0
Original Research: Obstructive Lung Diseases |

Tobacco Smoke Exposure, Airway Resistance, and Asthma in School-age ChildrenSmoke Exposure and Asthma: The Generation R Study FREE TO VIEW

Herman T. den Dekker, MD; Agnes M. M. Sonnenschein-van der Voort, PhD; Johan C. de Jongste, MD, PhD; Irwin K. Reiss, MD, PhD; Albert Hofman, MD, PhD; Vincent W. V. Jaddoe, MD, PhD; Liesbeth Duijts, MD, PhD
Author and Funding Information

From The Generation R Study Group (Drs den Dekker, Sonnenschein-van der Voort, and Jaddoe), Department of Pediatrics, Division of Respiratory Medicine (Drs den Dekker, Sonnenschein-van der Voort, de Jongste, and Duijts), Department of Epidemiology (Drs den Dekker, Sonnenschein-van der Voort, Hofman, Jaddoe, and Duijts), Department of Pediatrics, Division of Neonatology (Drs Reiss and Duijts), and Department of Pediatrics (Dr Jaddoe), Erasmus MC, Rotterdam, The Netherlands.

CORRESPONDENCE TO: Liesbeth Duijts, MD, PhD, Erasmus Medical Center-Sophia Children’s Hospital, Sp-3435, PO Box 2060, 3000 CB Rotterdam, The Netherlands; e-mail: l.duijts@erasmusmc.nl


FOR EDITORIAL COMMENT SEE PAGE 573

FUNDING/SUPPORT: The Generation R Study is made possible by financial support from the Erasmus MC Rotterdam, Erasmus University Rotterdam, and The Netherlands Organisation for Health Research and Development (ZonMw). Dr Sonnenschein-van der Voort is the recipient of a European Respiratory Society Fellowship [STRTF 93-2012] and received a grant from the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences [TMF2012/228]. Dr Jaddoe received an additional grant from The Netherlands Organisation for Health Research and Development [ZonMw-VIDI]. The research leading to these results has received funding from The Lung Foundation Netherlands [No. 3.2.12.089; 2012].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):607-617. doi:10.1378/chest.14-1520
Text Size: A A A
Published online

BACKGROUND:  Tobacco smoke exposure has been associated with early childhood asthma symptoms. We assessed the associations of tobacco smoke exposure during pregnancy and childhood with wheezing patterns, asthma, airway interrupter resistance (Rint), and fractional exhaled nitric oxide (Feno) in school-age children and whether birth characteristics explained the associations.

METHODS:  This study was embedded in a population-based prospective cohort study among 6,007 children. Paternal and maternal smoking during pregnancy (never, first trimester only, continued), secondhand tobacco smoke exposure during childhood, wheezing patterns, and asthma were prospectively assessed by questionnaires. Wheezing patterns were defined as never, early (≤ 3 years only), late (> 3 years only), and persistent (≤ 3 and > 3 years) wheezing. Rint and Feno were measured at age 6 years. Birth characteristics were available from registries.

RESULTS:  Continued maternal smoking during pregnancy was associated with increased risks of early and persistent wheezing (OR: 1.24 [1.01, 1.52]; 1.48 [1.13, 1.95]) and asthma (1.65 [1.07, 2.55], for at least five cigarettes per day), but not with Rint or Feno. Birth characteristics did not explain these associations. Childhood tobacco smoke exposure was associated with higher Rint (difference z score: 0.45 [0.00, 0.90]), but this effect attenuated after adjustment for birth characteristics. Maternal smoking during first trimester only or paternal smoking during pregnancy was not associated with Rint, Feno, wheezing, or asthma.

CONCLUSIONS:  Continued maternal smoking during pregnancy was associated with increased risks of asthma outcomes in school-age children, whereas childhood tobacco smoke exposure was associated with higher Rint. Birth characteristics may explain part of these associations.

Figures in this Article

Toxic environmental exposures in fetal life and infancy, including secondhand tobacco smoke exposure, are associated with an increased risk of childhood asthma.16 We have observed that continued maternal smoking throughout pregnancy was associated with an increased risk of preschool wheezing.7 These associations were independent of paternal smoking, smoke exposure in childhood, and being small for gestational age and suggest a direct adverse effect of fetal tobacco smoke exposure on lung development. Direct intrauterine mechanisms in response to fetal smoke exposure may include suboptimal development of the respiratory tract, which results in impaired lung growth with smaller airways and airway diameters leading to a higher airway resistance.79 Previous studies on the adverse effect of maternal smoking during pregnancy on childhood asthma at older ages are inconsistent.1,1013 This might be due to socioeconomic or lifestyle-related factors, or not taking current tobacco smoke exposure in childhood or important birth outcomes such as gestational age and weight at birth into account.14 To disentangle the effects of direct intrauterine adaptation mechanisms from unknown socioeconomic or lifestyle-related factors on childhood asthma, information on paternal smoking during pregnancy of the mother can be used.15 If stronger associations of maternal smoking during pregnancy with asthma or related outcomes are observed than for paternal smoking, taking secondhand tobacco smoke exposure in childhood into account, this would support the hypothesis that intrauterine adaptation mechanisms underlie the observed associations. Similar associations for maternal and paternal smoking with asthma or related outcomes would suggest that common and shared socioeconomic or lifestyle-related factors within families explain these associations.1517 Additionally, the effects of secondhand tobacco smoke exposure in childhood on airway resistance and asthma outcomes, and the roles of being born early or small for gestational age in the association of maternal smoking during pregnancy with childhood asthma, are not clear.7,18,19

Therefore, we first aimed to examine the associations of maternal and paternal smoking in different periods of pregnancy with airway resistance, airway inflammation, wheezing patterns, and physician-diagnosed asthma in school-aged children participating in a large population-based prospective cohort study. Second, we examined the associations of secondhand tobacco smoke exposure during childhood with lung function and asthma outcomes, taking into account parental smoke exposure during pregnancy. Third, we examined whether the associations of tobacco smoke exposure with lung function and asthma outcomes were modified by gestational age and weight at birth or atopy.

