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1.  Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001611.
In a systematic review and meta-analysis, Bahi Takkouche and colleagues examine the associations between exposure to tobacco smoke and allergic disorders in children and adults.
Please see later in the article for the Editors' Summary
Background
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.
Methods and Findings
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.
We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.
The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.
Conclusions
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The immune system protects the human body from viruses, bacteria, and other pathogens. Whenever a pathogen enters the body, immune system cells called T lymphocytes recognize specific molecules on its surface and release chemical messengers that recruit and activate other types of immune cells, which then attack the pathogen. Sometimes, however, the immune system responds to harmless materials (for example, pollen; scientists call these materials allergens) and triggers an allergic disease such as allergic rhinitis (inflammation of the inside of the nose; hay fever is a type of allergic rhinitis), allergic dermatitis (also known as eczema, a disease characterized by dry, itchy patches on the skin), and food allergy. Recent studies suggest that all these allergic (atopic) diseases are part of a continuous state called the “atopic march” in which individuals develop allergic diseases in a specific sequence that starts with allergic dermatitis during infancy, and progresses to food allergy, allergic rhinitis, and finally asthma (inflammation of the airways).
Why Was This Study Done?
Allergic diseases are extremely common, particularly in children. Allergic rhinitis alone affects 10%–30% of the world's population and up to 40% of children in some countries. Moreover, allergic diseases are becoming increasingly common. Allergic diseases affect the quality of life of patients and are financially costly to both patients and health systems. It is important, therefore, to identify the factors that cause or potentiate their development. One potential risk factor for allergic diseases is active or passive exposure to tobacco smoke. In some countries up to 80% of children are exposed to second-hand smoke so, from a public health point of view, it would be useful to know whether exposure to tobacco smoke is associated with the development of allergic diseases. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical approach for combining the results of several studies) to investigate this issue.
What Did the Researchers Do and Find?
The researchers identified 196 observational studies (investigations that observe outcomes in populations without trying to affect these outcomes in any way) that examined the association between smoke exposure and allergic rhinitis, allergic dermatitis, or food allergy. When all studies were analyzed together, allergic rhinitis was not associated with active smoking but was slightly associated with exposure to second-hand smoke. Specifically, compared to people not exposed to second-hand smoke, the pooled relative risk (RR) of allergic rhinitis among people exposed to second-hand smoke was 1.10 (an RR of greater than 1 indicates an increased risk of disease development in an exposed population compared to an unexposed population). Allergic dermatitis was associated with both active smoking (RR = 1.21) and exposure to second-hand smoke (RR = 1.07). In the populations of children and adolescents included in the studies, allergic rhinitis was associated with both active smoking and exposure to second-hand smoke (RRs of 1.40 and 1.09, respectively), as was allergic dermatitis (RRs of 1.36 and 1.06, respectively). Finally food allergy was associated with exposure to second-hand smoke (RR = 1.43) when cohort studies (a specific type of observational study) only were examined but not when all the studies were combined.
What Do These Findings Mean?
These findings provide limited evidence for a weak association between smoke exposure and allergic disease in adults but suggest that both active and passive smoking are associated with a modestly increased risk of allergic diseases in children and adolescents. The accuracy of these findings may be affected by the use of questionnaires to assess smoke exposure and allergic disease development in most of the studies in the meta-analysis and by the possibility that individuals exposed to smoke may have shared other characteristics that were actually responsible for their increased risk of allergic diseases. To shed more light on the role of smoking in allergic diseases, additional studies are needed that accurately measure exposure and outcomes. However, the present findings suggest that, in countries where many people smoke, 14% and 13% of allergic rhinitis and allergic dermatitis, respectively, among children may be attributable to active smoking. Thus, the elimination of active smoking among children and adolescents could prevent one in seven cases of allergic rhinitis and one in eight cases of allergic dermatitis in such countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001611.
