Comments
Abstract
Rationale: The extent to which maternal smoking in pregnancy (MSP) has persisting effects on respiratory health remains uncertain and the mechanisms involved are not fully understood. Alterations in immune function have been proposed as a mechanism contributing to respiratory disease.
Objectives: To determine whether MSP increases risk of respiratory disorders in adolescence and, if so, whether this occurs by decreased lung function, altered immune function, and/or enhanced atopy.
Methods: Data on spirometry, bronchial responsiveness, respiratory symptoms, total and allergen-specific IgE and IgG4, immune function, and inflammatory markers were obtained from 1,129 participants in the 14-year follow-up of the Western Australian Pregnancy (Raine) Cohort and related to MSP using regression analyses.
Measurements and Main Results: MSP was reported for 21.0% (237 of 1,129) of participants, with 92 (8.1%) reporting current smoking. MSP was associated with some altered immune measures at age 14. MSP was strongly related to reduced lung function in current nonsmokers (forced expiratory flow midexpiratory phase [FEF25–75%], P = 0.016; FEV1/FVC, P = 0.009) and increased risk for current asthma (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.16–2.92; P = 0.01), current wheeze (OR, 1.77; 95% CI, 1.14–2.75; P = 0.011), and exercise-induced wheeze (OR, 2.29; 95% CI, 1.37–3.85; P = 0.002), but not for bronchial hyperresponsiveness or atopy. Adjustment for immune measures and/or lung function in multivariate models did not greatly alter these associations and the increased risks for asthma and wheeze were not modified by sex, atopy, or maternal history of asthma or atopy.
Conclusions: MSP increases risk of asthma and wheezing in adolescence; mechanisms go beyond reducing lung function and exclude altering immune function or enhancing atopy.
The impact of maternal smoking during pregnancy on lung function and asthma risks in children is well known. However, how long these effects persist and how they are mediated is not clearly understood.
The data from the present study show that maternal smoking during pregnancy increases risk for asthma and wheeze that persist into adolescence independent of effects on lower lung function, immune function, or allergic sensitization in adolescents.
There is a great deal of evidence that maternal smoking during pregnancy (MSP) has detrimental effects on the health of children, including increased body mass index (BMI) (1–4), decreased lung function, and increased risk for development of asthma and wheeze (5–7). The mechanisms underlying these effects are uncertain; however, nicotine has reported detrimental effects on airway development (7). Prenatal tobacco smoke exposure is associated with a variety of epigenetic changes affecting gene expression, some of which are in keeping with an asthmatic phenotype (8, 9) and may be long lasting (8). Furthermore, it has been suggested that MSP can impair immune development and maturation, processes that begin in utero and continue after birth; these effects may modify risk for development of respiratory disease (10). MSP has been associated with a reduction in allergic sensitization in some cohorts, although there have been conflicting findings from different studies (11).
A previous study from our laboratory examining antenatal cytokines from 407 participants in the Western Australian Pregnancy (Raine) longitudinal birth cohort found that MSP was associated with lower concentrations of IL-4 and IFN-γ in cord blood and increased risk of wheeze and allergic sensitization at age 6 (12). This phenotype of low Th1/Th2 cytokine production observed in an unselected community cohort was also seen in infants at high genetic risk for atopy, who show delayed maturation of T-cell competence (13). Noakes and coworkers (14) examined the relationship between MSP and cord blood mononuclear cell cytokine responses and found that IL-13 production in response to house dust mite (HDM) or ovalbumin was higher in infants exposed to MSP (n = 17) than in unexposed (n = 40) neonates. They subsequently demonstrated in a different cohort that infants born to mothers who smoke (n = 60) showed significantly lower Toll-like receptor–mediated IL-6, tumor necrosis factor, and IL-10 production but higher IFN-γ production compared with infants born to mothers who do not smoke (n = 62) (15).
We have previous reported reduced lung function at birth in infants from the Raine cohort born to mothers who smoked during pregnancy (16) and have reported that prenatal and post-natal exposure to tobacco smoke in these children was associated with low lung function and increased the risk of asthma and bronchial hyperresponsiveness (BHR) at age 6 (17, 18). The present study was undertaken to determine whether these negative impacts of MSP on respiratory health persisted into adolescence and if so whether these effects acted through any or all of reduced lung function; altered immune function, characterized by modified or blunted cytokine responsiveness at age 14; or enhanced atopy.
