While the health risks linking tobacco use by pregnant woman has been long understood, vaping presents a new frontier. A recent mouse study from the Journal of the Endocrine Society appears to show that there are some definite ill effects of e-cigarettes and the health of the offspring.
We’ve known for decades about the health risks that tobacco use by a pregnant woman can pose to the fetus (as well as to herself). According to the U.S. Centers for Disease Control and Prevention (CDC), such risks include preterm birth, low birthweight, birth defects, and sudden infant death syndrome. A team of researchers from the Caron Lab at the University of North Carolina in Chapel Hill, asked the question, if tobacco is so harmful in pregnancy, are e-cigarettes that also contain nicotine really any safer?
Where There’s Vapor . . .
Led by Kathleen M. Caron, PhD, professor and chair of the Department of Cell Biology and Physiology, the team performed experiments to test fertility and implantation in female mice exposed to e-cigarette vapor.
Just as they published their findings in “E-Cigarette Exposure Delays Implantation and Causes Reduced Weight Gain in Female Offspring Exposed in Utero” in the Journal of the Endocrine Society in early September, reports of a new pulmonary disease called e-cigarette, or vaping, product use–associated lung injury (EVALI) had become widespread. As of early November 2019, nearly 2,000 cases have been reported to the CDC from all over the U.S. (except Alaska so far), and at least 37 deaths have been confirmed. It is not yet completely clear what mechanism leads to the severe lung inflammation, but researchers are investigating vitamin E acetate, a metabolite produced by the vaping cartridges, as a possible cause as well as how combustible material inside the device might be creating cyanide that gets inhaled.
“I think what the underlying problem is, is that these devices are not regulated by any regulatory agency,” Caron explains. “So, from vape shop to vape shop they could contain very different formulations; literally anything could be in them, in terms of toxicants and chemicals. That’s a huge problem.” According to a fall 2019 update on the CDC’s website, “Irrespective of the ongoing investigation . . . [e-cigarette], or vaping, products should never be used by youths, young adults, or women who are pregnant.”
Although the CDC and the U.S. Food and Drug Administration (FDA) have teamed up to urgently warn consumers to stop vaping, especially pregnant women, for some, the damage could already be done. Caron and team have identified some of what this damage is. “We were the first to look at the effects of e-cigarette vapors on fertility and pregnancy,” Caron says. “I’m a parent, and my kids tell me that they see middle and high school students vaping. So, we have a whole generation of young people who are not thinking about being reproductively active at this point in their lives, but they’re vaping. Might it effect their reproductive success later? We realized that these basic, fundamental studies have not been performed.”
Aside from potentially affecting future reproduction, in some parts of the world like Europe, pregnant women have been advised by their physicians to switch to e-cigarettes if they are current smokers, due at least in part to perceptions that e-cigarettes are safer than traditional cigarettes. “This recommendation is made even in the absence of basic foundational knowledge,” Caron says. “We were really concerned about that. Nobody has done a study in mice, let alone people, so we were really motivated to do this and do it quickly.”
Their multipart study was conducted more than a year ago — before EVALI had emerged. In one trial to test fertility, they exposed mice to e-cigarette aerosol consisting of nicotine plus propylene glycol and vegetable glycerin (PGVG) for three hours a day with two two-second puffs per minute. Control mice were exposed to room air. Exposure began on the first day of mating and continued five days a week for four months. They found that first pregnancy was delayed compared to that in air-exposed mice, but that subsequent litters were not delayed. The number of pups was also slightly smaller, and one vapor-exposed mouse delivered no pups at all. Researchers caution that these problems could be exacerbated depending on individual factors.
“I’m a parent, and my kids tell me that they see middle and high school students vaping. So, we have a whole generation of young people who are not thinking about being reproductively active at this point in their lives, but they’re vaping. Might it effect their reproductive success later? We realized that these basic, fundamental studies have not been performed.” – Kathleen M. Caron, PhD, professor and chair, Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, N.C.
In the trial to test implantation and how e-cigarette exposure delayed pregnancy, mice were exposed five days a week for four weeks prior to mating. Five and a half days after the establishment of the copulatory plug, vapor-exposed mice did not have implantation sites. Because they were nevertheless able to maintain pregnancy, researchers determined that implantation is delayed in these mice.
Their next step was to examine the effects of e-cigarette exposure on the offspring. At eight and a half months, exposed female offspring were significantly smaller in body weight compared to their air-exposed counterparts, suggesting that in utero e-cigarette exposure results in metabolic impairments and a failure to thrive. Male offspring showed slight fertility impairment.
Cause for Pause
“Fifty years of research in all kinds of animal models and in people tells us that cigarette smoking in pregnancy has bad effects on the mother and bad effects on the offspring,” Caron says. “We found similarly that this is the case with the mice that were exposed to the e-cigarette vapors. We haven’t yet dug deep into the why’s or the how’s, but we felt that the findings were significant and profound enough that they needed to be published quickly.”
Her team plans to conduct additional studies with larger numbers about how e-cigarettes affect pregnancy initiation and long-term effects in offspring. “By and large, a lot of what we know about human reproduction comes from the mouse, “ she explains, “so, while we can’t predict with certainty that what we found in the mouse would happen in a human, there’s a strong chance that these things will be correlated in humans as well. There’s certainly enough evidence here and strong enough trends to suggest that we should be looking at this more carefully.”
In addition, their study investigated a simple formulation of nicotine and PGVG (as opposed to any added flavors) and whether, when combusted and inhaled, it can have toxic effects. Their study does not distinguish whether these effects were due to nicotine or to PGVG. They are currently looking more closely into differentiating these effects in the lab.
“Inhaling chemicals will have effects on body organs; indeed, some of the pathways that we identified are important for reproduction, yet teenage girls are probably not thinking about this now. But I do think that is an important message — that inhaling untested chemical formulations is a dangerous thing to do and can have long-term effects.” – Kathleen M. Caron, PhD, professor and chair, Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, N.C.
With the emergence of EVALI and her study coinciding in a perfect storm of warning, Caron hopes we all take a step back and do a better job of educating young people about vaping. E-cigarette companies have come under fire recently for seeming to market to youth with their special flavors, particularly mint, which is the most popular flavor among middle and high school students. (However, as of this writing, the FDA is expected to ban all flavorings except tobacco and menthol due to both the meteoric rise in teenage vaping and to potential dangers associated with the flavored compounds themselves as they are heated and aerosolized.)
“Inhaling chemicals will have effects on body organs; indeed, some of the pathways that we identified are important for reproduction, yet teenage girls are probably not thinking about this now. But I do think that is an important message — that inhaling untested chemical formulations is a dangerous thing to do and can have long-term effects,” Caron says.
She has a message for clinicians as well: Although e-cigarettes are perceived as a safer alternative during pregnancy and were originally created to help smokers wean themselves off traditional cigarettes in a “cleaner” way, we actually did not have rigorous experimental data to support our perceptions, and unforeseen harms are emerging rapidly. “The implications really do intersect with reproductive endocrinology,” she says. For now, e-cigarettes do not look like such a safe alternative, especially for young adolescents.
— Horvath is a freelance writer based in Baltimore, Md. She wrote about the top endocrine science discoveries of 2019 in the December issue.
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