General Design

This study was embedded in the Generation R Study, a population-based prospective cohort study of pregnant women and their children in Rotterdam, The Netherlands. In each trimester of pregnancy, assessments were performed, including physical examination, fetal ultrasound examination, and questionnaires.20,21 All children were born between April 2002 and January 2006. Of all eligible children in the study area, 61% participated in the study at birth.20 The study protocol was approved by the Medical Ethical Committee of the Erasmus MC, Rotterdam (MEC 217.595/2002/20). Written informed consent was obtained from all participants. A total of 6,007 children were included for the current analyses (Fig 1).

Figure Jump LinkFigure 1 –  Flowchart of participants. FeNO = fractional exhaled nitric oxide; Rint = airway interrupter resistance.Grahic Jump Location
Fetal and Childhood Smoke Exposure

As previously described in detail,7 mothers reported their active tobacco use by three questionnaires during pregnancy. We grouped mothers’ tobacco use into three categories based on the first questionnaire: (1) never during pregnancy, (2) first trimester only, and (3) continued during pregnancy. Reported tobacco use in the second and third trimester were used to reclassify maternal smoking, when appropriate. Active paternal smoking was assessed in the first questionnaire by asking the mother whether the father smoked during her pregnancy (n = 5,411). The number of cigarettes smoked daily was classified as none, at most four cigarettes per day, and at least five cigarettes per day. Information about any in-house secondhand tobacco smoke exposure in childhood at age 6 years—irrespective of whether this source was the mother, father, or anyone else—was obtained by a questionnaire at the age of 6 years (response rate 76%; “Was the child exposed to any in-house tobacco smoke [never/yes, ≤ 1 time per week/yes, ≥ 2 times per week”]).

Childhood Asthma Outcomes

At age 6 years, airway interrupter resistance (Rint) was measured in kilopascals per liter (MicroRint; Micro Medical Ltd [CareFusion Corporation]) during tidal expiration, with occlusion of the airway at peak expiratory flow, according to European Respiratory Society and American Thoracic Society guidelines. Fractional exhaled nitric oxide (Feno) in parts per billion (ppb) was measured using the NIOX chemiluminescence analyzer (Aerocrine) according to European Respiratory Society and American Thoracic Society guidelines. Feno levels were natural log-transformed to obtain normality. Wheezing was reported by parental questionnaires annually from birth to age 4 years and at age 6 years. Wheezing patterns were defined in four categories as previously proposed22 and commonly used in epidemiologic studies: (1) no wheezing: no recorded wheezing at any age; (2) early wheezing: at least one wheezing episode during the first 3 years of life but no wheezing episodes at 4 and 6 years of age; (3) late wheezing: no wheezing episodes during the first 3 years of age but at least one wheezing episode at 4 or 6 years of age; and (4) persistent wheezing: at least one wheezing episode in the first 3 years of life and one episode of wheezing at 4 or 6 years of age.22,23 Physician-diagnosed ever asthma was assessed using questions adapted from the International Study of Asthma and Allergy in Childhood (ISAAC) at age 6 years.24

Covariates

We obtained information on maternal age, anthropometrics, socioeconomic status, history of asthma and atopy, parity, child’s ethnicity, and pet keeping by questionnaires completed by the mother at enrollment. Data on gestational age and birth weight were obtained by midwife and hospital registries. Detailed information on fetal and childhood smoke exposure, childhood asthma outcomes, and covariates, including child’s inhalant allergies, is provided in e-Appendix 1.

Statistical Analysis

First, we used multivariate logistic and linear regression analyses to examine the associations of maternal and paternal smoking during pregnancy, including reported number of cigarettes, with Rint, Feno, and increased risk of asthma at age 6 years. These models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, and child’s sex, ethnicity, breastfeeding, pet keeping, and secondhand tobacco smoke exposure at age 6 years (e-Appendix 1). Differences in prevalence of wheezing patterns in strata of maternal and paternal smoking during pregnancy were tested using univariate and multivariate polynomial regression models, with “no maternal smoking” and “never wheezing” as reference. The associations of paternal smoking with Rint, Feno, wheezing patterns, and asthma were assessed among mothers who did not smoke during pregnancy (n = 4,504). Second, we used similar regression analyses to examine the associations of secondhand tobacco smoke exposure, including secondhand tobacco smoke exposure per week, with Rint, Feno, and asthma at age 6 years. These associations were adjusted for the same covariates as the maternal model, and maternal and paternal smoking during pregnancy. Third, to assess whether these were explained by birth outcomes, we additionally adjusted the models for gestational age and weight at birth (birth outcome model). Also, we additionally adjusted models for atopy (inhalant allergy or eczema) at age 6 years to assess the potential confounding or mediating roles of atopy (e-Appendix 1). Finally, we categorized tobacco smoke exposure into four categories (never, smoke exposure during pregnancy only, smoke exposure in childhood only, smoke exposure during pregnancy and in childhood) and examined their associations with Rint, Feno, wheezing, and asthma using the birth outcome model.