Adolescents participating in the 14-year follow-up of the Raine Cohort (19) were studied. The cohort initially consisted of 2,860 live births and has been followed at birth, 1, 2, 3, 6, 8, 10, and 14 year of age and was recruited to participate in a randomized control trial of fetal monitoring. The prenatal study did not include any questions related to asthma or allergies or any childhood diseases, and no factors relevant to these were used to select the women for the study (see the online supplement for cohort description and Tables E1 and E2 in the online supplement). All aspects of the current study were approved by our institutional review board and parents gave written consent, with assent obtained from the teenagers. The antenatal questionnaire completed on enrolment at 16- to 18-week gestation asked about personal smoking and was used to assign MSP status to the adolescents. The reported smoking status indicated good agreement with serum cotinine on a random sample of the cohort (16).
Current asthma (17, 20) was defined as wheeze in the last 12 months in children with a doctor diagnosis of asthma ever. Children with current asthma who were using asthma medication were defined as having “medicated current asthma.” Spirometry was performed as described previously (18) according to American Thoracic Society guidelines. BHR was considered positive if FEV1 fell by at least 20% on a standard methacholine challenge (17, 18).
Total IgE and specific IgE and IgG4 to a panel of allergens were measured in serum collected at age 6 and age 14 by ImmunoCAP (Phadia AB, Uppsala, Sweden); the panel of allergens comprised HDM (Dermatophagoides pteronyssinus), rye grass pollen (rye; Lolium perenne), cat, couch grass (Cynodon dactylon), mold mix (Penicillium notatum, Cladosporium herbarum, Aspergillus fumigatus, Candida albicans, Alternaria alternata, Helminthosporium halodes), peanut, and food mix (egg white, milk, fish, wheat, peanut and soybean). Subjects were considered atopic if they had specific IgE greater than or equal to 0.35 kU/L for any of these allergens and/or total IgE greater than 300 kU/L (18).
Peripheral blood mononuclear cells were cultured (18) stimulated with HDM, rye, phytohemagglutinnin, and LPS with and without IFN-γ, or poly(I:C). Cytokine proteins were measured by time-resolved fluorometry (IL-5, IL-10, IL-12, IL-13, IFN-γ, and tumor necrosis factor-α) or mRNAs were measured by quantitative reverse-transcriptase polymerase chain reaction (IL-4 and IL-9). Cytokine production above unstimulated control (delta) was calculated and used in analyses.
The mast cell and eosinophil products prostaglandin F2α and eosinophil protein X were measured from urine and normalized against creatinine using ELISA (Cayman Chemical, Ann Arbor, MI; Phadia AB). Soluble CD14 was measured in plasma by ELISA (BioScientific, Gymea, Australia).
The groups of clinical and immunologic variables used in the analyses are shown in Figure 1. The effects of MSP on clinical and respiratory outcomes were determined using chi-square or Mann-Whitney U tests as appropriate. Associations between MSP and binary clinical outcomes were examined using logistic regression. Because of the large number of immunologic measures, we summarized each set (antibodies, inflammatory markers, adaptive and innate stimuli responses) using the treelet transform (21) into three components per set and examined the associations of each and all of these with MSP and with respiratory outcomes using regression analyses. Because this method of examining possible mediation effects can be subject to various biases from both measured and unmeasured confounders (22), we further examined whether MSP acted through poor lung function by restricting analyses to those with appropriate lung function. We also assumed that if there was no association between MSP and an intermediate variable or set of variables we would not further examine pathways through that set. Continuous variables were log10-transformed except for maternal BMI, FEV1/FVC, and forced expiratory flow midexpiratory phase (FEF25–75%)/FVC. Handling of confounders and possible mediation pathways is described in the online supplement.
Figure 1. Matrix of variables examined in this study of the Western Australian Pregnancy (Raine) Cohort at age 14 years. HDM = house dust mite; PHA = phytohemagglutinin.
