Maternal smoking is the most important adverse fetal exposure in Western countries, and is strongly associated with fetal growth retardation and low birth weight [63
]. Recent studies have demonstrated that maternal smoking during pregnancy is associated with increased risks of wheezing and asthma during childhood [93
]. Most studies were not able to assess the effect of maternal smoking exposure in different periods of pregnancy, which might be important for identifying critical periods. It is also not known whether the associations between maternal smoking during pregnancy and the risk of childhood asthma are explained by direct intrauterine effects, or reflect other unmeasured environmental confounders. Stronger effect estimates for maternal smoking than for paternal smoking during pregnancy with childhood asthma would suggest direct intra-uterine effects, whereas similar effect estimates suggest that the associations are explained by unmeasured socio-economic, or life style related factors [100
]. Also, as in all observational designs, residual confounding might still be an issue due to unmeasured social and life style related factors. This needs to be explored in detail. Recently, we have demonstrated that continued maternal smoking throughout pregnancy is associated with asthma symptoms, including wheezing, in preschool children [49
]. These associations were independent of paternal smoking and imply a direct adverse effect of smoke exposure on fetal lung development. The mechanisms by which maternal smoking during pregnancy affect body and lung growth are not fully understood, but may include direct toxic effects on the respiratory system and DNA methylation of genes. Recent studies showed general and biological pathway specific differences in DNA methylation patterns in children from mothers who smoked during pregnancy [102
]. Differences in DNA-methylation within the promoter regions of particular genes may alter the expression of the gene products related to growth and lung development. However, it is not known whether the associations between low birth weight and respiratory disease can be fully explained by fetal smoke exposure, and the related changes in DNA methylation.
Suboptimal fetal nutrition, due to maternal obesity or underweight, insufficient dietary intake, or placental dysfunction might also affect fetal growth and lung development [52
]. Maternal obesity and placenta dysfunction are strongly related to fetal growth, but their direct associations with respiratory health in the offspring are not fully understood yet [10
]. Insufficient maternal dietary intake of macronutrients during pregnancy may lead to impaired fetal body, lung and airway growth and subsequently to an increased risk of asthma in childhood [104
]. More specifically, maternal Mediterranean and Western dietary patterns during pregnancy are related to fetal growth patterns [117
]. Thus far, little is known whether these maternal dietary patterns also affect the risk of childhood asthma [119
]. The mechanisms by which dietary patterns affect body and lung growth development may also include DNA methylation [120
]. Lower intake of micronutrients such as folate, and vitamin B12 in mother’s diet may induce epigenetic changes, since folate and vitamin B12 are important methyl donors during pregnancy [122
]. Vitamin E has the potential to influence airway development via epigenetic mechanisms because it influences gene expression and airway epithelial cell signalling [112
]. The role of epigenetic mechanisms regarding the association of low maternal vitamin D intake during pregnancy with a higher incidence of asthma and wheeze in children is not known yet [123
]. The importance of the maternal intake of these micronutrients on respiratory health in childhood and adulthood might differ between developing and Western countries, since the nutritional status of mothers and children in these countries are different.