The UK National Health Service Choices website provides information about allergic rhinitis, hay fever (including personal stories), allergic dermatitis (including personal stories), and food allergy (including personal stories)
The US National Institute of Allergy and Infectious Disease provides information about allergic diseases
The UK not-for-profit organization Allergy UK provides information about all aspects of allergic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on allergic rhinitis and allergic dermatitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and food allergy (in English and Spanish)
doi:10.1371/journal.pmed.1001611
PMCID: PMC3949681  PMID: 24618794
2.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Background
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
Conclusions
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001596.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
doi:10.1371/journal.pmed.1001596
PMCID: PMC3904844  PMID: 24492409
3.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
4.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
5.  Direct and Passive Prenatal Nicotine Exposure and the Development of Externalizing Psychopathology 
The association between maternal smoking during pregnancy and childhood antisocial outcomes has been demonstrated repeatedly across a variety of outcomes. Yet debate continues as to whether this association reflects a direct programming effect of nicotine on fetal brain development, or a phenotypic indicator of heritable liability passed from mother to child. In the current study, we examine relations between maternal smoking and child behavior among 133 women and their 7–15-year-olds, who were recruited for clinical levels of psychopathology. In order to disentangle correlates of maternal smoking, women who smoked during pregnancy were compared with (a) those who did not smoke, and (b) those who did not smoke but experienced significant second-hand exposure. Second-hand exposure was associated with increased externalizing psychopathology in participant mothers’ offspring. Moreover, regression analyses indicated that smoke exposure during pregnancy predicted conduct disorder symptoms, over and above the effects of income, parental antisocial tendencies, prematurity, birth weight, and poor parenting practices. This is the first study to extend the findings of externalizing vulnerability to second hand smoke exposure.
doi:10.1007/s10578-007-0059-4
PMCID: PMC2711763  PMID: 17520361
Maternal smoking; Conduct disorder; Aggression; Second hand smoke; ADHD
6.  Association of Prenatal and Childhood Blood Lead Concentrations with Criminal Arrests in Early Adulthood 
PLoS Medicine  2008;5(5):e101.
Background
Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses.
Methods and Findings
Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead.
Conclusions
Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.
Kim Dietrich and colleagues find an association between developmental exposure to lead and adult criminal behavior.
Editors' Summary
Background.
Violent crime is an increasing problem in many countries, but why are some people more aggressive than others? Being male has been identified as a risk factor for violent criminal behavior in several studies, as have exposure to tobacco smoke before birth, having antisocial parents, and belonging to a poor family. Another potential risk factor for antisocial behavior as an adult is exposure to lead during childhood, although few studies have looked directly at whether childhood lead exposure is linked with criminal behavior in adulthood. Lead is a toxic metal that damages the nervous system when ingested or inhaled. It is present throughout the environment because of its widespread use in the past in paint, solder for water pipes, and gasoline. In 1978, 13.5 million US children had a blood lead level above 10 μg/dl, the current US Centers for Disease Control and Prevention blood lead level of concern (the average US blood lead level is 2 μg/dl). Lead paint and solder were banned in 1978 and 1986, respectively, by the US federal government; leaded gasoline was finally phased out in 1996. By 2002, only 310,000 US children had a blood lead level above 10 μg/dl. However, children exposed to lower levels of lead than this—through ingesting flakes or dust residues of old lead paint, for example—can have poor intellectual development and behavioral problems including aggression.
Why Was This Study Done?
Although some studies have suggested that childhood lead exposure is associated with later criminal behavior, these studies have often relied on indirect measurements of childhood lead exposure such as bone lead levels in young adults or a history of lead poisoning. Other studies that have measured childhood lead exposure directly have not followed their participants into adulthood. In this new study, the researchers investigate the association between actual measurements of prenatal and childhood blood lead concentrations and criminal arrests in early adulthood to get a clearer idea about whether early lead exposure is associated with subsequent violent behavior.
What Did the Researchers Do and Find?
Between 1979 and 1984, the researchers recruited pregnant women living in poor areas of Cincinnati, which had a high concentration of older, lead-contaminated housing, into the Cincinnati Lead Study. They measured the women's blood lead concentrations during pregnancy as an indication of their offspring's prenatal lead exposure and the children's blood lead levels regularly until they were six and half years old. They then obtained information from the local criminal justice records on how many times each of the 250 offspring had been arrested between becoming 18 years old and the end of October 2005. The researchers found that increased blood lead levels before birth and during early childhood were associated with higher rates of arrest for any reason and for violent crimes. For example, for every 5 μg/dl increase in blood lead levels at six years of age, the risk of being arrested for a violent crime as a young adult increased by almost 50% (the “relative risk” was 1.48).
What Do These Findings Mean?
These findings provide strong evidence that early lead exposure is a risk factor for criminal behavior, including violent crime, in adulthood. One possibility, which the authors were unable to assess in this study, is that lead exposure impairs intelligence, which in turn makes it more likely that a criminal offender will be caught (i.e., arrested). The authors discuss a number of limitations in their study—for example, they probably did not capture all criminal behavior (since most criminal behavior does not lead to arrest). Although both environmental lead levels and crime rates have dropped over the last 30 years in the US, the overall reduction was not uniform—inner-city children remain particularly vulnerable to lead exposure. The findings therefore suggest that a further reduction in childhood lead exposure might be an important and achievable way to reduce violent crime.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050101.