Additional information on used methods is provided in e-Appendix 1. Measures of association are presented in ORs for wheezing and asthma, in sympercents (symmetric percentage difference = regression coefficients of elog transformed Feno × 100%) for Feno measurements25 and in standardized z score differences for Rint measurements, all with their 95% CI. Statistical analyses were performed using SPSS, version 21.0 for Windows software (SPSS Inc; IBM).

Of the population for the current analysis, 67.6% (n = 4,063) were of European origin. Those of non-European ethnicity were mainly of Turkish (7.3%), Surinamese (6.8%), Moroccan (5.1%), or Dutch Antilles (2.5%) origin. Mean maternal age at inclusion was 30.6 years. Of all mothers, 25.0% (n = 1,503) smoked during pregnancy, of which 8.8% (n = 528) smoked during the first trimester only and 16.2% (n = 975) smoked continuously during pregnancy (Table 1). Of all fathers, 44% (n = 2,383) smoked during the pregnancies of their partner. Children were classified as never wheezing (45.6%, n = 2,149), early wheezing (28.6%, n = 1,266), late wheezing (7.4%, n = 324), and persistent wheezing (18.5%, n = 765). For the children, at age 6 years, average airway resistance (Rint) was 0.84 (SD, 0.29) kPa/L/s and median Feno was 7.5 (SD 8.5) ppb. Physician-diagnosed asthma was reported for 4.8% (n = 286) of the children. Other characteristics of parents and their children are given in Table 1 and e-Table 1. Participants without follow-up data at age 6 years had younger, lower educated parents who smoked more, mothers with a higher prepregnancy BMI, higher prevalence of parity and psychologic distress, and lower birth weight; more often, they were of non-European ethnicity than those participants with follow-up data (e-Table 2).

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Parents and Their Children

Values are means (SD), medians (2.5-97.5 percentile), or percentages (absolute numbers) based on imputed data. Missing data on paternal smoking during pregnancy (9.9%), secondhand tobacco smoke exposure (22.3%), child’s Rint (36.5%), Feno (23.1%), and asthma (26.7%) were not imputed. Feno = fractional exhaled nitric oxide; ppb = parts per billion; Rint = airway interrupter resistance.

Smoking Exposure and Rint, Feno, Wheezing Patterns, and Asthma

As compared with no maternal smoking, maternal smoking in the first trimester only was not associated with a higher mean Rint or Feno or increased risks of wheezing patterns and asthma in childhood (Tables 2, 3, confounder model). Continued maternal smoking during pregnancy was not associated with Rint or Feno. Continued maternal smoking of at least five cigarettes per day was associated with an increased risk of physician-diagnosed asthma (OR, 1.65 [1.07, 2.55]). The effect estimate did not materially change when we additionally adjusted for gestational age and birth weight (Table 2, birth outcome model). The effect estimate became stronger after adjustment for inhalant allergies and eczema (OR, 1.77 [1.13, 2.79]) (e-Table 3). The distribution of wheezing patterns was not different between children from mothers who did or did not smoke during first trimester only. As compared with children from mothers who did not smoke, those from mothers who continued smoking during pregnancy showed a higher prevalence of early wheezing (29.7% vs 28.1%, respectively) and persistent wheezing (25.2% vs 17.0%, respectively). Similarly, continued maternal smoking during pregnancy showed increased odds for early and persistent wheezing when taking confounders and birth outcomes into account (Table 3).

Table Graphic Jump Location
TABLE 2 ]  Associations of Maternal Smoking During Pregnancy With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, and child’s sex, ethnicity, breastfeeding, pet keeping, and secondhand tobacco smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. See Table 1 legend for expansion of abbreviations.

a 

P < .05.

Table Graphic Jump Location
TABLE 3 ]  Multivariate Analysis of the Association Between Parental Smoking During Pregnancy and Wheezing Patterns in Childhood

Values are ORs (95% CI) from multivariate polynomial regression models. “n =” represents No. of cases per group. Both models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, child’s sex, ethnicity, breastfeeding, pet keeping, and environmental smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and weight at birth.

a 

P < .05.

b 

P < .01.

Among children of mothers who did not smoke during pregnancy, paternal smoking was not associated with childhood Rint or Feno (z score difference: −0.4 [−0.34, 0.26] and sympercent change: −0.2 [−6.9, 6.5], respectively). In contrast to maternal smoking of at least five cigarettes per day, paternal smoking of at least five cigarettes per day during pregnancy was not associated with physician-diagnosed asthma (OR, 1.01 [0.58, 1.75]; Table 4). No differences in risk for wheezing patterns were observed between children from fathers who did not smoke or fathers who smoked during pregnancy (Table 3).

Table Graphic Jump Location
TABLE 4 ]  Associations of Paternal Smoking During Pregnancy With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for paternal age, educational level, history of asthma or atopy, and child’s sex, ethnicity, breastfeeding, pet keeping, and secondhand tobacco smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. Analyses on paternal smoking were restricted to mothers who did not smoke during pregnancy (n = 4,504). See Table 1 legend for expansion of abbreviations.

Compared with children not exposed to secondhand tobacco smoke, those who were exposed had a higher Rint (difference in z score, 0.45 [0.00, 0.90]), but no difference in Feno, or increased risk of asthma (Table 5). Additional adjustment for gestational age and size at birth did attenuate the size of the effect estimate for Rint (0.41 [−0.03, 0.86]).

Table Graphic Jump Location
TABLE 5 ]  Associations of Secondhand Tobacco Smoke Exposure With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, maternal and paternal smoking during pregnancy, and child’s sex, ethnicity, breastfeeding, and pet keeping. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. See Table 1 legend for expansion of abbreviations.

a 

P < .05.

