Studies have demonstrated that cigarette smoking is associated with a relative deficiency in circulating levels of n-3 long-chain polyunsaturated fatty acids, known as omega-3 fatty acids. Previous work by researchers at Vanderbilt University Medical Center showed a positive impact from fatty acids on cardiovascular health and colorectal polyps and cancer, so they decided to follow up by examining omega-3s’ potential to influence healthier pregnancies.
Harvey J. Murff, M.D., director of the Division of Geriatric Medicine at Vanderbilt, and Hilary A. Tindle, M.D., founding director of the Vanderbilt Tobacco, Addiction and Lifestyle (ViTAL), are leading the randomized, double-blind study of omega-3 fatty acids. The fatty acids will be taken as sardine oil by pregnant participants who smoke. The time frame will span 2020 to 2024, and subjects are being recruited from multiple sites in middle Tennessee.
The study – Investigating N-3 Fatty Acids to prevent Neonatal Tobacco Related Outcomes (INFANTS) – is designed to investigate whether large doses of fish oil can change smoking behaviors and, separately, pregnancy outcomes. Because pregnancy precludes standard medical interventions, like varenicline (Chantix) or buproprion (Wellbutrin), the study’s outcomes could spell the emergence of a safe and effective alternative for smoking cessation.
“Less than half of women quit smoking when they become pregnant. We need to offer women more than just ‘try your best,’” Murff said.
Smoking Drives Deficiency
Omega-3 fatty acids are stored in the cell membrane of red blood cells. They are recruited for hormone production and influence signaling and cell diffusion. As such, they have important roles in intrauterine growth, neurological development, and other gestational tasks.
Smoking raises levels of inflammatory eicosanoids, which are implicated in cancer but also associated with labor. In 2016, Murff and Tindle reported that Vanderbilt patients who smoked had lower levels of omega-3 fatty acids than those who had quit smoking or who had never smoked. This was true even after controlling for dietary sources of these fatty acids, such as fish consumption.
“Less than half of women quit smoking when they become pregnant. We need to offer women more than just ‘try your best.’”
Murff also found a deficiency of omega-3 fatty acids in smokers in earlier studies looking at the effects of fatty acids on patients with precancerous colorectal polyps. He says the deficiencies likely derive from exposure to cigarette smoke, which contains over 7,000 chemicals. Their net effect is to readily oxidize fatty acids, breaking them down prematurely.
Replenishing the deficiency caused by smoking, however, did not prove challenging.
“In the small subset that were smokers, we saw that they started out with lower levels, but just a month into the study, they were already at the same level as non-smokers,” he said.
Probing Behavioral Impact of Omega-3 Fatty Acids
Bolstering the biological attributes of fatty acid levels is evidence that they encourage behavioral changes, such as reducing or quitting smoking. Studies show that omega-3 deficiencies are associated with anxiety and depression and with addictive behaviors. In animal models, depleting these fatty acids causes changes in dopamine signaling inside the mesocorticolimbic system, the reward center of the brain.
“If our study supports our hypotheses, clinicians could immediately modify their neonatal care recommendations and have a potentially major impact on neonatal outcomes.”
“When you are low in these fatty acid levels, it negatively impacts reward signaling in the brain,” said Murff, adding that such conditions would make it harder to quit smoking. “Since smoking depletes these fatty acid stores to begin with, it becomes a kind of vicious cycle.”
Additional evidence comes from two small studies of non-pregnant women who smoked and were given two different doses of fish oil, finding that women reported less-intense nicotine cravings.
“For women who took a higher dose, it spontaneously reduced how much they smoked,” Murff said. “We then became very interested in what omega-3 fatty acids might do for pregnant women who smoked.”
Following a small pilot study, the INFANTS trial is now well underway, with 135 pregnant smokers recruited and randomized as of July 2022. To avoid nausea but insure against underdosing, patients work their way up to a relatively high dose of fish oil – about 4 grams – daily.
“In the small subset that were smokers, we saw that they started out with lower levels, but just a month into the study, they were already at the same level as non-smokers.”
Murff, Tindle and their team will look at the impact on smoking reduction and also the biological impact of smoking in patients who did not quit or reduce tobacco use. They will also track symptoms of anxiety and depression before, during and after the study.
“Our hypothesis is that participants who are assigned to the fish-oil arm will report fewer symptoms of anxiety and depression as compared to those taking placebo,” Tindle said.
She expects this may be due in part to quitting smoking, and in part to direct effects of the fatty acids on the brain.
“If our study supports our hypotheses, clinicians could immediately modify their neonatal care recommendations and have a potentially major impact on neonatal outcomes,” Murff said.