A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on childhood lead exposure and brain volume reduction in adulthood
Study researcher Kim Dietrich can be heard talking about “The Lethal Legacy of Lead”, a brief MP3 about lead exposure and violent crime
Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)
MedlinePlus provides a list of links to information on lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program
The UK Health Protection Agency also provides information about lead and its health hazards
doi:10.1371/journal.pmed.0050101
PMCID: PMC2689664  PMID: 18507497
7.  Exposure to Cigarette Smoke In Utero 
Epidemiology (Cambridge, Mass.)  2008;19(4):628-633.
Background
Smoking during pregnancy has been associated with asthma, obesity, and decreased cognitive functioning in the offspring. To study the role of in utero smoking exposure in offsprings’ adult health outcomes, it may be necessary to rely upon reports by the offspring themselves.
Methods
We studied 34,949 mother-daughter pairs participating in the Nurses’ Health Study II for whom data on the daughter’s early passive cigarette smoke exposure had been obtained from both mother and daughter. We calculated sensitivity and specificity of daughter’s early exposure to smoke (using mother’s report as the gold standard), as well as κ statistics. Mother and daughter reports were also analyzed as risk factors for asthma and birthweight to demonstrate face validity.
Results
Sensitivity of daughters’ reported prenatal exposure ranged from 74% to 85%, while specificity was between 90% and 95% (κ = 0.72– 0.81). Daughter’s reported childhood exposure as a proxy for mother’s report of smoking during pregnancy had a sensitivity of 89% and specificity of 88%. Results were similar for daughter’s report of father’s smoking during her childhood. Maternal smoking during pregnancy is consistently associated with reductions in offspring birthweight, and with asthma risk in offspring. The daughter’s risk of being very low (<1500 g) or low birthweight (<2500 g) or of having asthma were similar when exposure was defined according to mother’s report, daughter’s report of fetal smoke exposure, and daughter’s report of mother’s smoking during childhood.
Conclusions
Daughter’s report of mother’s smoking prenatally and in childhood are good proxy measures for mother’s own report of smoking during pregnancy.
doi:10.1097/EDE.0b013e3181761cbd
PMCID: PMC3938965  PMID: 18467961
8.  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
9.  Family history and the risk of early onset persistent, early onset transient and late onset asthma 
Epidemiology (Cambridge, Mass.)  2001;12(5):577-583.
Family history of asthma and allergies strongly influences asthma risk in children but the association may differ for early onset persistent, early onset transient, and late onset asthma. We analyzed the relation between family history and these types of asthma using cross-sectional data from a school-based study of 5,046 Southern California children. Parental and/or sibling history of asthma and allergy were generally more strongly associated with early onset persistent asthma compared with early onset transient or late onset asthma. For children with two asthmatic parents relative to those with none, the prevalence ratio (PR) for early onset persistent asthma was 12.1 [95% confidence interval (CI) 7.91–18.7] compared with 7.51 (95% CI 2.62–21.5) for early onset transient asthma and 5.38 (95% CI 3.40–8.50) for late onset asthma. Maternal smoking in pregnancy was predominantly related to the risk of early onset persistent asthma in the presence of parental history of allergy and asthma and the joint effects were more than additive (interaction contrast ratio = 3.10, 95% CI 1.45–4.75). Our results confirm earlier data that parental history of asthma and allergy is most strongly associated with early onset persistent asthma and suggest that among genetically predisposed children, an early life environmental exposure, maternal smoking during pregnancy, favors the development of early onset asthma that persists into later early childhood.
PMCID: PMC1618803  PMID: 11505179
asthma; wheeze; genetic susceptibility; parental; smoking; pregnancy; in utero; sibling
10.  Second-hand smoke exposure in Canada: Prevalence, risk factors, and association with respiratory and cardiovascular diseases 
OBJECTIVES:
The aims of the present study were to estimate the prevalence of second-hand smoke exposure in Canada, to identify sociodemographic risk factors for second-hand smoke exposure, and to examine the relationship between second-hand smoke exposure and respiratory and cardiovascular diseases.
METHODS:
Data from the 2000/2001 Statistics Canada Canadian Community Health Survey (n=130,880, aged 12 years or older) were analyzed. Second-hand smoke exposure was based on self-report within the past month. The presence of chronic health conditions was also based on self-report. Because ex-smokers would be expected a priori to have poorer health than never-smokers, the analysis was stratified by previous smoking status.
RESULTS:
Approximately 25% of never-smokers and 30% of ex-smokers self-reported recent second-hand smoke exposure. The following factors were identified as risk factors for second-hand smoke exposure: men; residences in Quebec, Atlantic Canada and the Territories; younger ages; nonimmigrant status; low education and income levels; social assistance receipt; and households without children younger than 12 years of age. After controlling for potential confounders, both never- and ex-smokers exposed to second-hand smoke had significantly higher odds of self-reporting asthma (20% to 30%) and chronic bronchitis (50%) than those not exposed to secondhand smoke. Among ex-smokers, those exposed to second-hand smoke also had significantly higher odds of self-reporting hypertension (20%) than those not exposed to second-hand smoke. No associations were observed between second-hand smoke exposure and emphysema or heart disease.
CONCLUSIONS:
Self-reported recent second-hand smoke exposure in Canada in 2000/2001 was high, and was associated with asthma, chronic bronchitis and hypertension in never- and ex-smokers. Potential causal associations and public health implications warrant additional research.
PMCID: PMC2679549  PMID: 18716689
Asthma; COPD; Epidemiology; Heart disease; Passive smoking
11.  Ethnic Variability in Persistent Asthma After In Utero Tobacco Exposure 
Pediatrics  2011;128(3):e623-e630.
BACKGROUND:
The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent.
OBJECTIVE:
To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children.
PATIENTS AND METHODS:
There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression.
RESULTS:
Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year.
CONCLUSIONS:
Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
doi:10.1542/peds.2011-0640
PMCID: PMC3164096  PMID: 21859918
asthma; tobacco; Latino; African American; pregnancy
12.  Maternal Bereavement and Childhood Asthma—Analyses in Two Large Samples of Swedish Children 
PLoS ONE  2011;6(11):e27202.
Background
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.
Methodology and Principal Findings
We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1–4 (n = 426 334) and 7–12 (n = 493 813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1–4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7–12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1–4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7–12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.
Conclusions/Significance
Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.
doi:10.1371/journal.pone.0027202
PMCID: PMC3210147  PMID: 22087265
13.  Developmental trajectories of Body Mass Index from infancy to 18 years of age: prenatal determinants and health consequences 
Background
Knowledge on the long-term development of adiposity throughout childhood/adolescence and its prenatal determinants and health sequelae is lacking. We sought to (1) identify trajectories of Body Mass Index (BMI) from 1 to 18 years of age, (2) examine associations of maternal gestational smoking and early pregnancy overweight with offspring BMI trajectories and (3) determine whether BMI trajectories predict health outcomes: asthma, lung function parameters (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio), and blood pressure, at 18 years.
Methods
The Isle of Wight birth cohort, a population-based sample of 1456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10 and 18 years. Group-based trajectory modelling was applied to test for the presence of latent BMI trajectories. Associations were assessed using log-binomial and linear regression models.
Results
Four trajectories of BMI were identified: ‘normal’, ‘early persistent obesity’, ‘delayed overweight’, and ‘early transient overweight’. Risk factors for being in the early persistent obesity trajectory included maternal smoking during pregnancy (RR 2.16, 95% CI 1.02 to 4.68) and early pregnancy overweight (3.16, 1.52 to 6.58). When comparing the early persistent obesity to the normal trajectory, a 2.15-fold (1.33 to 3.49) increased risk of asthma, 3.2% (0.4% to 6.0%) deficit in FEV1/FVC ratio, and elevated systolic 11.3 mm Hg (7.1 to 15.4) and diastolic 12.0 mm Hg (8.9 to 15.1) blood pressure were observed at age 18 years.
Conclusions
Maternal prenatal exposures show prolonged effects on offspring's propensity towards overweight-obesity. Distinct morbid BMI trajectories are evident during the first 18 years of life that are associated with higher risk of asthma, reduced FEV1/FVC ratio, and elevated blood pressure.
doi:10.1136/jech-2014-203808
PMCID: PMC4174013  PMID: 24895184
Obesity; Epidemiology; Paediatric; Maternal Health; Asthma
14.  Early-life Exposure to Organophosphate Pesticides and Pediatric Respiratory Symptoms in the CHAMACOS Cohort 
Environmental Health Perspectives  2014;123(2):179-185.
Background: Although pesticide use is widespread, the possible effect of early-life exposure to organophosphate (OP) on pediatric respiratory health is not well described.
