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1.  Pertussis vaccination and wheezing illnesses in young children: prospective cohort study 
BMJ : British Medical Journal  1999;318(7192):1173-1176.
To examine the relation between pertussis vaccination and the prevalence of wheezing illnesses in young children.
Prospective cohort study.
Three former health districts comprising Avon Health Authority.
9444 of 14 138 children enrolled in the Avon longitudinal study of pregnancy and childhood and for whom data on wheezing symptoms, vaccination status, and 15 environmental and biological variables were available.
Main outcome measures
Episodes of wheezing from birth to 6 months, 7-18 months, 19-30 months, and 31-42 months. These time periods were used to derive five categories of wheezing illness: early wheezing (not after 18 months); late onset wheezing (after 18 months); persistent wheezing (at every time period); recurrent wheezing (any combination of two or more episodes for each period); and intermittent wheezing (any combination of single episodes of reported wheezing). These categories were stratified according to parental self reported asthma or allergy.
Unadjusted comparisons of the defined wheezing illnesses in vaccinated and non-vaccinated children showed no significant association between pertussis vaccination and any of the wheezing outcomes regardless of stratification for parental asthma or allergy. Wheeze was more common in non-vaccinated children at 18 months, and there was a tendency for late onset wheezing to be associated with non-vaccination in children whose parents did not have asthma, but this was not significant. After adjustment for environmental and biological variables, logistic regression analyses showed no significant increased relative risk for any of the wheezing outcomes in vaccinated children: early wheezing (0.99, 95% confidence interval 0.80 to 1.23), late onset wheezing (0.85, 0.69 to 1.05), persistent wheezing (0.91, 0.47 to 1.79), recurrent wheezing (0.96, 0.72 to 1.26), and intermittent wheezing (1.06, 0.81 to 1.37).
No evidence was found that pertussis vaccination increases the risk of wheezing illnesses in young children. Further follow up of this population with objective measurement of allergy and bronchial responsiveness is planned to confirm these observations.
Key messagesPertussis vaccination has been proposed as a risk factor for the development of asthma and atopyThere was no evidence for increased wheezing illnesses in young children who were vaccinated against pertussis compared with non-vaccinated childrenFollow up studies of this population will help to further clarify the relation between early infections and vaccination and the development of atopic diseases, including asthmaLarge scale longitudinal studies beginning in pregnancy offer the opportunity to examine complex interactions between genetics and the environment in the cause of common childhood diseases
PMCID: PMC27852  PMID: 10221941
2.  Size at Birth, Infant Growth, and Blood Pressure at 3 Years of Age 
The Journal of pediatrics  2007;151(6):670-674.
Our aim was to determine the extent to which infant growth – in weight-for-length – from birth to 6 months is associated with systolic blood pressure (SBP) at 3 years, and to determine whether this association varies with birth size.
Study design
In 530 children from the prospective cohort Project Viva, we measured birth length and 6-month weight and length with research standard instruments and SBP at age 3 years with a Dinamap automated recorder. We derived weight-for-length z-scores (WFL-z) and analyzed data with mixed effect regression models.
Mean (SD) WFL-z was 0.47(0.75) at birth and 0.70(0.96) at 6 months. Mean (SD) SBP at 3 years was 91.7(9.4) mmHg. After adjusting for confounding variables and birth WFL-z, child SBP was 1.0mmHg (95% CI 0.2, 1.8) higher for each z-score increment in 6-month WFL-z. SBP of children in the lowest birth WFL-z quartile and the highest 6-month WFL-z quartile was 5.5mmHg (95% CI 2.6, 8.4) higher than of children in the highest birth and lowest 6-month WFL-z quartiles.
More rapid increase in weight-for-length, a measure of adiposity, in the first 6 months of life is associated with higher early childhood systolic blood pressure, particularly in children who are thin at birth.
PMCID: PMC2278009  PMID: 18035150
Hypertension; epidemiology
3.  Association of Birth Weight With Asthma-Related Outcomes at Age 2 Years 
Pediatric pulmonology  2006;41(7):643-648.
Summary. Background: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation.
Objective. To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years.
Methods. We studied 1,372 infants and toddlers born after 34 weeks’ gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor’s diagnosis of asthma, wheeze or reactive airwaydisease (“asthma”) by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value (“fetal growth”) using US national reference data.
Results. Infants’ mean birth weight was 3,527 (SD, 517; range, 1,559–5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight ≥4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500–3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years.
Conclusion. Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblingswere associated with increased riskof wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.
PMCID: PMC1488724  PMID: 16703577
asthma; birth weight; fetal growth; length of gestation; wheezing
4.  Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood 
Thorax  2001;56(3):192-197.
BACKGROUND—The relationship between infant feeding and childhood asthma is controversial. This study tested the hypothesis that the relation between breast feeding and childhood asthma is altered by the presence of maternal asthma.
METHODS—Healthy non-selected newborn infants (n=1246) were enrolled at birth. Asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported on ⩾2 questionnaires at 6, 9, 11or 13 years. Recurrent wheeze (⩾4 episodes in the past year) was reported by questionnaire at seven ages in the first 13 years of life. Duration of exclusive breast feeding was based on prospective physician reports or parental questionnaires completed at 18 months. Atopy was assessed by skin test responses at the age of 6years.
