It is common knowledge that smoking is linked to numerous poor health outcomes. Now, researchers find that this fact extends even before birth. Mariona Bustamante, a molecular epidemiologist at Barcelona Institute for Global Health, and her colleagues found that when pregnant women smoke, the habit impacts the placenta with consequences for the growing fetus. Maternal smoking during pregnancy associated with methylation signatures across the placental epigenome in genes involved in regulating inflammation, growth signaling, and cardiometabolic outcomes.

“Deregulated biological functions identified in our study provide biological plausibility for the effects of tobacco smoking on reproductive outcomes and can help policy makers implement public health campaigns to help stop smoking,” Bustamante said.

Despite anti-tobacco campaigns, maternal smoking during pregnancy is still common. In Europe, where Bustamante works, approximately one in ten mothers smokes. The impact on developing offspring is well-known: low birth weight, higher risk of preterm birth, and greater susceptibility to psychiatric conditions later in life. But the mechanisms underlying these effects—how, exactly, maternal smoking results in low birth weight, for example—are not well understood.

Bustamante and her colleagues suspected that maternal smoking affects the placenta, a vital organ for fetal development. The placenta provides oxygen and nutrients to the fetus, while getting rid of waste like carbon dioxide. It also produces hormones necessary for the fetus and the mother’s body as it adapts to pregnancy.

Bustamante and her colleagues thought that the epigenome, the span of heritable chemical modifications to DNA, of the placenta might reveal how smoking leads to poor fetal outcomes. The epigenome takes into account signals from the genome as well as the environment and regulates biological functions. It is also reversible. 

Although Bustamante would have liked to analyze the placenta epigenome in its entirety, she and her team settled on DNA methylation as it is quite stable and does not require fresh samples, which can be difficult to obtain.

By analyzing associations between maternal smoking during pregnancy and placental DNA methylation patterns, and methylation patterns and birth outcomes of 1,700 expecting mothers in the Pregnancy and Childhood Epigenetics consortium, Bustamante and her colleagues identified more than 400 sites across the placental epigenome where methylation levels associated with maternal smoking during pregnancy. They found that the changes in methylation levels were larger in mothers who smoked more.

Bustamante and her colleagues reported in the journal Nature Communications that almost half of the changed marks associated with pre-term or low birth weight. These marks were in or near genes that respond to environmental stressors and regulate inflammation, and tended to be close to genetic variants related to birth outcomes.

“The results suggest that the placental epigenome responds to maternal tobacco smoking by regulating genes involved in signalling by growth factors and inflammation among others, and that these changes might impair birth outcomes,” Bustamante said. 

She cautions however that more work is needed to say that one causes the other. She and her colleagues hope to address this question and others, such as whether smoking affects different types of cells in the placenta in the same way, in future research.

But being able to tie specific biological and immune pathways to the epigenetic effects of maternal smoking is exciting, according to Marina Sirota, a computational biologist at the University of California, San Francisco, who was not involved in the research. She said that single cell approaches in the future will be very valuable to further understand the epigenetic contributions of specific immune cells. 


T.M. Everson et al., “Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth,” Nat Commun,12(1):5095, 2021.