We observed no statistically significant interactions between gestational age or size at birth with maternal or paternal smoking during pregnancy, or secondhand tobacco smoke exposure in childhood (all P values for interaction > 0.05). When we used the combined tobacco smoke exposure variable, we observed that smoke exposure during pregnancy only was associated with persistent wheezing (OR, 1.32 [1.00, 1.74]) (e-Table 4). We did not observe associations of smoke exposure in childhood only or smoke exposure both during pregnancy and in childhood with Rint, Feno, and asthma (e-Table 4).

We observed, in a large population-based prospective cohort study from early pregnancy onwards, that children of mothers who continued smoking at least five cigarettes per day during pregnancy had an increased risk of early and persistent wheezing and asthma at school age. These associations were not explained or modified by gestational age or birth weight. Maternal smoking during the first trimester only and paternal smoking were not associated with childhood Rint, Feno, or asthma. This implies that the observed associations are due to continued intrauterine adverse effects, and not by unmeasured socioeconomic, behavioral, or genetic factors. Associations of smoke exposure with airway resistance were present for childhood secondhand tobacco smoke exposure, independent of any tobacco smoke exposure during pregnancy. This association seemed partly explained by gestational age and weight at birth.

Comparison of Main Findings With Other Studies

Many previous studies suggest a direct adverse effect of tobacco smoke exposure on lung development, although disentanglement of exposure to maternal smoking during pregnancy and secondhand tobacco smoke remains difficult.13,7,26,27 Our study is a follow-up of a study previously performed in the same population at a younger age, in which we observed that fetal exposure to continued maternal smoking is associated with increased risks of wheezing in preschool children.7 We do now show that the adverse effects of maternal smoking during pregnancy on wheezing patterns and asthma extends into school age, independent of paternal smoking, smoke exposure in childhood, and birth characteristics. A large meta-analysis performed by Burke et al1 observed that postnatal passive smoke exposure was associated with a 30% to 70% increased risk of incident wheezing and that prenatal maternal smoking was associated with a 21% to 85% increase in incidence of asthma in children aged ≤ 2 years. A pooled analysis focused on wheezing and asthma at older ages, and showed a 1.4- and 1.6-fold independent effect of maternal smoking during pregnancy on wheezing and asthma in children aged 4 to 6 years who were not exposed to secondhand tobacco smoke in their first year of life.2 Also, a linear dose-dependent association of maternal daily cigarette consumption during pregnancy with wheezing and asthma was observed. The sizes of these effect estimates were similar to those observed in our study. We additionally took other important confounders such as parental history of asthma and atopy into account.28 Younger gestational age and weight at birth might be associated with smaller airways and could subsequently lead to lower lung function, in particular lower airway patency.29,30 It is known that these birth characteristics play an important role in the development of respiratory symptoms and lower lung function in childhood and adulthood.19,30,31 We observed that the associations between maternal smoking with wheezing and asthma were not explained by gestational age and birth weight. We additionally observed that socioeconomic or lifestyle-related factors, using paternal smoking during pregnancy as a proxy,15 did not explain the associations of maternal smoking during pregnancy with Rint, wheezing, and asthma.

Burke et al1 observed that secondhand tobacco smoke exposure in childhood was associated with childhood asthma (age 5-18 years) with approximately similar effect estimates (OR, 1.20 [0.98-1.46]) as maternal smoke exposure during pregnancy. We only observed an association of secondhand tobacco smoke exposure with a higher Rint. This is consistent with earlier studies,32,33 although these studies did not take smoke exposure during pregnancy into account, did not use asthma as a separate outcome, or were performed in asthma-suspected children only. Additionally, we explored the role of birth characteristics and observed that the association between secondhand tobacco smoke exposure and Rint was partly explained by gestational age and size at birth.

Interpretation of Results

We observed that the associations of maternal smoking during pregnancy with Rint, Feno, wheezing patterns, and physician-diagnosed asthma were not explained or modified by gestational age or weight at birth. Thus, despite the strong associations between maternal smoking during pregnancy with birth characteristics, the pathways leading from fetal smoke exposure to physician-diagnosed asthma might be independent of early body growth. The effects of maternal smoking during pregnancy on airway remodeling, hyperresponsiveness, and inflammation in offspring was recently assessed in mice models.34 Smoking during pregnancy induced airway remodeling, including increased airway smooth muscle layer, collagen III deposition, and house dust mite-induced goblet cell numbers, which may contribute to increased methacholine responsiveness. This remodeling was irrespective of allergen exposure, although allergen exposure resulted in higher methacholine responsiveness in house dust mite-exposed offspring from mothers who are smokers when compared with mothers who are nonsmokers. Other pathways that have been suggested are adverse effects of nicotine leading to a reduced blood flow and decreased delivery of oxygen and nutrients to the fetus, a reduction in fetal breathing movements, or a reduction in number and metabolism of alveolar type 2 cells, which can affect abnormal growth and maturation of the airways and lungs independent of body size.3537 However, we did not observe associations of maternal smoking during pregnancy with Rint. Alternatively, recent studies propose that maternal smoking during pregnancy changes the expression of asthma-susceptibility genes by a reduction of histone deacetylase activity and changes in methylation patterns.3840 Thus far, it is not known to what extent these epigenetic changes persist throughout the course of life or which specific critical periods for epigenetic changes are important to have an effect on the risk of later lung disease.

Strengths and Weaknesses

The major strength of this study is that we used a population-based prospective cohort design, with detailed information about maternal and paternal smoking during pregnancy and secondhand tobacco smoke exposure in childhood. Some methodologic considerations need to be discussed.

First, follow-up data were available in 70% of our original study population. This nonresponse could have led to biased effect estimates, if associations of Rint, wheezing patterns, or asthma would be different between children included and not included in the analyses.

Second, information about parental smoking during pregnancy was prospectively collected. Reporting bias by underreporting of the participants might have occurred although assessing smoke exposure by questionnaires is valid in epidemiologic studies.41 Assessing smoke exposure by biomarkers (cotinine, nicotine) in urine, blood, and air has not been proven to enhance the quality of smoking data when studying asthma or asthma-related outcomes.41,42 We had no objectively measured data on inhalant allergy such as specific IgE sensitization measured with serum or skin prick tests.

Third, we did not have data on spirometry, the preferred measure in asthma assessment. Since lung function measurements using spirometry in children aged 6 years are only successful in approximately 50%, we did not perform these measurements at this age.43 The Rint technique showed a high feasibility in this age group, and is known to detect small changes in proximal and more distal airway function with good within-occasion and between-occasion reproducibility.44 Previous studies have shown that Rint is able to identify differences in baseline and change in airway caliber. The discriminating capacity of Rint to identify asthma was found to be useful with positive predictive values of 82%.4446 Also, Rint is associated with clinically relevant end points including asthma diagnosis or wheezing and is able to distinguish between groups of symptomatic and healthy young children.46

Fourth, asthma is a difficult diagnosis in young children. Both wheezing patterns and asthma were self-reported outcome measures. Although using validated questionnaires based on international guidelines,24 underreporting or overreporting might have occurred, which might have led to misclassification of the outcomes resulting in either overestimations or underestimations of the true associations. Finally, although we took many potential confounders into account, residual confounding might still be an issue, as in any observational study.

In conclusion, our results suggest that maternal smoking during pregnancy leads to increased risks of early and persistent wheezing and asthma in school-aged children. Secondhand tobacco smoke exposure in childhood is associated with higher Rint but this effect is partly explained by gestational age and weight at birth.

Author contributions: H. T. d. D., A. M. M. S.-v. d. V., and L. D. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. H. T. d. D., A. M. M. S.-v. d. V., V. W. V. J., and L. D. contributed to the study concept and design, data analysis and interpretation, drafting, and revision of the manuscript; and J. C. d. J., I. K. R., and A. H. contributed to the study concept, data interpretation, and revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The researchers are independent from the funders. The sponsors had no role in the study design, data analysis, interpretation of data, or writing of this report.

Other contributions: The Generation R Study is conducted by Erasmus MC in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam.

Additional information: The e-Appendix and e-Tables can be found in the Supplemental Materials section of the online article.

Feno

fractional exhaled nitric oxide

ppb

parts per billion

Rint

airway interrupter resistance

Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129(4):735-744. [CrossRef] [PubMed]
 
Neuman Å, Hohmann C, Orsini N, et al; ENRIECO Consortium. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med. 2012;186(10):1037-1043. [CrossRef] [PubMed]
 
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(6):679-686. [CrossRef] [PubMed]
 
Hoppin JA, Umbach DM, London SJ, Alavanja MC, Sandler DP. Diesel exhaust, solvents, and other occupational exposures as risk factors for wheeze among farmers. Am J Respir Crit Care Med. 2004;169(12):1308-1313. [CrossRef] [PubMed]
 
Anderson HR, Ruggles R, Pandey KD, et al; ISAAC Phase One Study Group. Ambient particulate pollution and the world-wide prevalence of asthma, rhinoconjunctivitis and eczema in children: Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC). Occup Environ Med. 2010;67(5):293-300. [CrossRef] [PubMed]
 
Gilliland FD, Berhane K, Li YF, Rappaport EB, Peters JM. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med. 2003;167(6):917-924. [CrossRef] [PubMed]
 
Duijts L. Fetal and infant origins of asthma. Eur J Epidemiol. 2012;27(1):5-14. [CrossRef] [PubMed]
 
Rehan VK, Asotra K, Torday JS. The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair. Lung. 2009;187(5):281-289. [CrossRef] [PubMed]
 
Maritz GS. Perinatal exposure to nicotine and implications for subsequent obstructive lung disease. Paediatr Respir Rev. 2013;14(1):3-8. [CrossRef] [PubMed]
 
Hollams EM, de Klerk NH, Holt PG, Sly PD. Persistent effects of maternal smoking during pregnancy on lung function and asthma in adolescents. Am J Respir Crit Care Med. 2014;189(4):401-407. [CrossRef] [PubMed]
 
Miyake Y, Tanaka K. Lack of relationship between birth conditions and allergic disorders in Japanese children aged 3 years. J Asthma. 2013;50(6):555-559. [CrossRef] [PubMed]
 
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(2):138-144. [CrossRef] [PubMed]
 
Stein RT, Holberg CJ, Sherrill D, et al. Influence of parental smoking on respiratory symptoms during the first decade of life: the Tucson Children’s Respiratory Study. Am J Epidemiol. 1999;149(11):1030-1037. [CrossRef] [PubMed]
 
Sonnenschein-van der Voort AM, Arends LR, de Jongste JC, et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J Allergy Clin Immunol. 2014;133(5):1317-1329. [CrossRef] [PubMed]
 
Smith GD, Leary S, Ness A, Lawlor DA. Challenges and novel approaches in the epidemiological study of early life influences on later disease.. In:Koletzko B, Decsi T, Molnár D, de la Hunty A., eds. Early Nutrition Programming and Health Outcomes in Later Life. Amsterdam, The Netherlands: Springer Netherlands; 2009:1-14.
 
