A recent Cochrane review [45] concluded that smoking cessation programs reduce the proportion of women who smoke and reduce the rate of preterm birth. This review concluded that the effect was larger when counseling was combined with other strategies such as providing feedback with biochemical measures. It also found incentive-based interventions to be effective, but these randomized controlled trials (RCTs) were underpowered to assess the effect on preterm births. A recent meta-analysis [46] involving 1.3 million women demonstrated that the introduction of antismoking legislation reduced preterm birth rates by 10 %. This was likely due to cessation in the smoking mother but also in those around her with subsequent decreased exposure to passive smoke. Cnattingius et al. [47] studied 250,000 women who delivered consecutive singletons examining women who either began smoking or stopped smoking in between the two deliveries. The risk of preterm birth was either increased or decreased respectively in a dose-dependent fashion, indicating that effective smoking cessation efforts should reduce preterm birth and by translation decrease post NICU respiratory morbidities.

Nicotine replacement therapies have also been studied as a means of smoking cessation; however, based on the studies discussed above, nicotine itself will continue to have significant adverse effects on lung development. Also, randomized clinical trials have not demonstrated that nicotine replacement is effective or safe in promoting smoking cessation during pregnancy. A recent Cochrane review [48] examined the safety and efficacy of six trials of NRT in 1745 pregnant smokers, and no significant differences for smoking cessation or other important birth-related outcomes were demonstrated between randomized groups. The U.S. Food and Drug Administration recently announced that it is extending its regulatory authority over all the electronic nicotine delivery systems which are being increasingly used, especially by middle and high school students [49].

Evidence from animal studies [50] and from a recent randomized clinical trial [37] of vitamin C supplementation (500 mg/day) to pregnant smokers unable to quit smoking indicates that vitamin C may help mediate some of the effects of in utero smoke exposure on offspring respiratory health. The newborns whose mothers had been randomized to vitamin C had significantly improved newborn pulmonary function tests and a decreased incidence of wheeze at 1 year of age compared to those whose mothers had been randomized to placebo. The effect of maternal smoking on newborn lung function was also associated with the maternal genotype for the α5 nAChR (rs16969968) (p < 0.001 for interaction), which is the α5 nAChR structural polymorphism that has the strongest link to lung disease [51] (Fig. 2). This study was not powered to examine preterm births between the randomized groups, but a large RCT [52] of vitamin C (1000 mg) and vitamin E (400 IU) supplementation during pregnancy found a reduction in preterm birth (RR 0.76; 95 % CI 0.58–0.99) and placenta abruption in the treated versus untreated smokers. Although the results of the initial trial of vitamin C supplementation to pregnant smokers were encouraging, a second randomized trial of a more diverse population with measurements of offspring forced expiratory flows as a sensitive measure of the peripheral airways is currently underway.

The independent and joint effects of prenatal smoking and LBW on subsequent childhood asthma were studied in 3389 prospectively followed children at 11–12 years of age [53]. This study demonstrated a strong interaction of LBW and prenatal smoking on the risk of physician-diagnosed asthma. The association of prenatal smoking with physician-diagnosed asthma in LBW infants had a risk ratio of 8.8 versus a risk ratio of 1.3 in normal birth weight children [53].

A recent meta-analysis of 62 studies examining the association of LBW and preterm birth with outdoor air pollution demonstrated that third trimester exposure to carbon monoxide (CO) and particulate matter with aerodynamic diameter of <10 μm (PM₁₀) was significantly associated with a higher preterm birth risk [54]. Particulate matter with aerodynamic diameter of <2.5 μm (PM_2.5) and sulfur dioxide (SO₂) have also been associated with higher risks of preterm delivery as have polycyclic aromatic hydrocarbons [55]. A study of 223,502 electronic medical records in the United Stated found that mothers with asthma may experience a higher risk for preterm birth after exposure to traffic-related pollutants such as CO and nitrogen dioxide (NO₂), especially for exposures 3 months preconception and in the early weeks of pregnancy [55]. In the last 6 weeks of pregnancy, preterm birth risk associated with particulate matter with aerodynamic diameter of <10 μm was higher among women with asthma [55].

The association between prenatal exposure to fine particulate matter PM_2.5 (inhalable material <2.5 μm diameter) and early childhood lung function was investigated by Jedrychowski et al. [56]. Pregnant women had measurements of PM_2.5 performed over a 48-h period during the second trimester of pregnancy, and the offspring were followed through 5 years of age. Pulmonary function tests were done in 176 children of nonsmokers at 5 years of age and showed a significant decrease in FVC at the highest quartile of PM_2.5 exposure [56]. The increased exposure to PM_2.5 was in turn associated with increased wheezing at 2 years, though this effect was no longer significant by 4 years of age [57]. Mortimer et al. similarly saw negative associations with prenatal and early exposures to PM₁₀ (inhalable material <10 μm in diameter), NO₂, and CO in asthmatic children, though associations were for specific subgroups of children [58]. Conversely, exposure to increased levels of CO during pregnancy increased allergic sensitization in children with asthma [59]. In a retrospective study of 37,401 children born in British Columbia [60], the incidence of asthma in 3–4 year olds was correlated with estimated levels of in utero and first year of life exposures to air pollution, and an increase in asthma risk was seen with increased exposure to NO₂, CO, and PM₁₀. Animal models have been developed to examine effects of both particulate and gaseous pollution, but the exact mechanisms by which exposure to air pollution alters lung development and leads to increased respiratory disease are still not completely clear.

Although it is difficult to distinguish the effects of prematurity and intrauterine growth restriction (IUGR) due to frequent difficulties in establishing gestational age, epidemiological data [61] suggest that IUGR is associated with persistently impaired respiratory development. In sheep, it was demonstrated that fetal growth restriction affected lung structure at 8 weeks, and 2 years after birth with thicker intra-alveolar septa and thicker alveolar blood–air barrier [62]. Fetal lambs with induced IUGR have decreased alveolar and vascular growth [63]. Therefore, decreasing any modifiable underlying etiology for IUGR such as in utero smoke or optimizing prenatal growth in the face of IUGR would likely improve lung development and decrease postnatal NICU respiratory morbidities.