[More] [Minimize]Results from questionnaires, lung function tests, and immunologic assays were available for 1,129 subjects seen at 14 years of age and comprise the study sample. MSP was reported for 21.0% (237 of 1,129) of the adolescents. MSP was strongly correlated with post-natal environmental tobacco smoke (ETS) exposure (see Table E3) and all MSP-positive subjects also had post-natal exposure to ETS. Ninety-two (8.1%) of the teenagers reported current smoking. One hundred and ten subjects (9.7%) fulfilled the definition of medicated current asthma and 124 (11.0%) had current asthma; 141 (12.5%) had current wheeze and 197 (17.4%) were positive for BHR. The prevalence of respiratory and allergic conditions at age 14 is shown in Table 1. Asthma (medicated current asthma, P = 0.029 and current asthma, P = 0.002) and current wheeze (P = 0.006) were more common among MSP-positive teenagers but BHR was not (P = 0.37). MSP-positive subjects also reported more exercise-induced wheeze (P < 0.001) and more had lower lung function (FEV1/FVC < 80%; P = 0.004), whereas the prevalence of atopy (P = 0.59) was not increased. Current smokers were excluded from further analyses because adjustment for current smoking would likely introduce bias because of its being on most postulated pathways from MSP (with odds ratio [OR] for current smoking from MSP of 3.2; 95% confidence interval [CI], 2.1–5.0) to respiratory outcomes. With (and also without, data not shown) adjustment for maternal asthma and maternal prepregnancy BMI (Table 2), MSP was a risk factor for current asthma (1.84 [1.16–2.92]; P = 0.01), current wheeze (1.77 [1.14–2.75]; P = 0.011), exercise-induced wheeze (2.29 [1.37–3.85]; P < 0.002), and poor lung function (2.00 [1.24–3.34]; P = 0.005). Differing effects of MSP by sex, maternal asthma status, and atopy were examined using interaction terms and none were significant (P > 0.15 in each analysis). MSP was associated with reduced lung function at age 14, including indices reflecting airway size and function, including lower FEF25–75% (P = 0.016), lower FEV1/FVC (P = 0.009), and FEF25–75%/FVC (P = 0.006) (Table 3).
| Whole Population (n = 1,129) | Nonsmokers (n = 1,037) | ||||||
|---|---|---|---|---|---|---|---|
| Condition | MSP Pos N (%) | MSP Neg N (%) | P Value | MSP Pos N (%) | MSP Neg N (%) | P Value | |
| Medicated current asthma* (n = 110) | Yes | 32 (13.9) | 78 (9.0) | 0.029 | 27 (14.1) | 72 (8.9) | 0.031 |
| No | 199 | 790 | 164 | 734 | |||
| Current asthma† (n = 124) | Yes | 39 (16.9) | 85 (9.8) | 0.002 | 34 (17.8) | 78 (9.7) | 0.001 |
| No | 192 | 783 | 157 | 728 | |||
| Current wheeze (n = 141) | Yes | 42 (18.2) | 99 (11.4) | 0.006 | 37 (19.4) | 90 (11.2) | 0.002 |
| No | 189 | 769 | 154 | 716 | |||
| Exercise-induced wheeze (n = 89) | Yes | 33 (14.3) | 56 (6.5) | <0.001 | 28 (14.7) | 53 (6.6) | <0.001 |
| No | 198 | 811 | 163 | 752 | |||
| Poor lung function‡ (n = 77) | Yes | 26 (11.0) | 51 (5.7) | 0.004 | 21 (10.8) | 46 (5.6) | 0.008 |
| No | 211 | 841 | 173 | 782 | |||
| BHR (n = 197) | Yes | 46 (19.4) | 151 (16.9) | 0.37 | 41 (21.1) | 140 (16.9) | 0.17 |
| No | 191 | 741 | 153 | 688 | |||
| Atopy (n = 677) | Yes | 138 (58.5) | 539 (60.4) | 0.59 | 115 (59.6) | 506 (61.1) | 0.67 |
| No | 98 | 353 | 78 | 322 | |||
| Outcome | N | n | OR (95% CI) | P Value |
|---|---|---|---|---|
| Medicated current asthma* | 898 | 99 | 1.49 (0.91–2.45) | 0.11 |
| Current asthma† | 869 | 111 | 1.84 (1.16–2.92) | 0.010 |
| Current wheeze | 854 | 126 | 1.77 (1.14–2.75) | 0.011 |
| Exercise-induced wheeze | 899 | 80 | 2.29 (1.37–3.85) | 0.002 |