Objectives: We investigated the relationship between early-life exposure to OPs and respiratory outcomes.
Methods: Participants included 359 mothers and children from the CHAMACOS birth cohort. Dialkyl phosphate (DAP) metabolites of OP pesticides, specifically diethyl (DE) and dimethyl (DM) phosphate metabolites, were measured in urine from mothers twice during pregnancy (mean = 13 and 26 weeks gestation) and from children five times during childhood (0.5–5 years). Childhood DAP concentrations were estimated by the area under curve (AUC). Mothers reported their child’s respiratory symptoms at 5 and 7 years of age. We used generalized estimating equations (GEE) to examine associations of prenatal and childhood DAP concentrations with repeated measures of respiratory symptoms and exercise-induced coughing at 5 and 7 years of age, adjusting for child’s sex and age, maternal smoking during pregnancy, secondhand tobacco smoke, season of birth, PM2.5, breastfeeding, mold and cockroaches in home, and distance from highway.
Results: Higher prenatal DAP concentrations, particularly DE, were nonsignificantly associated with respiratory symptoms in the previous 12 months at 5 or 7 years of age [adjusted odds ratio (aOR) per 10-fold increase = 1.44; 95% CI: 0.98, 2.12]. This association was strongest with total DAP and DE from the second half of pregnancy (aOR per 10-fold increase = 1.77; 95% CI: 1.06, 2.95; and 1.61; 95% CI: 1.08, 2.39, respectively). Childhood DAP, DE, and DM concentrations were associated with respiratory symptoms and exercise-induced coughing in the previous 12 months at 5 or 7 years of age (total DAPs: aOR per 10-fold increase = 2.53; 95% CI: 1.32, 4.86; and aOR = 5.40; 95% CI: 2.10, 13.91, respectively).
Conclusions: Early-life exposure to OP pesticides was associated with respiratory symptoms consistent with possible asthma in childhood.
Citation: Raanan R, Harley KG, Balmes JR, Bradman A, Lipsett M, Eskenazi B. 2015. Early-life exposure to organophosphate pesticides and pediatric respiratory symptoms in the CHAMACOS cohort. Environ Health Perspect 123:179–185; http://dx.doi.org/10.1289/ehp.1408235
doi:10.1289/ehp.1408235
PMCID: PMC4314248  PMID: 25369257
15.  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
16.  The impact of smoke-free legislation on fetal, infant and child health: a systematic review and meta-analysis protocol 
BMJ Open  2013;3(2):e002261.
Introduction
Second-hand smoke (SHS) exposure is estimated to kill 600 000 people worldwide annually. The WHO recommends that smoke-free indoor public environments are enforced through national legislation. Such regulations have been shown to reduce SHS exposure and, consequently, respiratory and cardiovascular morbidity. Evidence of particular health benefit in children is now emerging, including reductions in low birthweight deliveries, preterm birth and asthma exacerbations. We aim to comprehensively assess the impact of smoke-free legislation on fetal, infant and childhood outcomes. This can inform further development and implementation of global policy and strategies to reduce early life SHS exposure.
Methods
Two authors will search online databases (1975–present; no language restrictions) of published and unpublished/in-progress studies, and references and citations to articles of interest. We will consult experts in the field to identify additional studies. Studies should describe associations between comprehensive or partial smoking bans in public places and health outcomes among children (0–12 years): stillbirth, preterm birth, low birth weight, small for gestational age, perinatal mortality, congenital anomalies, bronchopulmonary dysplasia, upper and lower respiratory infections and wheezing disorders including asthma. The Cochrane Effectiveness Practice and Organisational Care (EPOC)-defined study designs are eligible. Study quality will be assessed using the Cochrane 7-domain-based evaluation for randomised and clinical trials, and EPOC criteria for quasiexperimental studies. Data will be extracted by two reviewers and presented in tabular and narrative form. Meta-analysis will be undertaken using random-effects models, and generic inverse variance analysis for adjusted effect estimates. We will report sensitivity analyses according to study quality and design characteristics, and subgroup analyses according to coverage of ban, age group and parental/maternal smoking status. Publication bias will be assessed.
Ethics and dissemination
Ethics assessment is not required.
Results
Will be presented in one manuscript. The protocol is registered with PROSPERO, registration number CRD42013003522.
doi:10.1136/bmjopen-2012-002261
PMCID: PMC3586104  PMID: 23408079
17.  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
18.  Greater risk of incident asthma cases in adults with Allergic Rhinitis and Effect of Allergen Immunotherapy: A Retrospective Cohort Study 
Respiratory Research  2005;6(1):153.
