Tobacco use is the most important modifiable risk factor associated with adverse
pregnancy outcomes and increases the risk of preterm birth, intrauterine growth
restriction and sudden infant death syndrome. Over 11% of women report smoking during
pregnancy, with higher rates seen in the Southeastern United States. Fewer than half of
pregnant smokers are able to quit on their own during pregnancy. Currently, FDA-approved
pharmacological strategies for smoking cessation are generally not used in pregnancy:
varenicline and bupropion are unsafe and nicotine replacement therapy has limited data to
support its efficacy in pregnant smokers. Identifying safe and effective therapies to
prevent tobacco-related pregnancy outcomes and/or increase smoking cessation in pregnant
women would have a substantial public health impact.
Our group and others have reported that cigarette smoking is associated with a relative
deficiency in circulating n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) levels.
Our overarching hypothesis is that smoking-induced n-3 LCPUFA deficiencies contribute to
tobacco-related adverse pregnancy outcomes and that supplementation of n-3 LCPUFAs in
pregnant smokers may prevent these complications. Support for this hypothesis comes from
a recent secondary analysis of the Omega-3 Fatty Acids Supplementation to Prevent Preterm
Birth trial which found that only smokers taking n-3 LCPUFAs had a reduction in preterm
labor risk as compared to non-smokers. While compelling, this study was a post hoc
analysis that included only a small sample of smokers and did not collect data on smoking
behaviors during follow up. Yet the ascertainment of longitudinal smoking behavior is
critical, as some clinical studies have found that supplemental n-3 LCPUFAs might also
reduce nicotine cravings and lower daily cigarette use. Thus, smokers may doubly benefit
from replenishing n-3 LCPUFAs via lower risk of preterm labor and/or increased smoking
cessation. We conducted a placebo-controlled pilot RCT of n-3 LCPUFAs in 28 pregnant
smokers and found the intervention to be feasible and well-tolerated. Compared to
placebo, n-3 LCPUFAs lowered both nicotine dependence at 4 weeks (change from baseline in
Fagerström Test for Nicotine Dependence -2.5 vs. 0, p = 0.01) and resulted in a
non-statistically significant reduction in cigarettes per day and urine cotinine. To
address important remaining knowledge gaps we propose the Investigating N-3 Fatty Acids
to prevent Neonatal Tobacco related outcomeS (INFANTS).
Our proposal has three Specific Aims.
Specific Aim 1: To determine the effect of supplemental n-3 LCPUFAs compared to placebo
on gestational age at delivery and preterm labor in pregnant smokers.
Specific Aim 2: To determine the effect of supplemental n-3 LCPUFAs compared to placebo
on tobacco use in pregnant smokers.
Specific Aim 3: To determine if the effect of supplemental n-3 LCPUFAs on preterm labor
is mediated by changes in smoking behavior and/or increases in circulating n-3 LCPUFAs.
The INFANTS study is a multicenter, randomized, double-blind, placebo controlled study
that will randomize 400 pregnant smokers to either supplemental n-3 LCPUFAs or placebo.
Participants will be enrolled between 12 and 24 weeks gestation and followed until
delivery. We will recruit participants from eight clinical centers in the
Middle-Tennessee area. We will assess smoking behavior after 12-weeks of supplementation
using self-report and validated biomarkers of tobacco exposure (urine cotinine). We will
measure response to supplementation using biological markers of n-3 LCPUFA status (red
blood cell phospholipid membrane fatty acid percentages). Our primary endpoint will be
preterm labor as reflected by gestational age at delivery, which will be extracted from
the medical record. Our secondary endpoint will be change from baseline in cigarettes per
day at 12 weeks biochemically confirmed through reduction in urine cotinine. We will
conduct mediation analysis to better understand the mechanisms contributing to the
effects of supplemental n-3 LCPUFAs on birth outcomes in pregnant smokers.
Our study is innovative in that it will be the first clinical trial of n-3 LCPUFAs
exclusively recruiting pregnant smokers. This will be the first study to evaluate the
impact on n-3 LCPUFAs on tobacco use in smokers who wish to quit, thus identifying a
novel strategy to reduce tobacco use that could be relevant for all smokers.
n-3 LCPUFAs supplements are well tolerated in pregnancy but currently are not recommended
as part of routine prenatal care in smokers. Thus if our study demonstrated that
supplemental n-3 LCPUFAs are effective at reducing the risk of tobacco-related adverse
neonatal outcomes and/or reducing tobacco use during pregnancy, our results could have an
immediate and major clinical impact on pregnancy care and neonatal outcomes in the United
States.