Despite years of public health campaigns warning of the dangers of smoking when pregnant, many women are unaware of the risk or find themselves unable to quit. As a result, far too many babies are still being exposed in the womb to toxins that enter their mothers’ bloodstreams when they inhale cigarette smoke. Among the many infant and child health problems that have been linked to maternal smoking are premature birth, low birth weight, asthma, reduced lung function, sudden infant death syndrome (SIDS), and cleft lip and/or palate.
Now, a large international study involving NIH-supported researchers provides a biological mechanism that may explain how exposure to cigarette toxins during fetal development can produce these health problems . That evidence centers on the impact of the toxins on the epigenome of the infant’s body tissues. The epigenome refers to chemical modifications of DNA (particularly methylation of cytosines), as well as proteins that bind to DNA and affect its function. The genome of an individual is the same in all cells of their body, but the epigenome determines whether genes are turned on or off in particular cells. The study found significant differences between the epigenetic patterns of babies born to women who smoked during pregnancy and those born to non-smokers, with many of the differences affecting genes known to play key roles in the development of the lungs, face, and nervous system.
In recent years, several smaller studies have provided evidence that maternal smoking can have epigenetic effects on an unborn child [2, 3, 4]. The latest study, led by NIH researchers Stephanie London, Bonnie Joubert, and their colleagues in the Pregnancy And Childhood Epigenetics (PACE) consortium, solidifies and adds to those findings by pulling together existing evidence from around the world to perform a larger and more statistically powerful analysis of the data.
In the study, reported recently in the American Journal of Human Genetics, London, Joubert, and colleagues analyzed data from 6,685 mothers and their newborns, representing 13 research cohorts from the United States and across Europe. Sixty-two percent of mothers identified themselves as non-smokers. Thirteen percent identified themselves as “sustained smokers,” who smoked daily throughout most of their pregnancies. Another 25 percent fit into a third, catch-all group of “any smoking during pregnancy,” which ran the gamut from sustained and occasional smokers to those who quit smoking earlier in their pregnancies. Cord blood or other samples taken from the newborns of all of the mothers at birth were independently analyzed for the presence of chemical marks across the DNA in their genomes.
An analysis of these data revealed more than 6,000 places where the chemical marks on the DNA of babies born to sustained smokers differed from those of babies born to non-smokers. Babies born to mothers who fell into the less specific “any smoking during pregnancy” category still showed more than 4,600 epigenetic modifications to their DNA.
Those chemical modifications involved the increase or decrease of methylation marks in about equal measure. Remarkably, only about half of these marks had turned up before in previous studies. In other words, thanks to the increased power of the combined analysis, the new study uncovered almost 3,000 epigenetic modifications in or near 2,017 genes that had never been linked to maternal smoking.
Many of the changes appear in locations that would be expected to influence the expression of genes with important roles in lung and nervous system development. Other genes affected include those that have been implicated in birth defects such as cleft lip and/or palate. Interestingly, the epigenetic changes observed in the babies show plenty of overlap with patterns that are also seen in adult smokers. Later samples from some of the children in the study also suggest the persistence of thousands of those chemical modifications until at least age 4.
London is careful to point out that the new findings don’t confirm a direct causal connection between these observed epigenetic modifications and the health complications associated with maternal smoking. They do provide a potential mechanism that now warrants careful attention and further study. These findings also document epigenetics as a potential biomarker of fetal exposure to maternal cigarette smoking—a tool that can aid future studies.
According to the latest estimates, about 12 percent of pregnant women in the United States continue to smoke . Perhaps these latest results, if widely disseminated, can help to convince more pregnant mothers to quit, for their own health and for that of their unborn children.
 DNA methylation in newborns and maternal smoking in pregnancy: Genome-wide consortium meta-analysis. Joubert BR, Felix JF, Yousefi P, Wilcox A, Melén E, et al. London SJ. Am J Hum Genet. 2016 Apr 7;98(4):680-696.
 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Joubert BR, Håberg SE, Nilsen RM, Wang X, Vollset SE, Murphy SK, Huang Z, Hoyo C, Midttun Ø, Cupul-Uicab LA, Ueland PM, Wu MC, Nystad W, Bell DA, Peddada SD, London SJ. Environ Health Perspect. 2012 Oct;120(10):1425-1431.
 Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation. Breton CV, Siegmund KD, Joubert BR, Wang X, Qui W, Carey V, Nystad W, Håberg SE, Ober C, Nicolae D, Barnes KC, Martinez F, Liu A, Lemanske R, Strunk R, Weiss S, London S, Gilliland F, Raby B; Asthma BRIDGE consortium.PLoS One. 2014 Jun 25;9(6):e99716.
 Prenatal smoke exposure and genomic DNA methylation in a multiethnic birth cohort. Flom JD, Ferris JS, Liao Y, Tehranifar P, Richards CB, Cho YH, Gonzalez K, Santella RM, Terry MB. Cancer Epidemiol Biomarkers Prev. 2011 Dec;20(12):2518-2523.
 Trends in smoking before, during, and after pregnancy–Pregnancy Risk Assessment Monitoring System, United States, 40 sites, 2000-2010. Tong VT, Dietz PM, Morrow B, D’Angelo DV, Farr SL, Rockhill KM, England LJ; Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2013 Nov 8;62(6):1-19.
Tobacco Use and Pregnancy (Centers for Disease Control and Prevention)
Epigenomics (National Human Genome Research Institute/NIH)
Pregnancy And Childhood Epigenetics (PACE) (National Institute of Environmental Health Sciences/NIH)
NIH Support: National Institute of Environmental Health Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung and Blood Institute; National Institute on Minority Health and Health Disparities; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke.