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1.  Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing 
Pediatrics  2008;122(1):e107-e114.
Objective
Associations between single-nucleotide polymorphisms in the β2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects β2-adrenergic receptor gene expression and associations of β2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of β2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.
Methods
We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.
Results
Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism–specific results. No associations were found for Glu27Gln.
Conclusions
Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16–Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of β2-adrenergic receptor gene variants on respiratory health outcomes.
doi:10.1542/peds.2007-3370
PMCID: PMC2748980  PMID: 18558635
β-2 adrenergic receptor; prenatal exposure; secondhand-smoke exposure; asthma; wheeze
2.  The impact of secondhand smoke on asthma control among Black and Latino children 
Background
Among people with asthma, the clinical impact and relative contribution of maternal smoking during pregnancy (in utero smoking) and current secondhand smoke exposure on asthma control is poorly documented, and there is a paucity of research involving minority populations.
Objectives
To examine the association between poor asthma control and in utero smoking and current secondhand smoke exposure among Latino and Black children with asthma.
Methods
Case-only analysis of 2 multi-center case-control studies conducted from 2008–2010 using similar protocols. We recruited 2,481 Latinos and Blacks with asthma (ages 8–17) from the mainland United States and Puerto Rico. Ordinal logistic regression was used to estimate the effect of in utero smoking and current secondhand smoke exposures on National Heart Lung and Blood Institute-defined asthma control.
Results
Poor asthma control among children 8–17 years of age was independently associated with in utero smoking (odds ratio; 95% confidence interval = 1.5; 1.1–2.0). In utero smoking via the mother was also associated with secondary asthma outcomes, including early onset asthma (1.7; 1.1–2.4), daytime symptoms (1.6; 1.1–2.1), and asthma-related limitation of activities (1.6; 1.2–2.2).
Conclusions
Maternal smoking while in utero is associated with poor asthma control in Black and Latino subjects assessed at 8–17 years of age.
doi:10.1016/j.jaci.2012.03.017
PMCID: PMC3367092  PMID: 22552109
Secondhand smoke; prenatal exposure delayed effects; asthma; health status disparities
3.  Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function 
Thorax  2000;55(4):271-276.
BACKGROUND—Exposure to environmental tobacco smoke (ETS) during childhood and in utero exposure to maternal smoking are associated with adverse effects on lung growth and development.
METHODS—A study was undertaken of the associations between maternal smoking during pregnancy, exposure to ETS, and pulmonary function in 3357 school children residing in 12 Southern California communities. Current and past exposure to household ETS and exposure to maternal smoking in utero were assessed by a self-administered questionnaire completed by parents of 4th, 7th, and 10th grade students in 1993.Standard linear regression techniques were used to estimate the effects of in utero and ETS exposure on lung function, adjusting for age, sex, race, Hispanic ethnicity, height, weight, asthma, personal smoking, and selected household characteristics.
RESULTS—In utero exposure to maternal smoking was associated with reduced peak expiratory flow rate (PEFR) (-3.0%, 95% CI -4.4 to -1.4), mean mid expiratory flow (MMEF) (-4.6%, 95% CI -7.0 to -2.3), and forced expiratory flow (FEF75) (-6.2%, 95% CI -9.1 to -3.1), but not forced expiratory volume in one second (FEV1). Adjusting for household ETS exposure did not substantially change these estimates. The reductions in flows associated with in utero exposure did not significantly vary with sex, race, grade, income, parental education, or personal smoking. Exposure to two or more current household smokers was associated with reduced MMEF (-4.1%, 95% CI -7.6 to -0.4) and FEF75 (-4.4%, 95% CI -9.0 to 0.4). Current or past maternal smoking was associated with reductions in PEFR and MMEF; however, after adjustment for in utero exposure, deficits in MMEF and FEF75 associated with all measurements of ETS were substantially reduced and were not statistically significant.
CONCLUSIONS—In utero exposure to maternal smoking is independently associated with decreased lung function in children of school age, especially for small airway flows.


doi:10.1136/thorax.55.4.271
PMCID: PMC1745733  PMID: 10722765
4.  Household environmental tobacco smoke and risks of asthma, wheeze and bronchitic symptoms among children in Taiwan 
Respiratory Research  2010;11(1):11.
Background
Although studies show that maternal smoking during pregnancy increases the risks of respiratory outcomes in childhood, evidence concerning the effects of household environmental tobacco smoke (ETS) exposure remains inconsistent.
Methods
We conducted a population-based study comprised of 5,019 seventh and eighth-grade children in 14 Taiwanese communities. Questionnaire responses by parents were used to ascertain children's exposure and disease status. Logistic regression models were fitted to estimate the effects of ETS exposures on the prevalence of asthma, wheeze, and bronchitic symptoms.
Results
The lifetime prevalence of wheeze was 11.6% and physician-diagnosed asthma was 7.5% in our population. After adjustment for potential confounders, in utero exposure showed the strongest effect on all respiratory outcomes. Current household ETS exposure was significantly associated with increased prevalence of active asthma, ever wheeze, wheeze with nighttime awakening, and bronchitis. Maternal smoking was associated with the increased prevalence of a wide range of wheeze subcategories, serious asthma, and chronic cough, but paternal smoking had no significant effects. Although maternal smoking alone and paternal smoking alone were not independently associated with respiratory outcomes, joint exposure appeared to increase the effects. Furthermore, joint exposure to parental smoking showed a significant effect on early-onset asthma (OR, 2.01; 95% CI, 1.00-4.02), but did not show a significant effect on late-onset asthma (OR, 1.17; 95% CI, 0.36-3.87).
Conclusion
We concluded that prenatal and household ETS exposure had significant adverse effects on respiratory health in Taiwanese children.
doi:10.1186/1465-9921-11-11
PMCID: PMC2828425  PMID: 20113468
5.  Changes in Environmental Tobacco Smoke Exposure and Asthma Morbidity Among Urban School Children 
Chest  2008;135(4):911-916.
Background:
Environmental tobacco smoke (ETS) exposure is associated with poor asthma outcomes in children. However, little is known about natural changes in ETS exposure over time in children with asthma and how these changes may affect health-care utilization. This article documents the relationship between changes in ETS exposure and childhood asthma morbidity among children enrolled in a clinical trial of supervised asthma therapy.
Methods:
Data for this analysis come from a large randomized clinical trial of supervised asthma therapy in which 290 children with persistent asthma were randomized to receive either usual care or supervised asthma therapy. No smoking cessation counseling or ETS exposure education was provided to caregivers; however, children were given 20 min of asthma education, which incorporated discussion of the avoidance of asthma triggers, including ETS. Asthma morbidity and ETS exposure data were collected from caregivers via telephone interviews at baseline and at the 1-year follow-up.
Results:
At baseline, 28% of caregivers reported ETS exposure in the home and 19% reported exposure outside of the primary household only. Among children whose ETS exposure decreased from baseline, fewer hospitalizations (p = 0.034) and emergency department (ED) visits (p ≤ 0.001) were reported in the 12 months prior to the second interview compared to the 12 months prior to the first interview. Additionally, these children were 48% less likely (p = 0.042) to experience an episode of poor asthma control (EPAC).
Conclusions:
This is the first study to demonstrate an association between ETS exposure reduction and fewer EPACs, respiratory-related ED visits, and hospitalizations. These findings emphasize the importance of ETS exposure reduction as a mechanism to improve asthma control and morbidity. Potential policy implications include supporting ETS reductions and smoking cessation interventions for parents and caregivers of children with asthma. Research to identify the most cost-effective strategy is warranted.
Trial registration:
Clinicaltrials.gov Identifier: NCT00110383
doi:10.1378/chest.08-1869
PMCID: PMC2763557  PMID: 19017893
asthma; children; environmental tobacco smoke; tobacco smoke pollution
6.  Environmental tobacco smoke, parental atopy, and childhood asthma. 
Environmental Health Perspectives  2001;109(6):579-582.
We hypothesized that the joint effect of genetic propensity to asthma and exposure to environmental tobacco smoke on the risk of childhood asthma is greater than expected on the basis of their independent effects. We performed a population-based 4-year cohort study of 2,531 children born in Oslo, Norway. We collected information on the child's health and environmental exposures at birth and when the child was 6, 12, 18, and 24 months and 4 years of age. The outcomes of interest were bronchial obstruction during the first 2 years and asthma at the age of 4 years. Parental atopy was defined as a history of maternal or paternal asthma or hay fever. Exposure to environmental tobacco smoke was defined on the basis of questionnaire information on household smokers at birth. In logistic regression analysis adjusting for confounding, parental atopy alone increased the risk of bronchial obstruction [odds ratio 1.62; 95% confidence interval (CI) 1.10-2.40] and asthma (1.66; 95% CI, 1.08-2.54). In children without parental atopy, there was little effect of exposure to environmental tobacco smoke on bronchial obstruction (1.29; 95% CI, 0.88-1.89) and asthma (0.84; 95% CI, 0.53-1.34). The presence of parental atopy and exposure had a substantial effect both on bronchial obstruction (2.88; 95% CI, 1.91-4.32) and asthma (2.68; 95% CI, 1.70-4.22). The results are consistent with the hypothesized joint effect of parental atopy and exposure to environmental tobacco smoke. This phenomenon--denoted as effect modification of environmental exposure by genetic constitution, or gene by environment interaction--suggests that some genetic markers could indicate susceptibility to environmental factors.
PMCID: PMC1240339  PMID: 11445511
7.  Effects of active tobacco smoking on the prevalence of asthma-like symptoms in adolescents 
The prevalence of asthma in adolescents markedly varies between different localities as found by the International Study of Asthma and Allergies in Childhood (ISAAC) and this may be due to environmental factors. Although tobacco smoke exposure is related to an increase in the prevalence of asthma, there is lack of information on that respect in children from developing countries, where active tobacco smoking usually starts early in adolescence. This study was undertaken to assess the effect of tobacco smoking on the prevalence of asthma symptoms in a random sample of 4738 adolescents aged 13.4 ± 1.05 years who responded the ISAAC video questionnaires plus questions on tobacco smoking. The prevalence of tobacco smoking in the last 12 months was 16.2%, with significant female predominance. The persistent smokers had a significantly higher prevalence of asthma-like symptoms ever and in the last 12 months (wheezing, wheezing with exercise, nocturnal wheezing, severe wheezing, and dry nocturnal cough) than ex-smokers and nonsmokers. More than 27% of asthma symptoms in our adolescents are attributable to active tobacco consumption (population attributable risk). This study strongly suggests that potent and more effective campaigns against tobacco smoking should be implemented in developing countries, where active tobacco smoking is dramatically increasing in children.
PMCID: PMC2692110  PMID: 18044067
asthma; prevalence; ISAAC; tobacco; video questionnaires
8.  A Twin Study of Early-Childhood Asthma in Puerto Ricans 
PLoS ONE  2013;8(7):e68473.
Background
The relative contributions of genetics and environment to asthma in Hispanics or to asthma in children younger than 3 years are not well understood.
Objective
To examine the relative contributions of genetics and environment to early-childhood asthma by performing a longitudinal twin study of asthma in Puerto Rican children ≤3 years old.
Methods
678 twin infants from the Puerto Rico Neo-Natal Twin Registry were assessed for asthma at age 1 year, with follow-up data obtained for 624 twins at age 3 years. Zygosity was determined by DNA microsatellite profiling. Structural equation modeling was performed for three phenotypes at ages 1 and 3 years: physician-diagnosed asthma, asthma medication use in the past year, and ≥1 hospitalization for asthma in the past year. Models were additionally adjusted for early-life environmental tobacco smoke exposure, sex, and age.
Results
The prevalences of physician-diagnosed asthma, asthma medication use, and hospitalization for asthma were 11.6%, 10.8%, 4.9% at age 1 year, and 34.1%, 40.1%, and 8.5% at 3 years, respectively. Shared environmental effects contributed to the majority of variance in susceptibility to physician-diagnosed asthma and asthma medication use in the first year of life (84%–86%), while genetic effects drove variance in all phenotypes (45%–65%) at age 3 years. Early-life environmental tobacco smoke, sex, and age contributed to variance in susceptibility.
Conclusion
Our longitudinal study in Puerto Rican twins demonstrates a changing contribution of shared environmental effects to liability for physician-diagnosed asthma and asthma medication use between ages 1 and 3 years. Early-life environmental tobacco smoke reduction could markedly reduce asthma morbidity in young Puerto Rican children.
doi:10.1371/journal.pone.0068473
PMCID: PMC3700929  PMID: 23844206
9.  The interaction of GSTM1 null variants with tobacco smoke exposure and the development of childhood asthma 
Background
The glutathione S-transferase M1 (GSTM1) null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress.
Objective
To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics.
Methods
We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and postnatal, longitudinal environmental tobacco smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes.
Results
Associations of GSTM1 null variants with asthma (p= .03), younger age of asthma symptom onset (p=.03), and greater airflow obstruction (reduced FEV1/FVC, p=.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1 null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection.
Conclusion
These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.
doi:10.1111/j.1365-2222.2009.03372.x
PMCID: PMC2773694  PMID: 19860819
Asthma; GSTM1; copy number variation (CNV); gene by environment; intrauterine smoke exposure; tobacco smoke
10.  Indoor air pollution and childhood asthma: effective environmental interventions. 
Environmental Health Perspectives  1995;103(Suppl 6):55-58.
Exposure to indoor air pollutants such as tobacco smoke and dust mites may exacerbate childhood asthma. Environmental interventions to reduce exposures to these pollutants can help prevent exacerbations of the disease. Among the most important interventions is the elimination of environmental tobacco smoke from the environments of children with asthma. However, the effectiveness of reducing asthmatic children's exposure to environmental tobacco smoke on the severity of their symptoms has not yet been systematically evaluated. Dust mite reduction is another helpful environmental intervention. This can be achieved by enclosing the child's mattresses, blankets, and pillows in zippered polyurethane-coated casings. Primary prevention of asthma is not as well understood. It is anticipated that efforts to reduce smoking during pregnancy could reduce the incidence of asthma in children. European studies have suggested that reducing exposure to food and house dust mite antigens during lactation and for the first 12 months of life diminishes the development of allergic disorders in infants with high total IgE in the cord blood and a family history of atopy. Many children with asthma and their families are not receiving adequate counseling about environmental interventions from health care providers or other sources.
PMCID: PMC1518930  PMID: 8549490
11.  In Utero Smoke Exposure and Impaired Response to Inhaled Corticosteroids in Children with Asthma 
Background
Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in asthmatic children.
Objectives
To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma, and whether IUS modifies the response to treatment with inhaled corticosteroids (ICS).
Methods
To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program (CAMP), a four-year, multicenter, randomized double masked placebo controlled trial of 1041 children ages 5–12 comparing the long term efficacy of ICS with mast cell stabilizing agents or placebo.
Results
Although improvement was seen in both groups, asthmatic children with IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared to unexposed children (p=.01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared to untreated children (1.25 fold-increase, 95% CI 1.03, 1.50, p=.02) the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04 fold-increase, 95% CI 0.65, 1.68, p=.88).
Conclusions
IUS reduces age-related improvements in airway responsiveness among asthmatic children. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
doi:10.1016/j.jaci.2010.06.016
PMCID: PMC2937829  PMID: 20673983
asthma; in utero smoke exposure; airway responsiveness; inhaled corticosteroids
12.  Prenatal and postnatal tobacco smoke exposure and respiratory health in Russian children 
Respiratory Research  2006;7(1):48.
Background
Only few studies have assessed the relative impact of prenatal and postnatal exposure to tobacco smoke on the child's later asthma or chronic respiratory symptoms and to our knowledge no studies have elaborated respiratory infections and allergies in this context.
Objective
To assess the effects of prenatal and postnatal exposure to tobacco smoke on respiratory health of Russian school children.
Methods
We studied a population of 5951 children (8 to12 years old) from 9 Russian cities, whose parents answered a questionnaire on their children's respiratory health, home environment, and housing characteristics. The main health outcomes were asthma, allergies, chronic respiratory symptoms, chronic bronchitis, and upper respiratory infections. We used adjusted odds ratios (ORs) from logistic regression analyses as measures of effect.
Results
Prenatal exposure due to maternal smoking had the strongest effects on asthma (adjusted OR 2.46, 95% CI 1.19–5.08), chronic bronchitis (adjusted OR 1.45, 95% CI 1.08–1.96) and respiratory symptoms, such as wheezing (adjusted OR 1.30, 95% CI 0.90–1.89). The associations were weaker for exposure during early-life (adjusted ORs 1.38/1.27/1.15 respectively) and after 2 years of age (adjusted ORs 1.45/1.34/1.18) compared to prenatal exposure and the weakest or non-existent for current exposure (adjusted ORs 1.05/1.09/1.06). Upper respiratory infections were associated more strongly with early-life exposure (adjusted OR 1.25, 95% CI 1.09–1.42) than with prenatal (adjusted OR 0.74, 95% CI 0.54–1.01) or current exposure (adjusted OR1.05, 95% CI 0.92–1.20). The risk of allergies was also related to early life exposure to tobacco smoke (adjusted OR 1.26, 95% CI 1.13–1.42).
Conclusion
Adverse effects of tobacco smoke on asthma, chronic bronchitis, and chronic respiratory symptoms are strongest when smoking takes place during pregnancy. The relations are weaker for exposure during early-life and after 2 years of age and weakest or non-existent for current exposure.
doi:10.1186/1465-9921-7-48
PMCID: PMC1484481  PMID: 16569224
13.  Early-life environmental risk factors for asthma: findings from the Children's Health Study. 
Environmental Health Perspectives  2004;112(6):760-765.
Early-life experiences and environmental exposures have been associated with childhood asthma. To investigate further whether the timing of such experiences and exposures is associated with the occurrence of asthma by 5 years of age, we conducted a prevalence case-control study nested within the Children's Health Study, a population-based study of > 4,000 school-aged children in 12 southern California communities. Cases were defined as physician-diagnosed asthma by age 5, and controls were asthma-free at study entry, frequency-matched on age, sex, and community of residence and countermatched on in utero exposure to maternal smoking. Telephone interviews were conducted with mothers to collect additional exposure and asthma histories. Conditional logistic regression models were fitted to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Asthma diagnosis before 5 years of age was associated with exposures in the first year of life to wood or oil smoke, soot, or exhaust (OR = 1.74; 95% CI, 1.02-2.96), cockroaches (OR = 2.03; 95% CI, 1.03-4.02), herbicides (OR = 4.58; 95% CI, 1.36-15.43), pesticides (OR = 2.39; 95% CI, 1.17-4.89), and farm crops, farm dust, or farm animals (OR = 1.88; 95% CI, 1.07-3.28). The ORs for herbicide, pesticide, farm animal, and crops were largest among children with early-onset persistent asthma. The risk of asthma decreased with an increasing number of siblings (ptrend = 0.01). Day care attendance within the first 4 months of life was positively associated with early-onset transient wheezing (OR = 2.42; 95% CI, 1.28-4.59). In conclusion, environmental exposures during the first year of life are associated with childhood asthma risk.
PMCID: PMC1241973  PMID: 15121522
14.  Transgenerational tobacco smoke exposure and childhood cancer: An observational study 
Aim
Although tobacco smoke is an established risk factor for adult cancer, studies of the association between parental smoking and childhood cancer have produced inconsistent results. To investigate the transgenerational relationship between pre-natal and post-natal tobacco smoke exposure from the grandmother’s pregnancies until after the post-natal period and childhood cancer.
