Discussion

In this prospective birth cohort, maternal smoking during pregnancy was associated with lower FEV₁/FVC ratios in the offspring at age 16 years. In addition, our findings indicate that exposure to maternal

smoking during pregnancy increases peripheral airway resistance shown by IOS indices. A tendency of an association between adolescent smoking at age 16 years was also associated with lower FEV₁/FVC ratios and increased peripheral airway resistance, suggesting early signs of airflow obstruction. We observed no significant associations between SHS exposure during infancy or at age 16 years with lung function at age 16 years.

This is one of few prospective studies that assesses exposure to maternal smoking during pregnancy and concurrently accounts for exposure to adolescent smoking in relation to lung function in adolescents. Our finding for decreased FEV₁/FVC ratios in children exposed to maternal smoking during pregnancy corroborates some prior studies [27–29], whereas other studies have found declines in FEV₁ or FVC, which were not observed in the present study [30, 31]. Our results confirm and extend those from the Isle of Wight cohort, which also found reduced FEV₁/FVC ratios among adolescents (mean age 18 years) exposed to maternal smoking during pregnancy [28]. However, this study did not assess the association between adolescent smoking and lung function. Additionally, in a cohort of 519 participants, Guerraet al. [9] observed an early accelerated decline in FEV₁/FVC ratios in 26-year-olds, but only in subjects exposed to both adolescent smoking and maternal smoking during pregnancy.

To our knowledge this is the first study to show the association between maternal smoking during pregnancy and indices from IOS in adolescents. We observed significant increases in peripheral airway resistance in adolescents exposed to maternal smoking during pregnancy. This is supported by previous studies which found reduced forced expiratory flow at 25–75% of FVC, which is indicative of airflow in small airways [28, 31].

In addition, we observed lower FEV₁/FVC ratios among adolescent smokers, which is consistent with some [4, 32], but not all [7, 9] previous studies on adolescents. Based on lung function from IOS measures we observed increased airway resistance at 5–20 Hz, which is suggestive of small airway impairment. It is challenging to separate the effects of maternal smoking during pregnancy from adolescent smoking; however, we observed nonsignificant declines in lung function following adjustment for maternal smoking during pregnancy, as well as a tendency towards reduced FEV₁/FVC ratio in adolescent smokers without prior exposure to maternal smoking during pregnancy.

A unique and novel aspect of our study was the use of saliva cotinine concentrations in adolescents in relation to lung function. Implementing a ≥12 ng·mL⁻¹ cut-off as a biomarker of adolescent smoking, we confirmed our finding of reduced FEV₁/FVC ratios among smoking participants. We found that some individuals who reported not smoking were above the 12 ng·mL⁻¹ cut-point. These individuals could have been highly exposed to SHS, or did not report accurately. Additionally, some participants' cotinine concentrations fell below the cut-point, but still indicated they were occasional smokers. This is probably because they smoked infrequently or do not inhale sufficiently to increase the cotinine concentration. Both sex and symptoms of wheeze have been suggested to influence the effect of tobacco smoke exposure on lung function, but we saw no evidence of this [4, 31, 33].

Few studies on tobacco smoke exposure and lung function have used both spirometry and IOS to assess lung function, and to our knowledge none have assessed saliva cotinine concentrations to discriminate smoking status in relation to lung function in adolescents. The high participation rate and long follow-up, which extended from birth to age 16 years, are additional strengths and essential in understanding influential periods of exposure and causal associations.

Our findings should be interpreted in the context of some limitations. The use of questionnaires to ascertain smoking habits from parents and participants has the potential for misreporting. The saliva cotinine concentrations suggested that there is likely some degree of underreporting of smoking among the participants. Nevertheless, we observed significantly lower FEV₁/FVC ratios in adolescent smokers, which could be an underestimation of the true effect. Although the sample size of the cohort included in the analysis is reasonably large, it is possible we were unable to detect significant associations in other indices of lung function due to statistical power, particularly in view of low prevalence rates of tobacco smoke exposure prenatally and during childhood.

Lung development begins during embryogenesis and alveolarisation continues into early adulthood. Tobacco smoke contains >4000 chemicals, many of which are detrimental to the respiratory system. Nicotine, which easily passes the placental barrier, is associated with impaired lung development [34, 35]. The precise mechanisms by which tobacco smoke impacts lung function and development remains unclear. Animal studies suggest that exposure to tobacco smoke during intrauterine life modifies the homeostatic epithelial–mesenchymal interaction in the developing alveolus, which results in the production of myofibroblasts in both the large and small airways, a hallmark of chronic lung disease [28]. Exposure to maternal smoking during pregnancy probably alters the structures and function of the lung during gestation, which in turn can permanently impact properties of the lung such as elastic recoil, smooth muscle and epithelial organisation [36]. We saw a tendency for increased FVC among participants exposed to maternal smoking during pregnancy as well as adolescent smoking, which has been suggested in other studies, and translates directly to a decline in FEV₁/FVC ratio [28, 29]. Exposure to maternal smoking during pregnancy can affect both airways and alveolar growth [37], but our results suggest the reduction is more pronounced in the airways, which is supported by increases in airway resistance.

Although participants exposed to maternal smoking during pregnancy more often smoked in adolescence, it is not clear if this is a causal association. Nicotine exposure during early brain development could influence nicotine addiction. Similarly, an indirect association is also plausible, since parental smoking after the child is born is more common in these families and could indirectly influence adolescent smoking behaviour [38]. Therefore, the consequences of maternal smoking during pregnancy are probably multifactorial.

Adolescents with pre-existing lung impairments may be particularly susceptible to the effects of smoking. Moreover, commencing smoking in adolescence is likely to negatively impact lung growth, and smoking among adults is causally associated with chronic obstructive pulmonary disease (COPD), lung cancer, pneumonia and chronic bronchitis [39]. In addition, the lungs of smokers show diffuse changes affecting the airway lining, epithelium and bronchiole structure [40].

Although a 1–2%-unit decline in FEV₁/FVC ratio may be small, impairments in lung function at an early age can limit the peak development in adulthood, and potentially set a course for COPD or other lung-related diseases. As such, our results add to the growing body of literature showing an influence of early life exposures on lung function development [10]. Since humans do not reach their maximal pulmonary function until their early twenties it remains necessary to further study the effects of tobacco smoking into adulthood [4].

In conclusion, we found that exposure to maternal smoking during pregnancy was associated with lower FEV₁/FVC ratios and increased airway resistance at age 16 years, indicating that perinatal tobacco smoke exposure has a persistent influence on lung function up to adolescence. In addition, our results suggest that adolescent smoking is associated with reduced FEV₁/FVC ratios and increased peripheral airway resistance, suggesting the development of airflow obstruction from only a short duration of smoking.