Raherison C, Pénard-Morand C, Moreau D, et al. In utero and childhood exposure to parental tobacco smoke, and allergies in schoolchildren. Respir Med. 2007;101(1):107-117. [CrossRef] [PubMed]
 
Xepapadaki P, Manios Y, Liarigkovinos T, et al. Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children. Pediatr Allergy Immunol. 2009;20(5):423-429. [CrossRef] [PubMed]
 
Jaakkola JJ, Ahmed P, Ieromnimon A, et al. Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol. 2006;118(4):823-830. [CrossRef] [PubMed]
 
Kotecha SJ, Watkins WJ, Heron J, Henderson J, Dunstan FD, Kotecha S. Spirometric lung function in school-age children: effect of intrauterine growth retardation and catch-up growth. Am J Respir Crit Care Med. 2010;181(9):969-974. [CrossRef] [PubMed]
 
Jaddoe VW, van Duijn CM, Franco OH, et al. The Generation R Study: design and cohort update 2012. Eur J Epidemiol. 2012;27(9):739-756. [CrossRef] [PubMed]
 
Jaddoe VW, Bakker R, van Duijn CM, et al. The Generation R Study Biobank: a resource for epidemiological studies in children and their parents. Eur J Epidemiol. 2007;22(12):917-923. [CrossRef] [PubMed]
 
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ; The Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332(3):133-138. [CrossRef] [PubMed]
 
Brussee JE, Smit HA, Koopman LP, et al. Interrupter resistance and wheezing phenotypes at 4 years of age. Am J Respir Crit Care Med. 2004;169(2):209-213. [CrossRef] [PubMed]
 
Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8(3):483-491. [CrossRef] [PubMed]
 
Cole TJ. Sympercents: symmetric percentage differences on the 100 log(e) scale simplify the presentation of log transformed data. Stat Med. 2000;19(22):3109-3125. [CrossRef] [PubMed]
 
Silvestri M, Franchi S, Pistorio A, Petecchia L, Rusconi F. Smoke exposure, wheezing, and asthma development: a systematic review and meta-analysis in unselected birth cohorts. Pediatr Pulmonol. 2015;50(4):353-362. [CrossRef] [PubMed]
 
Pattenden S, Antova T, Neuberger M, et al. Parental smoking and children’s respiratory health: independent effects of prenatal and postnatal exposure. Tob Control. 2006;15(4):294-301. [CrossRef] [PubMed]
 
Arshad SH, Karmaus W, Raza A, et al. The effect of parental allergy on childhood allergic diseases depends on the sex of the child. J Allergy Clin Immunol. 2012;130(2):427.e6-434.e6. [CrossRef]
 
Shaheen S, Barker DJ. Early lung growth and chronic airflow obstruction. Thorax. 1994;49(6):533-536. [CrossRef] [PubMed]
 
Kotecha SJ, Edwards MO, Watkins WJ, et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax. 2013;68(8):760-766. [CrossRef] [PubMed]
 
Canoy D, Pekkanen J, Elliott P, et al. Early growth and adult respiratory function in men and women followed from the fetal period to adulthood. Thorax. 2007;62(5):396-402. [CrossRef] [PubMed]
 
Kooi EM, Vrijlandt EJ, Boezen HM, Duiverman EJ. Children with smoking parents have a higher airway resistance measured by the interruption technique. Pediatr Pulmonol. 2004;38(5):419-424. [CrossRef] [PubMed]
 
Kalliola S, Pelkonen AS, Malmberg LP, et al. Maternal smoking affects lung function and airway inflammation in young children with multiple-trigger wheeze. J Allergy Clin Immunol. 2013;131(3):730-735. [CrossRef] [PubMed]
 
Blacquière MJ, Timens W, Melgert BN, Geerlings M, Postma DS, Hylkema MN. Maternal smoking during pregnancy induces airway remodelling in mice offspring. Eur Respir J. 2009;33(5):1133-1140. [CrossRef] [PubMed]
 
Lambers DS, Clark KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol. 1996;20(2):115-126. [CrossRef] [PubMed]
 
Manning FA, Feyerabend C. Cigarette smoking and fetal breathing movements. Br J Obstet Gynaecol. 1976;83(4):262-270. [CrossRef] [PubMed]
 
Maritz GS, Dennis H. Maternal nicotine exposure during gestation and lactation interferes with alveolar development in the neonatal lung. Reprod Fertil Dev. 1998;10(3):255-261. [CrossRef] [PubMed]
 
Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008;359(19):1985-1994. [CrossRef] [PubMed]
 
Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest. 2011;139(3):640-647. [CrossRef] [PubMed]
 
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(5):462-467. [CrossRef] [PubMed]
 
Shipton D, Tappin DM, Vadiveloo T, Crossley JA, Aitken DA, Chalmers J. Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study. BMJ. 2009;339:b4347. [CrossRef] [PubMed]
 
Carlsten C, Dimich-Ward H, DyBuncio A, Becker AB, Chan-Yeung M. Cotinine versus questionnaire: early-life environmental tobacco smoke exposure and incident asthma. BMC Pediatr. 2012;12:187. [CrossRef] [PubMed]
 
Gaffin JM, Sheehan WJ, Morrill J, et al. Tree nut allergy, egg allergy, and asthma in children. Clin Pediatr (Phila). 2011;50(2):133-139. [CrossRef] [PubMed]
 
Beydon N, Mahut B, Maingot L, et al. Baseline and post-bronchodilator interrupter resistance and spirometry in asthmatic children. Pediatr Pulmonol. 2012;47(10):987-993. [CrossRef] [PubMed]
 
Black J, Baxter-Jones AD, Gordon J, Findlay AL, Helms PJ. Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography. Pediatr Pulmonol. 2004;37(6):548-553. [CrossRef] [PubMed]
 
Kaminsky DA. What does airway resistance tell us about lung function? Respir Care. 2012;57(1):85-96. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Flowchart of participants. FeNO = fractional exhaled nitric oxide; Rint = airway interrupter resistance.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Parents and Their Children

Values are means (SD), medians (2.5-97.5 percentile), or percentages (absolute numbers) based on imputed data. Missing data on paternal smoking during pregnancy (9.9%), secondhand tobacco smoke exposure (22.3%), child’s Rint (36.5%), Feno (23.1%), and asthma (26.7%) were not imputed. Feno = fractional exhaled nitric oxide; ppb = parts per billion; Rint = airway interrupter resistance.