Methods
Exposure to tobacco smoke was recorded for three generations. Data were collected through personal interviews using the paediatric environmental history, and were compared among 128 children with cancer and 128 matched controls. The contingency tables and a logistic multivariable regression model were used to control for possible confounding factors.
Results
Smoke exposure during oogenesis (maternal grandmother smokers) – odds ratio (OR) 2.2 (95% confidence interval (CI) 1.1–4.9) – and during the mother’ pregnancies – OR 1.8 (95% CI 1.1–3.3) – were significantly associated with an increased risk of childhood cancer.
Conclusions
Tobacco smoke exposure during the grandmother’s and mother’s pregnancies increase the risk of cancer in the descendants. The results suggest that the biological plausibility of the association between parental smoking and paediatric cancer can be explained by the large latency period of paediatric carcinogenesis.
doi:10.1111/j.1440-1754.2010.01710.x
PMCID: PMC3190978  PMID: 20412413
case-control studies; childhood cancer; tobacco smoke pollution
15.  In utero exposure to tobacco smoke and subsequent reduced fertility in females 
Human Reproduction (Oxford, England)  2010;25(11):2901-2906.
BACKGROUND
Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent.
METHODS
We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15–44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking.
RESULTS
The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account.
CONCLUSIONS
This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility.
doi:10.1093/humrep/deq235
PMCID: PMC2955556  PMID: 20817739
tobacco smoking; in utero exposure; fertility
16.  In utero exposure to maternal smoking and women's risk of fetal loss in the Norwegian Mother and Child Cohort (MoBa) 
BACKGROUND
Whether in utero exposure to tobacco smoke increases a woman's risk of fetal loss later in life is unknown, though data on childhood exposure suggest an association may exist. This study evaluated the association between in utero exposure to tobacco smoke and fetal loss in the Norwegian Mother and Child Cohort Study (MoBa), which enrolled ∼40% of the pregnant women in Norway from 1999 to 2008.
METHODS
Information on exposure to tobacco smoke in utero, the woman's own smoking behavior during pregnancy and other factors was obtained by a questionnaire completed at ∼17 weeks of gestation. Subsequent late miscarriage (fetal death <20 weeks) and stillbirth (fetal death ≥20 weeks) were ascertained from the Norwegian Medical Birth Registry. This analysis included 76 357 pregnancies (MoBa data set version 4.301) delivered by the end of 2008; 59 late miscarriages and 270 stillbirths occurred. Cox proportional hazards models were fit for each outcome and for all fetal deaths combined.
RESULTS
The adjusted hazard ratio (HR) of late miscarriage was 1.23 [95% confidence interval (CI), 0.72–2.12] in women with exposure to maternal tobacco smoke in utero when compared with non-exposed women. The corresponding adjusted HR for stillbirths was 1.11 (95% CI, 0.85–1.44) and for all fetal deaths combined, it was 1.12 (95% CI, 0.89–1.43).
CONCLUSIONS
The relatively wide CI around the HR for miscarriage reflected the limited power to detect an association, due to enrollment around 17 weeks of gestation. However, for in utero exposure to tobacco smoke and risk of stillbirth later in life, where the study power was adequate, our data provided little support for an association.
doi:10.1093/humrep/deq334
PMCID: PMC3024897  PMID: 21147823
tobacco smoking; in utero exposure; miscarriage; pregnancy; stillbirth
17.  Reducing asthma health disparities in poor Puerto Rican children: The effectiveness of a culturally tailored family intervention 
Background
Island and mainland Puerto Rican children have the highest rates of asthma and asthma morbidity of any ethnic group in the United States.
Objective
We evaluated the effectiveness of a culturally adapted family asthma management intervention called CALMA (an acronym of the Spanish for “Take Control, Empower Yourself and Achieve Management of Asthma”) in reducing asthma morbidity in poor Puerto Rican children with asthma.
Methods
Low-income children with persistent asthma were selected from a national health plan insurance claims database by using a computerized algorithm. After baseline, families were randomly assigned to either the intervention or a control group.
Results
No significant differences between control and intervention group were found for the primary outcome of symptom-free days. However, children in the CALMA intervention group had 6.5% more symptom-free nights, were 3 times more likely to have their asthma under control, and were less likely to visit the emergency department and be hospitalized as compared to the control group. Caregivers receiving CALMA were significantly less likely to feel helpless, frustrated, or upset because of their child’s asthma and more likely to feel confident to manage their child’s asthma.
Conclusion
A home-based asthma intervention program tailored to the cultural needs of low income Puerto Rican families is a promising intervention for reducing asthma morbidity.
doi:10.1016/j.jaci.2007.10.022
PMCID: PMC3136215  PMID: 18061648
Family asthma management intervention; controlled clinical trial; Puerto Rican; children
18.  Asthma and other recurrent wheezing disorders in children (chronic) 
Clinical Evidence  2012;2012:0302.