| Poor lung function‡ | 918 | 64 | 2.00 (1.14–3.50) | 0.015 |
| BHR§ | 807 | 175 | 1.31 (0.88–1.96) | 0.18 |
| Atopy|| | 384 | 597 | 0.99 (0.71–1.37) | 0.93 |
| Total Population (n = 1,129) | Nonsmokers (n = 1,022) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Measure | MSP | N | Mean (SEM) | Mean Rank | P Value | N | Mean (SEM) | Mean Rank | P Value |
| % Predicted FEV1 | Negative | 889 | 96.3 (0.41) | 561 | 0.598 | 825 | 96.4 (0.43) | 511 | 0.774 |
| Positive | 237 | 96.9 (0.84) | 573 | 194 | 96.1 (0.93) | 505 | |||
| % Predicted FVC | Negative | 889 | 92.0 (0.41) | 552 | 0.018 | 825 | 92.0 (0.42) | 503 | 0.114 |
| Positive | 237 | 94.3 (0.84) | 608 | 194 | 93.7 (0.93) | 540 | |||
| %Predicted FEF25-75% | Negative | 889 | 99.6 (0.70) | 572 | 0.056 | 825 | 99.6 (0.72) | 519 | 0.016 |
| Positive | 237 | 96.7 (1.33) | 526 | 194 | 95.6 (1.48) | 463 | |||
| FEV1/FVC, % | Negative | 892 | 91.6 (0.22) | 578 | 0.007 | 828 | 91.6 (0.22) | 523 | 0.009 |
| Positive | 237 | 90.1 (0.49) | 514 | 194 | 89.9 (0.54) | 461 | |||
| FEF25-75%/FVC, % | Negative | 892 | 1.10 (0.01) | 579 | 0.006 | 828 | 1.10 (0.01) | 524 | 0.006 |
| Positive | 237 | 1.05 (0.02) | 513 | 194 | 1.05 (0.02) | 459 | |||
Few immunologic measures differed between MSP-positive and MSP-negative subjects (see Tables E4–E7). Total IgE titers were lower with MSP (geometric mean 61.1 vs. 74.0 kU/L; P = 0.05), as were titers of HDM-IgG4 (geometric mean 4.5 vs. 6.3 kU/L; P = 0.03) and Couch grass-IgG4 (geometric mean 0.01 vs. 0.05 kU/L; P < 0.01). In contrast, the number of peripheral circulating neutrophils (geometric mean 3.0 vs. 2.8 × 109; P = 0.05) and basophils (geometric mean 0.03 vs. 0.02 × 109; P = 0.01) was higher with MSP.
To examine whether the association of MSP with asthma outcomes was through a lung function pathway, models in Table 2 were reestimated including FEV1/FVC % as an added explanatory variable (Table 4). There was only slight attenuation of the effects, indicating that MSP was unlikely to be acting solely through poorer lung function. Similar models including the major components from the treelet analyses of antibodies and inflammatory markers showed similar or slighter changes (Table 4). When analyses were done separately in participants with poor or adequate lung function, MSP effects were slightly weaker in those with good lung function (Table 4, Model 4) and stronger in those with poor lung function (data not shown). The lack of association between MSP and cytokine responses precluded examination of those pathways.
| Model 1 | Model 2 | Model 3 | Model 4 | |||||
|---|---|---|---|---|---|---|---|---|
| Outcome | OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value |
| Medicated current asthma* | 1.49 (0.91–2.45) | 0.11 | 1.43 (0.87–2.36) | 0.16 | 1.49 (0.88–2.55) | 0.14 | 1.34 (0.77–2.31) | 0.303 |
| Current asthma† | 1.84 (1.16–2.92) | 0.010 | 1.76 (1.10–2.80) | 0.018 | 1.77 (1.08–2.90) | 0.024 | 1.74 (1.05–2.86) | 0.030 |
| Current wheeze | 1.77 (1.14–2.75) | 0.011 | 1.70 (1.09–2.65) | 0.020 | 1.74 (1.08–2.79) | 0.022 | 1.68 (1.05–2.71) | 0.031 |
| Exercise-induced wheeze | 2.29 (1.37–3.85) | 0.002 | 2.20 (1.31–3.70) | 0.003 | 2.37 (1.37–4.09) | 0.002 | 2.05 (1.17–3.59) | 0.012 |
MSP is a well-recognized risk factor for respiratory disease in children, but the precise mechanisms are largely speculative. The results of the present study confirm that this association persists into adolescence. Although MSP was associated with lower lung function, diminished lung function did not account for the increased risks for asthma and wheeze associated with MSP.
We have previously reported that children in this cohort born to mothers who smoked during pregnancy had a less mature immune system at birth, as judged from detectable levels of cytokines in cord blood, and that this was associated with an increased risk of asthma and atopy at 6 years of age (12). We had anticipated that MSP may increase asthma risk in adolescents by increasing allergic sensitization and enhancing allergy-related immune responses, independent of any effects on lung function. However, our data do not support this hypothesis. We saw little evidence of a less mature or reduced immune response in the present study. Total IgE and allergen-specific IgE and IgG4 levels tended to be lower with MSP, but most did not differ significantly between groups (see Table E4). The increased risks for asthma and wheeze associated with MSP seemed to be independent of adolescent immune function (Table 4). From the broad panel of adaptive and innate immune responses that we have measured in the current study, the only cytokine response that differed significantly according to MSP status was IL-12 induced by LPS+IFN-γ, which was significantly lower with MSP. We have previously reported in this cohort that, among those individuals sensitized to HDM, IL-12 production reduces the risk of asthma and reduces asthma severity (18). Human in vitro studies (23) have shown that nicotine exposure affected dendritic cell maturation leading to reduced IL-12 production and activation of Th1 immune responses, an effect that was overcome only when environmental stimuli strongly supported a Th1 rather than Th2 response. Within our current study, IL-12 response did not modify risk for any of the outcomes examined. Thus, although it is possible that MSP and subsequent post-natal smoke exposure may directly reduce the capacity for IL-12 production, particularly in subjects with atopy characterized by high production of Th2 cytokines, our study does not suggest that MSP increases the risk for respiratory disorders via altered immune function in an unselected cohort of adolescents. We have previously reported that the timing of allergic sensitization is critical in increasing asthma risk associated with viral lower respiratory infections in early life (24, 25), in that the increased risk from lower respiratory infections in early life were only seen in those with contemporaneous allergic sensitization. No increased risk was seen in subjects who developed allergic sensitization later in life. Thus, although there is no influence of MSP on allergic sensitization or on allergy-related immune responses in adolescents, this does not preclude this pathway being important in the first few years of life.
Although several previous studies have observed that deficient immune function in neonates or infants is linked to MSP or parental smoking in early life (12, 14, 15), to our knowledge only one has addressed whether this impaired immune function persists into late childhood (26). Tebow and coworkers (26) examined the relationship between parental smoking after pregnancy and peripheral blood mononuclear cells production of IFN-γ and IL-4 in response to mitogens concavalin A and phorbol myristate acetate in 512 participants in the Tucson Children’s Respiratory Study, who had been followed from the neonatal period until age 10 years. Dose–response relationships were observed between parental smoking post-pregnancy (cumulative pack-years) and the risk of impaired IFN-γ responses in the child regardless of whether the mother smoked in pregnancy. In the present study we did not find reductions in allergen or mitogen-induced cytokine responses with MSP, with the exception of the IL-12 response referred to earlier, which, given the number of comparisons, may have been caused by chance.
The literature is divided on whether MSP or post-natal ETS exposure modifies risk for atopy in children, with different studies finding that smoke exposure increased risk (27–29), decreased risk (30, 31), or did not modify risk (32, 33). In some studies parental smoking only modified risk for atopy after stratification by maternal atopy (27, 28). In the present study we did not find an association between MSP and atopy at age 14 in the entire cohort or after stratification for either maternal history or atopy or asthma. Our results suggest that MSP does not increase risk for current respiratory disorders in adolescence through increasing allergic sensitization.
Numerous studies have found that MSP and/or post-natal tobacco smoke exposure affects lung development, resulting in diminished lung function in childhood (34, 35). A previous report on the Raine cohort (16) demonstrated lower lung function at birth, as measured by peak tidal expiratory flow as a proportion of expiratory time, associated with MSP, with a significant dose–response found between peak tidal expiratory flow as a proportion of expiratory time and the daily number of cigarettes smoked. The data from the present study demonstrate lower lung function in adolescents born to mothers who smoked during pregnancy. When examining lung function as a continuous variable, we found MSP effects on indices of airway caliber and function. FEF25–75%, expressed as % predicted, was lower in the MSP group, especially when current smokers were excluded from the analysis (Table 3). In addition, we found both lower volume-corrected airway caliber, as judged from FEF25–75%/FVC (36–39) and more airway obstruction, as judged from a lower FEV1/FVC ratio, with MSP. Fetal exposure to nicotine via active placental transport has been shown in animal models to negatively affect lung and airway development, reducing surface complexity of the lung parenchyma, increasing collagen deposition in large and small airways, up-regulating surfactant protein gene expression, and inducing neuroendocrine cell hyperplasia (7, 40). We were not able to examine separately the effects of prenatal and post-natal tobacco smoke exposure because of the high correlation between MSP and post-natal ETS exposure; all MSP-positive subjects also had post-natal ETS exposure (see Table E3). Most studies, including the present one, have difficulty in separating potential effects of prenatal from post-natal tobacco smoke exposure. The literature is unclear on whether prenatal or post-natal smoke exposure confers the most risk for asthma and associated respiratory disorders (41–45). A metaanalysis examining the effects of childhood ETS exposure on asthma development found that duration of exposure seems to be an important risk factor that has been underestimated by previous studies and metaanalyses (46). Unfortunately, we are not able to contribute definitive data to this debate from the present study.