Asthma and rhinitis are often co-morbid conditions. As rhinitis often precedes asthma it is possible that effective treatment of allergic rhinitis may reduce asthma progression.
The aim of our study is to investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of allergen immunotherapy in attenuating the incidence of asthma.
Hospital-referred non-asthmatic adults, aged 18–40 years between 1990 and 1991, were retrospectively followed up until January and April 2000. At the end of follow up, available subjects were clinically examined for asthma diagnosis and history of allergen specific immunotherapy, second-hand smoking and the presence of pets in the household. A total of 436 non-asthmatic adults (332 subjects with allergic rhinitis and 104 with no allergic rhinitis nor history of atopy) were available for final analyses.
The highest OR (odds ratio) associated with a diagnosis of asthma at the end of follow-up was for the diagnosis of allergic rhinitis at baseline (OR, 7.8; 95%CI, 3.1–20.0 in the model containing the covariates of rhinitis diagnosis, sex, second-hand smoke exposure, presence of pets at home, family history of allergic disorders, sensitization to Parietaria judaica; grass pollen; house dust mites; Olea europea: orchard; perennial rye; and cat allergens). Female sex, sensitization to Parietaria judaica and the presence of pets in the home were also significantly predictive of new onset asthma in the same model. Treatment with allergen immunotherapy was significantly and inversely related to the development of new onset asthma (OR, 0.53; 95%CI, 0.32–0.86).
In the present study we found that allergic rhinitis is an important independent risk factor for asthma. Moreover, treatment with allergen immunotherapy lowers the risk of the development of new asthma cases in adults with allergic rhinitis.
doi:10.1186/1465-9921-6-153
PMCID: PMC1351177  PMID: 16381607
19.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Summary
Background
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
Objective
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
Methods
We evaluated 1448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm<37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates.
Results
In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% CI, 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (p=0.049).
Conclusions
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
doi:10.1002/ppul.22501
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
20.  Wheeze associated with prenatal tobacco smoke exposure: a prospective, longitudinal study 
Archives of Disease in Childhood  2000;83(4):307-312.
AIMS—To determine whether maternal smoking during pregnancy is a risk factor for reported wheeze in early childhood that is independent of postnatal environmental tobacco smoke (ETS) exposure and other known risk factors.
METHODS—A total of 8561 mothers and infants completed questions about smoking during pregnancy, ETS exposure, and the mother's recall of wheeze during early childhood.
RESULTS—A total of 1869 (21.8%) children had reported wheeze between 18 and 30 months of age, and 3496 (40.8%) had reported wheeze in one or more of the three study periods (birth to 6 months, 6-18 months, 18-30 months). The risk of wheeze between 18 and 30 months of age was higher if the mother smoked during pregnancy. This relation did not show a dose-response effect and became less obvious after adjustment for the effects of other factors. Average daily duration of ETS exposure reported at 6 months of age showed a dose-response effect and conferred a similar risk of reported wheeze. Factors associated with early childhood wheeze had the following adjusted odds ratios: maternal history of asthma 2.03(1.74 to 2.37); preterm delivery 1.66 (1.30 to 2.13); male sex 1.42 (1.28 to 1.59); rented accommodation 1.29 (1.11 to 1.51); and each additional child in household 1.13 (1.04 to 1.24).
CONCLUSIONS—Maternal smoking during pregnancy may be a risk factor for reported wheeze during early childhood that is independent of postnatal ETS exposure. For wheeze between 18 and 30 months of age, light smoking during the third trimester of pregnancy appears to confer the same risk as heavier smoking.


doi:10.1136/adc.83.4.307
PMCID: PMC1718491  PMID: 10999864
21.  Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study 
BMJ : British Medical Journal  1999;319(7213):815-819.
Objectives
To investigate the association between the duration of exclusive breast feeding and the development of asthma related outcomes in children at age 6 years.
Design
Prospective cohort study.
Setting
Western Australia.
Subjects
2187 children ascertained through antenatal clinics at the major tertiary obstetric hospital in Perth and followed to age 6 years.
Main outcome measures
Unconditional logistic regression to model the association between duration of exclusive breast feeding and outcomes related to asthma or atopy at 6 years of age, allowing for several important confounders: sex, gestational age, smoking in the household, and early childcare.