Table Graphic Jump Location
TABLE 2 ]  Associations of Maternal Smoking During Pregnancy With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, and child’s sex, ethnicity, breastfeeding, pet keeping, and secondhand tobacco smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. See Table 1 legend for expansion of abbreviations.

a 

P < .05.

Table Graphic Jump Location
TABLE 3 ]  Multivariate Analysis of the Association Between Parental Smoking During Pregnancy and Wheezing Patterns in Childhood

Values are ORs (95% CI) from multivariate polynomial regression models. “n =” represents No. of cases per group. Both models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, child’s sex, ethnicity, breastfeeding, pet keeping, and environmental smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and weight at birth.

a 

P < .05.

b 

P < .01.

Table Graphic Jump Location
TABLE 4 ]  Associations of Paternal Smoking During Pregnancy With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for paternal age, educational level, history of asthma or atopy, and child’s sex, ethnicity, breastfeeding, pet keeping, and secondhand tobacco smoke exposure at age 6 y. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. Analyses on paternal smoking were restricted to mothers who did not smoke during pregnancy (n = 4,504). See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 5 ]  Associations of Secondhand Tobacco Smoke Exposure With Rint, Feno, and Asthma of Children at Age 6 y

Values are z score differences in Rint, sympercent changes in Feno, and ORs for asthma (95% CI) from linear and logistic regression models. “n =” represents No. of total group (Rint, Feno) or No. of cases per total group (asthma). Models were adjusted for maternal age, prepregnancy BMI, educational level, history of asthma or atopy, psychologic distress during pregnancy, parity, maternal and paternal smoking during pregnancy, and child’s sex, ethnicity, breastfeeding, and pet keeping. The birth outcome adjusted model was additionally adjusted for gestational age and size at birth. See Table 1 legend for expansion of abbreviations.

a 

P < .05.

References

Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129(4):735-744. [CrossRef] [PubMed]
 
Neuman Å, Hohmann C, Orsini N, et al; ENRIECO Consortium. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med. 2012;186(10):1037-1043. [CrossRef] [PubMed]
 
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(6):679-686. [CrossRef] [PubMed]
 
Hoppin JA, Umbach DM, London SJ, Alavanja MC, Sandler DP. Diesel exhaust, solvents, and other occupational exposures as risk factors for wheeze among farmers. Am J Respir Crit Care Med. 2004;169(12):1308-1313. [CrossRef] [PubMed]
 
Anderson HR, Ruggles R, Pandey KD, et al; ISAAC Phase One Study Group. Ambient particulate pollution and the world-wide prevalence of asthma, rhinoconjunctivitis and eczema in children: Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC). Occup Environ Med. 2010;67(5):293-300. [CrossRef] [PubMed]
 
Gilliland FD, Berhane K, Li YF, Rappaport EB, Peters JM. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med. 2003;167(6):917-924. [CrossRef] [PubMed]
 
Duijts L. Fetal and infant origins of asthma. Eur J Epidemiol. 2012;27(1):5-14. [CrossRef] [PubMed]
 
Rehan VK, Asotra K, Torday JS. The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair. Lung. 2009;187(5):281-289. [CrossRef] [PubMed]
 
Maritz GS. Perinatal exposure to nicotine and implications for subsequent obstructive lung disease. Paediatr Respir Rev. 2013;14(1):3-8. [CrossRef] [PubMed]
 
Hollams EM, de Klerk NH, Holt PG, Sly PD. Persistent effects of maternal smoking during pregnancy on lung function and asthma in adolescents. Am J Respir Crit Care Med. 2014;189(4):401-407. [CrossRef] [PubMed]
 
Miyake Y, Tanaka K. Lack of relationship between birth conditions and allergic disorders in Japanese children aged 3 years. J Asthma. 2013;50(6):555-559. [CrossRef] [PubMed]
 
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(2):138-144. [CrossRef] [PubMed]
 
Stein RT, Holberg CJ, Sherrill D, et al. Influence of parental smoking on respiratory symptoms during the first decade of life: the Tucson Children’s Respiratory Study. Am J Epidemiol. 1999;149(11):1030-1037. [CrossRef] [PubMed]
 
Sonnenschein-van der Voort AM, Arends LR, de Jongste JC, et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J Allergy Clin Immunol. 2014;133(5):1317-1329. [CrossRef] [PubMed]
 
Smith GD, Leary S, Ness A, Lawlor DA. Challenges and novel approaches in the epidemiological study of early life influences on later disease.. In:Koletzko B, Decsi T, Molnár D, de la Hunty A., eds. Early Nutrition Programming and Health Outcomes in Later Life. Amsterdam, The Netherlands: Springer Netherlands; 2009:1-14.
 