Introduction
Childhood asthma is the most common chronic paediatric illness. There is no cure for asthma but good treatment to palliate symptoms is available. Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyperresponsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pet animals, exposure to tobacco smoke, and exercise.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta2 agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 48 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (long-acting), corticosteroids (inhaled standard or higher doses), leukotriene receptor antagonists (oral), omalizumab, and theophylline (oral).
Key Points
Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.
Regular monotherapy with inhaled corticosteroids improves symptoms, reduces exacerbations, and improves physiological outcomes in children with asthma symptoms requiring regular short-acting beta2 agonist treatment. Their effect on final adult height is minimal and when prescribed within recommended doses have an excellent safety record. Regular monotherapy with other treatments is not superior to low-dose inhaled corticosteroids.
Leukotriene receptor antagonists may have a role as first-line prophylaxis in very young children.
There is consensus that long-acting beta2 agonists should not be used for first-line prophylaxis. CAUTION: Monotherapy with long-acting beta2 agonists does not reduce asthma exacerbations but may increase the chance of severe asthma episodes.
Theophylline was used as first-line prevention before the introduction of inhaled corticosteroids. Although there is weak evidence that theophylline is superior to placebo, theophylline should no longer be used as first-line prophylaxis in childhood asthma because of clear evidence of the efficacy and safety of inhaled corticosteroids. Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.
When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited RCT evidence of benefit compared with adding placebo/no additional treatments. Addition of long-acting beta2 agonists may reduce symptoms and improve physiological measures compared with increased dose of corticosteroids in older children. Long-acting beta2 agonists are not currently licensed for use in children under 5 years of age.Consensus suggests that younger children are likely to benefit from addition of leukotriene receptor antagonists. Although there is weak evidence that addition of theophylline to inhaled corticosteroids does improve symptom control and reduce exacerbations, theophylline should only be added to inhaled corticosteroids in children aged over 5 years when the addition of long-acting beta2 agonists and leukotriene receptor antagonists have both been unsuccessful.
Omalizumab may be indicated in the secondary care setting for older children (aged over 5 years) with poorly controlled allergic asthma despite use of intermediate- and high-dose inhaled corticosteroids once the diagnosis is confirmed and compliance and psychological issues are addressed. However, we need more data to draw firm conclusions.
PMCID: PMC3285219  PMID: 22305975
19.  Pulmonary effects of passive smoking: the Indian experience 
Tobacco Induced Diseases  2002;1(2):129-136.
There are only a few studies done on pulmonary effects of passive smoking from India, which are summarized in this paper. Several vernacular tobacco products are used in India, bidis (beedis) being the commonest form of these. Bidis contain a higher concentration of nicotine and other tobacco alkaloids compared to the standard cigarettes (e.g., the sum of total nicotine and minor tobacco alkaloids was 37.5 mg in bidi compared to 14–16 mg in Indian or American cigarettes in one study). A large study performed on 9090 adolescent school children demonstrated environmental tobacco smoke (ETS) exposure to be associated with an increased risk of asthma. The odds ratio for being asthmatic in ETS-exposed as compared to ETS-unexposed children was 1.78 (95% CI: 1.33–2.31). Nearly one third of the children in this study reported non-specific respiratory symptoms and the ETS exposure was found to be positively associated with the prevalence of each symptom. Passive smoking was also shown to increase morbidity and to worsen the control of asthma among adults. Another study demonstrated exposure to ETS was a significant trigger for acute exacerbation of asthma. Increased bronchial hyper-responsiveness was also demonstrated among the healthy nonsmoking adult women exposed to ETS. Passive smoking leads to subtle changes in airflow mechanics. In a study among 50 healthy nonsmoking women passively exposed to tobacco smoke and matched for age with 50 unexposed women, forced expiratory volume in first second (FEV1) and peak expiratory flow (PEF) were marginally lower among the passive smokers (mean difference 0.13 L and 0.20 L-1, respectively), but maximal mid expiratory flow (FEF25–75%), airway resistance (Raw) and specific conductance (sGaw) were significantly impaired. An association between passive smoking and lung cancer has also been described. In a study conducted in association with the International Agency for Research on Cancer, the exposure to ETS during childhood was strongly associated with an enhanced incidence of lung cancer (OR = 3.9, 95% CI 1.9–8.2). In conclusions several adverse pulmonary effects of passive smoking, similar to those described from the western and developed countries, have been described from India.
doi:10.1186/1617-9625-1-2-129
PMCID: PMC2671649  PMID: 19570253
20.  Pulmonary effects of passive smoking: the Indian experience 
Tobacco Induced Diseases  2002;1(1):10.
