increased health risk to the fetus and neonate, though not necessarily equal to that of combustible tobacco cigarettes. Animal Studies Animal studies in rodents and non-human primates have demon- strated an adverse effect of nicotine on fetal airway development and lung histology. When nicotine pumps were implanted in pregnant rhesus monkeys, offspring were found to have a reduced total body weight and alveolar hypoplasia with upregulation of Î±7 receptors in the airway car- tilage and vessels of fetal lungs (Sekhon et al., 1999). Exposure to nicotine during fetal and early postnatal life also has been shown to transiently disrupt vascularization of the lung and alter lung development, but not lung function in a rodent model. Mean linear intercepts of lungs in mice exposed to prenatal and postnatal nicotine was increased and vascular endothelial growth receptor 2 was decreased in lungs at 3 weeks but not 12 weeks of age (Petre et al., 2011). Other studies have shown that prenatal nicotine exposure can stim- ulate lung branching through Î±7 nicotinic receptors in murine lung explants, possibly contributing to dysanaptic lung growth (Â ongtrakool W et al., 2007). Supporting this finding was an additional study that demon- strated that offspring of mice exposed to prenatal nicotine had decreased forced expiratory flows and decreased airway diameters (Wongtrakool et al., 2012). Exposure to prenatal combustible tobacco cigarette smoke also has been shown to promote Th2 polarization in mice (Singh et al., 2011). One study examined the effects of whole-body exposure of pregnant mice and their offspring to nicotine-containing e-cigarette aerosols from late prenatal to early postnatal life, approximating the duration of corti- cal brain development in the mouse. They reported alterations in risk- taking behaviors in adult mice previously exposed to nicotine-containing e-cigarettes during fetal and early life compared with mice exposed to e-cigarettes without nicotine (Smith et al., 2015). In another study, neoÂ natal mice exposed to nicotine-containing e-cigarettes were found to have impaired alveolar growth and decreased lung cell proliferation compared with controls (McGrath-Morrow et al., 2015). Taken together, although several animal studies have demonstrated an adverse effect of in utero nicotine on lung development and postnatal lung function and behavior, no doseâresponse studies were performed. In addition, studies of the effects of nicotine on fetal and early prena- tal development in animal models have used nicotine pumps, systemic
468 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES nicotine injections, and whole-body e-cigarette exposures, which may not replicate the human exposure. In addition, it is unknown whether the particle size of emissions or flavoring contained in some e-cigarette emis- sions can adversely affect fetal development. Further studies are needed before recommendations can be made regarding the risks of e-cigarette use during pregnancy to fetal development and if e-cigarette use as a substitute for combustible tobacco cigarette smoking is a safer alternative compared with NRT. SYNTHESIS Given the lack of direct empirical evidence of e-cigarettesâ effects on the mother or fetus, from either human or animal studies, little can be said regarding an integrated evaluation. Although the extensive research on tobacco and limited evidence on nicotine in isolation gives some focus to the questions regarding the potential effects of e-cigarettes, the need for direct evaluation is clear. Conclusion 13-1. There is no available evidence whether or not e-cigarettes affect pregnancy outcomes. Conclusion 13-2. There is insufficient evidence whether or not mater- nal e-cigarette use affects fetal development. REFERENCES Abbott, L. C., and U. H. Winzer-Serhan. 2012. Smoking during pregnancy: Lessons learned from epidemiological studies and experimental studies using animal models. Critical Reviews in Toxicology 42(4):279â303. Agrawal, A., A. J. Budney, and M. T. Lynskey. 2012. The co-occurring use and misuse of cannabis and tobacco: A review. Addiction 107(7):1221â1233. Baeza-Loya, S., H. Viswanath, A. Carter, D. L. Molfese, K. M. Velasquez, P. R. Baldwin, D. G. Thompson-Lake, C. Sharp, J. C. Fowler, R. De La Garza, 2nd, and R. Salas. 2014. Perceptions about e-cigarette safety may lead to e-smoking during pregnancy. Bulletin of the Menninger Clinic 78(3):243â252. Boldo, E., S. Medina, M. Oberg, V. Puklova, O. Mekel, K. Patja, D. Dalbokova, M. Krzyzanowski, and M. Posada. 2010. Health impact assessment of environmental tobacco smoke in European children: Sudden infant death syndrome and asthma episodes. Public Health Reports 125(3):478â487. Bryce, R., and S. J. Robson. 2015. E-cigarettes and pregnancy. Is a closer look appropriate? Australian and New Zealand Journal of Obstetrics and Gynaecology 55(3):218â221. Coleman, T., S. Cooper, J. G. Thornton, M. J. Grainge, K. Watts, J. Britton, S. Lewis. 2012. A randomized trial of nicotine-replacement therapy patches in pregnancy. New England Journal of Medicine 366(9):808â818. Dempsey, D., P. Jacob, 3rd, and N. L. Benowitz. 2000. Nicotine metabolism and elimination kinetics in newborns. Clinical Pharmacology & Therapeutics 67(5):458â465.
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DEVELOPMENTAL AND REPRODUCTIVE EFFECTS 471 Wongtrakool, C., N. Wang, D. M. Hyde, J. Roman, and E. R. Spindel. 2012. Prenatal nicotine exposure alters lung function and airway geometry through Î±7 nicotinic receptors. American Journal of Respiratory Cell and Molecular Biology 46(5):695â702.