Raherison C, Pénard-Morand C, Moreau D, et al. In utero and childhood exposure to parental tobacco smoke, and allergies in schoolchildren. Respir Med. 2007;101(1):107-117. [CrossRef] [PubMed]
 
Xepapadaki P, Manios Y, Liarigkovinos T, et al. Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children. Pediatr Allergy Immunol. 2009;20(5):423-429. [CrossRef] [PubMed]
 
Jaakkola JJ, Ahmed P, Ieromnimon A, et al. Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol. 2006;118(4):823-830. [CrossRef] [PubMed]
 
Kotecha SJ, Watkins WJ, Heron J, Henderson J, Dunstan FD, Kotecha S. Spirometric lung function in school-age children: effect of intrauterine growth retardation and catch-up growth. Am J Respir Crit Care Med. 2010;181(9):969-974. [CrossRef] [PubMed]
 
Jaddoe VW, van Duijn CM, Franco OH, et al. The Generation R Study: design and cohort update 2012. Eur J Epidemiol. 2012;27(9):739-756. [CrossRef] [PubMed]
 
Jaddoe VW, Bakker R, van Duijn CM, et al. The Generation R Study Biobank: a resource for epidemiological studies in children and their parents. Eur J Epidemiol. 2007;22(12):917-923. [CrossRef] [PubMed]
 
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ; The Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332(3):133-138. [CrossRef] [PubMed]
 
Brussee JE, Smit HA, Koopman LP, et al. Interrupter resistance and wheezing phenotypes at 4 years of age. Am J Respir Crit Care Med. 2004;169(2):209-213. [CrossRef] [PubMed]
 
Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8(3):483-491. [CrossRef] [PubMed]
 
Cole TJ. Sympercents: symmetric percentage differences on the 100 log(e) scale simplify the presentation of log transformed data. Stat Med. 2000;19(22):3109-3125. [CrossRef] [PubMed]
 
Silvestri M, Franchi S, Pistorio A, Petecchia L, Rusconi F. Smoke exposure, wheezing, and asthma development: a systematic review and meta-analysis in unselected birth cohorts. Pediatr Pulmonol. 2015;50(4):353-362. [CrossRef] [PubMed]
 
Pattenden S, Antova T, Neuberger M, et al. Parental smoking and children’s respiratory health: independent effects of prenatal and postnatal exposure. Tob Control. 2006;15(4):294-301. [CrossRef] [PubMed]
 
Arshad SH, Karmaus W, Raza A, et al. The effect of parental allergy on childhood allergic diseases depends on the sex of the child. J Allergy Clin Immunol. 2012;130(2):427.e6-434.e6. [CrossRef]
 
Shaheen S, Barker DJ. Early lung growth and chronic airflow obstruction. Thorax. 1994;49(6):533-536. [CrossRef] [PubMed]
 
Kotecha SJ, Edwards MO, Watkins WJ, et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax. 2013;68(8):760-766. [CrossRef] [PubMed]
 
Canoy D, Pekkanen J, Elliott P, et al. Early growth and adult respiratory function in men and women followed from the fetal period to adulthood. Thorax. 2007;62(5):396-402. [CrossRef] [PubMed]
 
Kooi EM, Vrijlandt EJ, Boezen HM, Duiverman EJ. Children with smoking parents have a higher airway resistance measured by the interruption technique. Pediatr Pulmonol. 2004;38(5):419-424. [CrossRef] [PubMed]
 
Kalliola S, Pelkonen AS, Malmberg LP, et al. Maternal smoking affects lung function and airway inflammation in young children with multiple-trigger wheeze. J Allergy Clin Immunol. 2013;131(3):730-735. [CrossRef] [PubMed]
 
Blacquière MJ, Timens W, Melgert BN, Geerlings M, Postma DS, Hylkema MN. Maternal smoking during pregnancy induces airway remodelling in mice offspring. Eur Respir J. 2009;33(5):1133-1140. [CrossRef] [PubMed]
 
Lambers DS, Clark KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol. 1996;20(2):115-126. [CrossRef] [PubMed]
 
Manning FA, Feyerabend C. Cigarette smoking and fetal breathing movements. Br J Obstet Gynaecol. 1976;83(4):262-270. [CrossRef] [PubMed]
 
Maritz GS, Dennis H. Maternal nicotine exposure during gestation and lactation interferes with alveolar development in the neonatal lung. Reprod Fertil Dev. 1998;10(3):255-261. [CrossRef] [PubMed]
 
Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008;359(19):1985-1994. [CrossRef] [PubMed]
 
Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest. 2011;139(3):640-647. [CrossRef] [PubMed]
 
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(5):462-467. [CrossRef] [PubMed]
 
Shipton D, Tappin DM, Vadiveloo T, Crossley JA, Aitken DA, Chalmers J. Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study. BMJ. 2009;339:b4347. [CrossRef] [PubMed]
 
Carlsten C, Dimich-Ward H, DyBuncio A, Becker AB, Chan-Yeung M. Cotinine versus questionnaire: early-life environmental tobacco smoke exposure and incident asthma. BMC Pediatr. 2012;12:187. [CrossRef] [PubMed]
 
Gaffin JM, Sheehan WJ, Morrill J, et al. Tree nut allergy, egg allergy, and asthma in children. Clin Pediatr (Phila). 2011;50(2):133-139. [CrossRef] [PubMed]
 
Beydon N, Mahut B, Maingot L, et al. Baseline and post-bronchodilator interrupter resistance and spirometry in asthmatic children. Pediatr Pulmonol. 2012;47(10):987-993. [CrossRef] [PubMed]
 
Black J, Baxter-Jones AD, Gordon J, Findlay AL, Helms PJ. Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography. Pediatr Pulmonol. 2004;37(6):548-553. [CrossRef] [PubMed]
 
Kaminsky DA. What does airway resistance tell us about lung function? Respir Care. 2012;57(1):85-96. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data

Online Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543