There are only a few studies done on pulmonary effects of passive smoking from India, which are summarized in this paper. Several vernacular tobacco products are used in India, bidis (beedis) being the commonest form of these. Bidis contain a higher concentration of nicotine and other tobacco alkaloids compared to the standard cigarettes (e.g., the sum of total nicotine and minor tobacco alkaloids was 37.5 mg in bidi compared to 14–16 mg in Indian or American cigarettes in one study). A large study performed on 9090 adolescent school children demonstrated environmental tobacco smoke (ETS) exposure to be associated with an increased risk of asthma. The odds ratio for being asthmatic in ETS-exposed as compared to ETS-unexposed children was 1.78 (95% CI: 1.33–2.31). Nearly one third of the children in this study reported non-specific respiratory symptoms and the ETS exposure was found to be positively associated with the prevalence of each symptom. Passive smoking was also shown to increase morbidity and to worsen the control of asthma among adults. Another study demonstrated exposure to ETS was a significant trigger for acute exacerbation of asthma. Increased bronchial hyper-responsiveness was also demonstrated among the healthy nonsmoking adult women exposed to ETS. Passive smoking leads to subtle changes in airflow mechanics. In a study among 50 healthy nonsmoking women passively exposed to tobacco smoke and matched for age with 50 unexposed women, forced expiratory volume in first second (FEV1) and peak expiratory flow (PEF) were marginally lower among the passive smokers (mean difference 0.13 L and 0.20 L-1, respectively), but maximal mid expiratory flow (FEF25–75%), airway resistance (Raw) and specific conductance (sGaw) were significantly impaired. An association between passive smoking and lung cancer has also been described. In a study conducted in association with the International Agency for Research on Cancer, the exposure to ETS during childhood was strongly associated with an enhanced incidence of lung cancer (OR = 3.9, 95% CI 1.9–8.2). In conclusions several adverse pulmonary effects of passive smoking, similar to those described from the western and developed countries, have been described from India.
doi:10.1186/1617-9625-1-10
PMCID: PMC2669550
21.  Asthma and other wheezing disorders in children 
Clinical Evidence  2006;2006:0302.
Introduction
Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyperresponsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pet animals, exposure to tobacco smoke, and anxiety.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute asthma in children? What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? What are the effects of treatments and of prophylactic treatments for acute wheezing in infants? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 84 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (high-dose nebulised, long-acting [inhaled salmeterol], short-acting [oral salbutamol or by nebuliser, or metered-dose inhaler/spacer versus nebuliser]), corticosteroids (oral prednisolone, systemic, inhaled higher or lower doses [beclometasone]), ipratropium bromide (single or multiple dose inhaled), leukotriene receptor antagonists (oral montelukast), nedocromil (inhaled), oxygen, sodium cromoglycate (inhaled), or theophylline (oral or intravenous).
Key Points
Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.
The consensus is that oxygen, high dose nebulised beta2 agonists and systemic corticosteroids should be used to treat an acute asthma attack. High dose beta2 agonists may be equally effective when given intermittently or continuously via a nebuliser, or from a metered dose inhaler using a spacer, in children with an acute asthma attack.Admission to hospital may be averted by adding ipratropium bromide to beta2 agonists, or by using high dose nebulised or oral corticosteroids.
Prophylactic inhaled corticosteroids improve symptoms and lung function in children with asthma. Their effect on final adult height is unclear. Inhaled nedocromil, inhaled long acting beta2 agonists, oral theophylline and oral leukotriene receptor antagonists are less effective than corticosteroids.Inhaled sodium cromoglycate does not seem to improve symptoms.
CAUTION: Monotherapy with long acting beta2 agonists reduces the frequency of asthma episodes, but may increase the chance of severe asthma episodes and death when those episodes occur. Intravenous theophylline may improve lung function in children with severe asthma, but can cause cardiac arrhythmias and convulsions.
We don't know whether adding higher doses of corticosteroids, long acting beta2 agonists, oral leukotriene receptor antagonists or oral theophylline to standard treatment improves symptoms or lung function in children with uncontrolled asthma.
In infants with acute wheeze, short acting beta2 agonists via a nebuliser or a spacer may improve symptoms, but we don't know whether high dose inhaled or oral corticosteroids or inhaled ipratropium bromide are beneficial.
Oral short acting beta2 agonists and inhaled high dose corticosteroids may prevent or improve wheeze in infants but can cause adverse effects. We don't know whether lower dose inhaled or oral corticosteroids, inhaled ipratropium bromide or inhaled short acting beta2 agonists improve wheezing episodes in infants.
PMCID: PMC2907635
22.  Risk Factors for Allergic Rhinitis in Costa Rican Children with Asthma 
Allergy  2009;65(2):256-263.
Background
Risk factors for allergic rhinitis (AR) in asthmatics are likely distinct from those for AR or asthma alone. We sought to identify clinical and environmental risk factors for AR in children with asthma.
Methods
We performed a cross-sectional study of 616 Costa Rican children aged 6–14 years with asthma. Candidate risk factors were drawn from questionnaire data, spirometry, methacholine challenge testing, skin testing, and serology. Two outcome measures, skin test reaction (STR)-positive AR and physician-diagnosed AR, were examined by logistic regression.
Results
STR-positive AR had high prevalence (80%) in Costa Rican children with asthma, and its independent risk factors were nasal symptoms after exposure to dust or mold, parental history of AR, older age at asthma onset, oral steroid use in the past year, eosinophilia, and positive IgEs to dust mite and cockroach. Physician-diagnosed AR had lower prevalence (27%), and its independent risk factors were nasal symptoms after pollen exposure, STR to tree pollens, a parental history of AR, inhaled steroid and short-acting β2 agonist use in the past year, household mold/mildew, and fewer older siblings. A physician’s diagnosis was only 29.5% sensitive for STR-positive AR.