Results
After adjustment for confounders, the introduction of milk other than breast milk before 4 months of age was a significant risk factor for all asthma and atopy related outcomes in children aged 6 years: asthma diagnosed by a doctor (odds ratio 1.25, 95% confidence interval 1.02 to 1.52); wheeze three or more times since 1 year of age (1.41, 1.14 to 1.76); wheeze in the past year (1.31, 1.05 to 1.64); sleep disturbance due to wheeze within the past year (1.42, 1.07 to 1.89); age when doctor diagnosed asthma (hazard ratio 1.22, 1.03 to 1.43); age at first wheeze (1.36, 1.17 to 1.59); and positive skin prick test reaction to at least one common aeroallergen (1.30, 1.04 to 1.61).
Conclusion
A significant reduction in the risk of childhood asthma at age 6 years occurs if exclusive breast feeding is continued for at least the 4 months after birth. These findings are important for our understanding of the cause of childhood asthma and suggest that public health interventions to optimise breast feeding may help to reduce the community burden of childhood asthma and its associated traits.
Key messagesAsthma is the leading cause of admission to hospital in Australian children and its prevalence is increasingWhether breast feeding protects against asthma or atopy, or both, is controversialAsthma is a complex disease, and the relative risks between breast feeding and asthma or atopy are unlikely to be large; this suggests the need for investigation in a large prospective birth cohort with timely assessment of atopic outcomes and all relevant exposuresExclusive breast feeding for at least 4 months is associated with a significant reduction in the risk of asthma and atopy at age 6 years and with a significant delay in the age at onset of wheezing and asthma being diagnosed by a doctorPublic health interventions to promote an increased duration of exclusive breast feeding may help to reduce the morbidity and prevalence of childhood asthma and atopy
PMCID: PMC314207  PMID: 10496824
22.  Metabolic Abnormalities in Children with Asthma 
Rationale: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children.
Objectives: To analyze the relationship between asthma diagnosis and body mass in children across the entire range of weight percentile categories, and to test the hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma.
Methods: Cross-sectional analysis of a representative sample of public school children from a statewide community-based screening program, including a total of 17,994 children, 4 to 12 years old, living in predominantly rural West Virginia, and enrolled in kindergarten, second, or fifth grade classrooms.
Measurements and Main Results: We analyzed demographics; family history; smoke exposure; parent-reported asthma diagnosis; body mass index; evidence of acanthosis nigricans as a marker for developing insulin resistance; and fasting serum lipid profile including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Regardless of their body mass index percentile, children diagnosed with asthma were more likely than children without asthma to have higher triglyceride levels and acanthosis nigricans after controlling for sex differences and smoke exposure.
Conclusions: This study provides the first set of community-based data linking asthma, body mass, and metabolic variables in children. In particular, these findings uniquely describe a statistically significant association between asthma and abnormal lipid and glucose metabolism beyond body mass index associations.
doi:10.1164/rccm.201004-0603OC
PMCID: PMC3056222  PMID: 20851922
body mass index; cardiovascular risk; diabetes; insulin resistance; obesity
23.  Determinants of self-reported smoking and misclassification during pregnancy, and analysis of optimal cut-off points for urinary cotinine: a cross-sectional study 
BMJ Open  2013;3(1):e002034.
Objectives
To estimate the prevalence and factors associated with smoking and misclassification in pregnant women from INMA (INfancia y Medio Ambiente, Environment and Childhood) project, Spain, and to assess the optimal cut-offs for urinary cotinine (UC) that best distinguish daily and occasional smokers with varying levels of second-hand smoke (SHS) exposure.
Design
We used logistic regression models to study the relationship between sociodemographic variables and self-reported smoking and misclassification (self-reported non-smokers with UC >50 ng/ml). Receiver operating characteristic (ROC) curves were used to calculate the optimal cut-off point for discriminating smokers. The cut-offs were also calculated after stratification among non-smokers by the number of sources of SHS exposure. The cut-off points used to discriminate smoking status were the level of UC given by Youden's index and for 50 and 100 ng/ml for daily smokers, or 25 and 50 ng/ml for occasional smokers.
Participants
At the third trimester of pregnancy, 2263 pregnant women of the INMA Project were interviewed between 2004 and 2008 and a urine sample was collected.
Results
Prevalence of self-reported smokers at the third trimester of pregnancy was 18.5%, and another 3.9% misreported their smoking status. Variables associated with self-reported smoking and misreporting were similar, including born in Europe, educational level and exposure to SHS. The optimal cut-off was 82 ng/ml (95% CI 42 to 133), sensitivity 95.2% and specificity 96.6%. The area under the ROC curve was 0.986 (95% CI 0.982 to 0.990). The cut-offs varied according to the SHS exposure level being 42 (95% CI 27 to 57), 82 (95% CI 46 to 136) and 106 ng/ml (95% CI 58 to 227) for not being SHS exposed, exposed to one, and to two or more sources of SHS, respectively. The optimal cut-off for discriminating occasional smokers from non-smokers was 27 ng/ml (95% CI 11 to 43).