One mechanism proposed in the literature for how tobacco smoke exposure increases the risk of respiratory diseases, including asthma, is via epigenetic modification of gene expression (47, 48). Epigenetics are presumed to underlie the observation of increased asthma in children whose maternal grandmother smoked during the mother’s gestation (49). Although the effect was stronger if the mother smoked during the child’s gestation a significant effect was also seen in children born to mothers who do not smoke (49). An increase in global DNA methylation and increased methylation of promoter CpG islands has been reported in children born to mothers who smoked during pregnancy (8). We did not study gene methylation in the present study and cannot comment on any potential epigenetic effects on lung function because we did not study lung tissue. However, the lack of persistent effect of MSP on immune responses suggests that even if epigenetic effects were responsible for the effects on immune maturation we reported previously (12), they are not likely to be involved in conveying asthma risk in the teenagers studied.
MSP was associated with an increased risk for asthma and wheeze outcomes and lower lung function in the present study. Although MSP was strongly associated with low lung function, the adjusted analyses (Table 4) show that the effects of MSP on lung function do not account for the MSP-associated increase in asthma risk in adolescents. Both MSP and a reduction in FEV1/FVC ratio were independent risk modifiers for current asthma, current wheeze, and exercise-induced wheeze. Because there are no major effects of MSP on atopy or asthma-related immune responses, immunologic mechanisms are unlikely to be responsible for the independent increase in asthma risk from MSP. We must point out that although MSP effects on immune mechanisms are not responsible for the MSP effect on increasing asthma risk, this does not mean that immune factors impose no risk for asthma in adolescents. On the contrary, the usual “immune suspects” including allergen-specific IgE, markers of eosinophilic inflammation, and allergy-associated cytokine profiles are risk factors for asthma during adolescence in the Raine cohort (18).
In summary, MSP and subsequent exposure to ETS is associated with lower lung function and an independent increased risk of asthma that persists into adolescence. There was no effect of MSP on allergic sensitization or asthma-associated immune responses. Primary prevention of asthma and related respiratory conditions must include efforts to prevent MSP and post-natal ETS exposure.
The authors acknowledge the National Health and Medical Research Council and the Telethon Institute for Child Health Research for their long-term contribution to funding the Raine study over the last 20 years. The authors are extremely grateful to the study participants and their families, and the whole Raine Study Team, which includes the Cohort Manager, Data Manager, and data collection researchers. They also acknowledge the contributions of Jenny Tizard, Michael Serrahla, Marie Deverell, and Barbara Holt to the study.