Conclusions
Risk factors for AR in children with asthma depend on the definition of AR. Indoor allergens drive risk for STR-positive AR. Outdoor allergens and home environmental conditions are risk factors for physician-diagnosed AR. We propose that children with asthma in Costa Rica and other Latin American nations undergo limited skin testing or specific IgE measurements to reduce the current under-diagnosis of AR.
doi:10.1111/j.1398-9995.2009.02159.x
PMCID: PMC2807901  PMID: 19796208
allergic rhinitis; asthma; physician diagnosis; risk factor; skin test
23.  Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma 
Rationale: Transforming growth factor (TGF)-β1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-β1 gene expression. We hypothesized that the effects of functional TGF-β1 variants on asthma occurrence vary by these exposures.
Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study.
Methods: Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry.
Measurements and Main Results: Children with the −509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11–2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the −509CC/CT genotype with no in utero exposure to maternal smoking, those with the −509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46–7.80; interaction, P = 0.11). The association between TGF-β1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the −509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29–7.44) compared with children with CC/CT genotype living > 1500 m from a freeway.
Conclusions: Children with the TGF-β1 −509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.
doi:10.1164/rccm.200704-561OC
PMCID: PMC2176104  PMID: 17673695
maternal smoking; traffic; asthma; genetics; gene–environment interaction; association study
24.  In Utero Nicotine Exposure Promotes M2 Activation in Neonatal Mice Alveolar Macrophages 
Pediatric research  2012;72(2):147-153.
Background
Maternal smoking in utero has been associated with adverse health outcomes including lower respiratory tract infections in infants and children, but the mechanisms underlying these associations continue to be investigated. We hypothesized that nicotine plays a significant role in mediating the effects of maternal tobacco smoke on neonatal alveolar macrophage (AM) function, the resident immune cell in the neonatal lung.
Methods
Primary AMs were isolated at postnatal day 7 from a murine model of in utero nicotine exposure. The murine AM cell line MH-S was used for additional in vitro studies.
Results
In utero nicotine increased IL-13 and transforming growth factor beta one (TGFβ1) in the neonatal lung. Nicotine-exposed AMs demonstrated increased TGFβ1 and increased markers of alternative activation with diminished phagocytic function. However, AMs from mice deficient in the α7 nicotinic acetylcholine receptor (α7 nAChR) had less TGFβ1, reduced alternative activation and improved phagocytic functioning despite similar in utero nicotine exposure.
Conclusion
In utero nicotine exposure, mediated in part via the α7 nAChR, may increase the risk of lower respiratory tract infections in neonates by changing the resting state of AM towards alternative activation. These findings have important implications for immune responses in the nicotine-exposed neonatal lung.
doi:10.1038/pr.2012.55
PMCID: PMC3600420  PMID: 22562289
25.  In Utero Exposure to Maternal Tobacco Smoke and Subsequent Obesity, Hypertension, and Gestational Diabetes Among Women in The MoBa Cohort 
Environmental Health Perspectives  2011;120(3):355-360.
Background: Environmental factors influencing the developmental origins of health and disease need to be identified and investigated. In utero exposure to tobacco smoke has been associated with obesity and a small increase in blood pressure in children; however, whether there is a corresponding increased risk of conditions such as diabetes and hypertension during adulthood remains unclear.
Objective: Our goal was to assess the association of self-reported in utero exposure to tobacco smoke with the prevalence of obesity, hypertension, type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) in women 14–47 years of age.
Methods: We conducted a cross-sectional analysis of the Norwegian Mother and Child Cohort Study, which enrolled pregnant women in Norway from 1999 thorough 2008. Exposure to tobacco smoke in utero (yes vs. no) was ascertained on the baseline questionnaire (obtained at ~ 17 weeks’ gestation); the outcomes were ascertained from the Medical Birth Registry of Norway and the questionnaire. Our analysis included 74,023 women.
Results: Women exposed to tobacco smoke in utero had 1.53 times the odds of obesity [95% confidence interval (CI): 1.45, 1.61] relative to those unexposed, after adjusting for age, education, and personal smoking. After further adjustment for body mass index, the odds ratio for hypertension was 1.68 (95% CI: 1.19, 2.39); for T2DM 1.14 (95% CI: 0.79, 1.65); and for GDM 1.32 (95% CI: 1.10, 1.58) among exposed compared with unexposed.
Conclusions: Exposure to tobacco smoke in utero was associated with obesity, hypertension, and GDM in adult women. The possibility that the associations were attributable to unmeasured confounding cannot be excluded.
doi:10.1289/ehp.1103789
PMCID: PMC3295347  PMID: 22128036
diabetes mellitus; gestational diabetes; hypertension; in utero; maternal smoking; MoBa; obesity; tobacco smoke

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