Conclusions
Prevalence of smoking during pregnancy in Spain remains high. UC is a reliable biomarker for classifying pregnant women according to their smoking status. However, cut-offs would differ based on baseline exposure to SHS.
doi:10.1136/bmjopen-2012-002034
PMCID: PMC3563144  PMID: 23355667
Epidemiology; Public Health; Toxicology; Preventive Medicine
24.  Influence of smoking on asthmatic symptoms and allergen sensitisation in early childhood 
Postgraduate Medical Journal  2000;76(901):694-699.
BACKGROUND—Apart from heredity, several early life environmental factors are implicated in the development of childhood asthma. Maternal smoking is believed to increase asthmatic symptoms but its influence on the development of allergen sensitisation is debatable.
STUDY DESIGN—A whole population birth cohort was reviewed at ages 1, 2, and 4 years. Of 1218 children seen at 4 years, 981 (80.5%) were skin prick tested with a battery of common food and aeroallergens. Smoking history was recorded at birth and updated at each follow up and its impact on the development of asthma and allergen sensitisation in the children was assessed.
RESULTS—Two hundred and fifty mothers smoked during pregnancy (20.5%) and 307 (25.2%) after childbirth. Maternal smoking in pregnancy was associated with low birth weight (mean (SD): 3.3 (0.5) v 3.5 (0.5) kg; p<0.001). Smoking mothers were more often from lower social classes (31.8% v 16%, p<0.001) and they breast fed their babies for a shorter duration (8.5 (11.4) v 16.6 (15.2) weeks; p<0.001). The difference in breast feeding duration was partly due to a higher proportion of smoking mothers who never breast fed their babies. Although at age 2 years asthmatic symptoms were associated with exposure to maternal tobacco smoke (odds ratio 2.2, 95% confidence interval 1.5 to 3.4; p<0.001), this association was lost by 4 years. However, maternal smoking was a significant risk factor in a subgroup of children with asthmatic symptoms but negative skin prick test. Maternal smoking did not increase allergen sensitisation at age 4 years. No effect of paternal smoking on asthma was observed in the children.


Keywords: maternal smoking; asthma; allergen sensitisation
doi:10.1136/pmj.76.901.694
PMCID: PMC1741811  PMID: 11060143
25.  Use of Acid-Suppressive Drugs in Pregnancy and the Risk of Childhood Asthma: Bidirectional Crossover Study using the General Practice Research Database 
Drug Safety  2013;36(11):1097-1104.
Background
Recent studies have reported an association between maternal use of gastric acid-suppressive drugs during pregnancy and asthma in the offspring, but the association could have been confounded by unmeasured risk factors.
Objective
We assessed the association between the use of acid-suppressive drugs during pregnancy and the risk of developing childhood asthma using a bidirectional crossover design.
Methods
Mother–infant matched sets in the UK General Practitioners Research Database were used to identify children with a drug-treated asthma diagnosis during the years 2006–2010 who were matched to a sibling without asthma as controls. Primary exposure was use of any anti-suppressive drug during pregnancy, and subgroup analyses were conducted according to drug class (e.g. proton pump inhibitors or histamine 2 receptor antagonists) and trimester. Conditional logistic regression was used to estimate odds ratios (OR) with their corresponding 95 % confidence intervals (CIs).
Results
A total of 1,874 children with asthma and 1,874 control siblings were included in the analysis. The exposure rate among case and control pregnancies was 22 and 20 %, respectively. After adjustments for gender, birth order, mother’s age and general practice visits, the exposure to any gastric-acid suppressive drug during pregnancy slightly increased the risk for developing asthma (OR 1.23, 95 % CI 1.01–1.51; p = 0.042). A trend towards increased risks was observed for those who used proton pump inhibitors and/or histamine 2 receptor antagonists (adjusted OR 1.72, 95 % CI 1.00–2.98; p = 0.048).
Conclusions
These findings lend support to the emerging evidence that exposure to acid-suppressive drugs during pregnancy is associated with childhood asthma. More basic research is now warranted to investigate the mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-013-0093-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s40264-013-0093-z
PMCID: PMC3824882  PMID: 24018582

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