| 1. | Oken EHS, Huh SY, Taveras EM, Rich-Edwards JW, Gillman MW. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes Res 2005;13:2021–2028. |
| 2. | Olson CMSM, Strawderman MS, Dennison BA. Maternal weight gain during pregnancy and child weight at age 3 years. Matern Child Health J 2009;13:839–846. |
| 3. | Suzuki KKN, Kondo N, Sato M, Tanaka T, Ando D, Yamagata Z. Maternal smoking during pregnancy and childhood growth trajectory: a random effects regression analysis. J Epidemiol 2012;22:175–178. |
| 4. | Wang LMH, Mamudu HM, Wu T. The impact of maternal prenatal smoking on the development of childhood overweight in school-aged children. Pediatr Obes 2013;8:178–188. |
| 5. | Cheraghi M, Salvi S. Environmental tobacco smoke (ETS) and respiratory health in children. Eur J Pediatr 2009;168:897–905. |
| 6. | Hylkema MN, Blacquière MJ. Intrauterine effects of maternal smoking on sensitization, asthma, and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:660–662. |
| 7. | Maritz GS, Harding R. Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: evidence for altered lung development. Int J Environ Res Public Health 2011;8:875–898. |
| 8. | Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 2009;180:462–467. |
| 9. | Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010;126:453–465. |
| 10. | Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun 2010;34:J258–J265. |
| 11. | D’Vaz N, Franklin P. Household smoking, maternal atopy and allergic sensitization in children: is it all academic? Respirology 2012;17:1029–1030. |
| 12. | Macaubas C, de Klerk NH, Holt BJ, Wee C, Kendall G, Firth M, Sly PD, Holt PG. Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet 2003;362:1192–1197. |
| 13. | Holt PG, Clough JB, Holt BJ, Baron-Hay MJ, Rose AH, Robinson BWS, Thomas WR. Genetic ‘risk’ for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy 1992;22:1093–1099. |
| 14. | Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58:1053–1058. |
| 15. | Noakes PS, Hale J, Thomas R, Lane C, Devadason SG, Prescott SL. Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses. Eur Respir J 2006;28:721–729. |
| 16. | Stick SM, Burton PR, Gurrin L, Sly PD, LeSouëf PN. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060–1064. |
| 17. | Collins RA, Parsons F, Deverell M, Hollams EM, Holt PG, Sly PD. Risk factors for bronchial hyperresponsiveness in teenagers differ with sex and atopic status. J Allergy Clin Immunol 2011;128:301–307 e301. |
| 18. | Hollams EM, Deverell M, Serralha M, Suriyaarachchi D, Parsons F, Zhang GC, de Klerk N, Holt BJ, Ladyman C, Sadowska A, et al. Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling. J Allergy Clin Immunol 2009;124:463–470, e1–e16. |
| 19. | Newnham JP, Evans SF, Michael CA, Stanley FJ, Landau LI. Effects of frequent ultrasound during pregnancy: a randomised controlled trial. Lancet 1993;342:887–891. |
| 20. | Joseph-Bowen J, de Klerk N, Holt PG, Sly PD. Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood. J Allergy Clin Immunol 2004;114:1040–1045. |
| 21. | Gorst-Rasmussen A, Dahm CC, Dethlefsen C, Scheike T, Overvad K. Exploring dietary patterns by using the treelet transform. Am J Epidemiol 2011;173:1097–1104. |
| 22. | Richiardi L, Bellocco R, Zugna D. Mediation analysis in epidemiology: methods, interpretation and bias. Int J Epidemiol 2013;42:1511–1519. |
| 23. | Nouri-Shirazi M, Guinet E. A possible mechanism linking cigarette smoke to higher incidence of respiratory infection and asthma. Immunol Lett 2006;103:167–176. |
| 24. | Kusel MM, Kebadze T, Johnston SL, Holt PG, Sly PD. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze. Eur Respir J 2012;39:876–882. |
| 25. | Kusel MMH, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, Sly PD. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007;119:1105–1110. |
| 26. | Tebow G, Sherrill DL, Lohman IC, Stern DA, Wright AL, Martinez FD, Halonen M, Guerra S. Effects of parental smoking on interferon gamma production in children. Pediatrics 2008;121:e1563–e1569. |
| 27. | Keil T, Lau S, Roll S, Grüber C, Nickel R, Niggemann B, Wahn U, Willich SN, Kulig M. Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: longitudinal analysis from birth to 10 years. Allergy 2009;64:445–451. |
| 28. | Lannerö E, Wickman M, van Hage M, Bergström A, Pershagen G, Nordvall L. Exposure to environmental tobacco smoke and sensitisation in children. Thorax 2008;63:172–176. |
| 29. | Raherison C, Pénard-Morand C, Moreau D, Caillaud D, Charpin D, Kopferschmitt C, Lavaud F, Taytard A, Maesano IA. Smoking exposure and allergic sensitization in children according to maternal allergies. Ann Allergy Asthma Immunol 2008;100:351–357. |
| 30. | Kuyucu S, Saraçlar Y, Tuncer A, Saçkesen C, Adalioglu G, Sümbüloglu V, Sekerel BE. Determinants of atopic sensitization in Turkish school children: effects of pre- and post-natal events and maternal atopy. Pediatr Allergy Immunol 2004;15:62–71. |
| 31. | Vonk JM, Boezen HM, Postma DS, Schouten JP, van Aalderen WMC, Boersma ER. Perinatal risk factors for bronchial hyperresponsiveness and atopy after a follow-up of 20 years. J Allergy Clin Immunol 2004;114:270–276. |
| 32. | Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A; NACMAAS Study Group. Tobacco smoke exposure, wheeze, and atopy. Pediatr Pulmonol 2004;37:492–498. |
| 33. | Strachan DP, Cook DG. Health effects of passive smoking. 5. Parental smoking and allergic sensitisation in children. Thorax 1998;53:117–123. |
| 34. | Gilliland FD, Berhane K, McConnell R, Gauderman WJ, Vora H, Rappaport EB, Avol E, Peters JM. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 2000;55:271–276. |
| 35. | Moshammer H, Hoek G, Luttmann-Gibson H, Neuberger MA, Antova T, Gehring U, Hruba F, Pattenden S, Rudnai P, Slachtova H, et al. Parental smoking and lung function in children: an international study. Am J Respir Crit Care Med 2006;173:1255–1263. |
| 36. | Litonjua AA, Sparrow D, Weiss ST. The FEF25-75/FVC ratio is associated with methacholine airway responsiveness. The Normative Aging Study. Am J Respir Crit Care Med 1999;159:1574–1579. |
| 37. | Parker AL, Abu-Hijleh M, McCool FD. Ratio between forced expiratory flow between 25% and 75% of vital capacity and FVC is a determinant of airway reactivity and sensitivity to methacholine. Chest 2003;124:63–69. |
| 38. | Tager IB, Balmes J, Lurmann F, Ngo L, Alcorn S, Künzli N. Chronic exposure to ambient ozone and lung function in young adults. Epidemiology 2005;16:751–759. |
| 39. | Tager IB, Weiss ST, Muñoz A, Welty C, Speizer FE. Determinants of response to eucapneic hyperventilation with cold air in a population-based study. Am Rev Respir Dis 1986;134:502–508. |
| 40. | Sekhon HS, Keller JA, Benowitz NL, Spindel ER. Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys. Am J Respir Crit Care Med 2001;164:989–994. |
| 41. | Alati R, Al Mamun A, O’Callaghan M, Najman JM, Williams GM. In utero and postnatal maternal smoking and asthma in adolescence. Epidemiology 2006;17:138–144. |
| 42. | Håberg SE, Stigum H, Nystad W, Nafstad P. Effects of pre- and postnatal exposure to parental smoking on early childhood respiratory health. Am J Epidemiol 2007;166:679–686. |
| 43. | Jaakkola JJ, Kosheleva AA, Katsnelson BA, Kuzmin SV, Privalova LI, Spengler JD. Prenatal and postnatal tobacco smoke exposure and respiratory health in Russian children. Respir Res 2006;7:48. |
| 44. | Lux AL, Henderson AJ, Pocock SJ; ALSPAC Study Team. Wheeze associated with prenatal tobacco smoke exposure: a prospective, longitudinal study. Arch Dis Child 2000;83:307–312. |
| 45. | Pattenden S, Antova T, Neuberger M, Nikiforov B, De Sario M, Grize L, Heinrich J, Hruba F, Janssen N, Luttmann-Gibson H, et al. Parental smoking and children’s respiratory health: independent effects of prenatal and postnatal exposure. Tob Control 2006;15:294–301. |
| 46. | Vork KL, Broadwin RL, Blaisdell RJ. Developing asthma in childhood from exposure to secondhand tobacco smoke: insights from a meta-regression. Environ Health Perspect 2007;115:1394–1400. |
| 47. | Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respir Res 2006;7:21. |
| 48. | Kabesch M, Michel S, Tost J. Epigenetic mechanisms and the relationship to childhood asthma. Eur Respir J 2010;36:950–961. |
| 49. | Li Y-F, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 2005;127:1232–1241. |
Supported by the National Health and Medical Research Council and the Telethon Institute for Child Health Research. Core Management of the Raine study has been funded by the University of Western Australia; Curtin University; the University of Western Australia Faculty of Medicine, Dentistry and Health Sciences; the Raine Medical Research Foundation; Telethon Institute for Child Health Research; and the Women's and Infants Research Foundation. The 14-year follow-up was funded by the National Health and Medical Research Council (#211912, #003209) and the Raine Medical Research Foundation.
Author Contributions: Conception and design, E.M.H., P.G.H., and P.D.S. Analysis and interpretation, all authors. Drafting the manuscript, E.M.H. and P.D.S.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201302-0323OC on November 19, 2013
Author disclosures are available with the text of this article at www.atsjournals.org.