RESULTS—The relationship between breast feeding, asthma, and wheeze differed with the presence or absence of maternal asthma and atopy in the child. After adjusting for confounders, children with asthmatic mothers were significantly more likely to have asthma if they had been exclusively breast fed (OR 8.7, 95% CI 3.4 to 22.2). This relationship was only evident for atopic children and persisted after adjusting for confounders. In contrast, the relation between recurrent wheeze and breast feeding was age dependent. In the first 2 years of life exclusive breast feeding was associated with significantly lower rates of recurrent wheeze (OR 0.45, 95% CI 0.2 to 0.9), regardless of the presence or absence of maternal asthma or atopy in the child. Beginning at the age of 6 years, exclusive breast feeding was unrelated to prevalence of recurrent wheeze, except for children with asthmatic mothers in whom it was associated with a higher odds ratio for wheeze (OR 5.7, 95% CI 2.3 to 14.1), especially if the child was atopic.
CONCLUSION—The relationship between breast feeding and asthma or recurrent wheeze varies with the age of the child and the presence or absence of maternal asthma and atopy in the child. While associated with protection against recurrent wheeze early in life, breast feeding is associated with an increased risk of asthma and recurrent wheeze beginning at the age of 6 years, but only for atopic children with asthmatic mothers.

PMCID: PMC1758780  PMID: 11182011
5.  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
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.
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
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
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)
PMCID: PMC3904844  PMID: 24492409
6.  Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies 
PLoS Medicine  2014;11(10):e1001748.
Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders.
Please see later in the article for the Editors' Summary
The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Methods and Findings
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time.
Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march.
Please see later in the article for the Editors' Summary
Editors' Summary
Our immune system protects us from viruses, bacteria, and other pathogens by recognizing specific molecules on the invader's surface and initiating a sequence of events that culminates in the death of the pathogen. Sometimes, however, our immune system responds to harmless materials (allergens such as pollen) and triggers allergic, or atopic, symptoms. Common atopic symptoms include eczema (transient dry itchy patches on the skin), wheeze (high pitched whistling in the chest, a symptom of asthma), and rhinitis (sneezing or a runny nose in the absence of a cold or influenza). All these symptoms are very common during childhood, but recent epidemiological studies (examinations of the patterns and causes of diseases in a population) have revealed age-related changes in the proportions of children affected by each symptom. So, for example, eczema is more common in infants than in school-age children. These findings have led to the idea of “atopic march,” a natural progression of symptoms within individual children that starts with eczema, then progresses to wheeze and finally rhinitis.
Why Was This Study Done?
The concept of atopic march has led to the initiation of studies that aim to prevent the development of asthma in children who are thought to be at risk of asthma because they have eczema. Moreover, some guidelines recommend that clinicians tell parents that children with eczema may later develop asthma or rhinitis. However, because of the design of the epidemiological studies that support the concept of atopic march, children with eczema who later develop wheeze and rhinitis may actually belong to a distinct subgroup of children, rather than representing the typical progression of atopic diseases. It is important to know whether atopic march adequately describes the natural history of atopic diseases during childhood to avoid the imposition of unnecessary strategies on children with eczema to prevent asthma. Here, the researchers use machine learning techniques to model the developmental profiles of eczema, wheeze, and rhinitis during childhood in two large population-based birth cohorts by taking into account time-related (longitudinal) changes in symptoms within individuals. Machine learning is a data-driven approach that identifies structure within the data (for example, a typical progression of symptoms) using unsupervised learning of latent variables (variables that are not directly measured but are inferred from other observable characteristics).
What Did the Researchers Do and Find?
The researchers used data from two UK birth cohorts—the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Manchester Asthma and Allergy Study (MAAS)—for their study (9,801 children in total). Both studies enrolled children at birth and monitored their subsequent health at regular review clinics. At each review clinic, information about eczema, wheeze, and rhinitis was collected from the parents using validated questionnaires. The researchers then used these data and machine learning methods to identify groups of children with similar patterns of onset of eczema, wheeze, and rhinitis over the first 11 years of life. Using a type of statistical model called a latent disease profile model, the researchers found that the data were best described by eight latent classes—no disease (51.3% of the children), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%).
What Do These Findings Mean?
These findings show that, in two large UK birth cohorts, the developmental profiles of eczema, wheeze, and rhinitis were heterogeneous. Most notably, the progression of symptoms fitted the profile of atopic march in fewer than 7% of children with symptoms. The researchers acknowledge that their study has some limitations. For example, small differences in the wording of the questions used to gather information from parents about their children's symptoms in the two cohorts may have slightly affected the findings. However, based on their findings, the researchers propose that, because eczema, wheeze, and rhinitis are common, these symptoms often coexist in individuals, but as independent entities rather than as a linked progression of symptoms. Thus, using eczema as an indicator of subsequent asthma risk and assigning “preventative” measures to children with eczema is flawed. Importantly, clinicians need to understand the heterogeneity of patterns of atopic diseases in children and to communicate this variability to parents when advising them about the development and resolution of atopic symptoms in their children.
Additional Information
Please access these websites via the online version of this summary at
The UK National Health Service Choices website provides information about eczema (including personal stories), asthma (including personal stories), and rhinitis
The US National Institute of Allergy and Infectious Diseases provides information about atopic diseases
The UK not-for-profit organization Allergy UK provides information about atopic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on eczema, wheezing, and rhinitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and asthma (in English and Spanish)
Information about ALSPAC and MAAS is available
Wikipedia has pages on machine learning and latent disease profile models (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4204810  PMID: 25335105
7.  Frequent use of chemical household products is associated with persistent wheezing in pre-school age children 
Thorax  2005;60(1):45-49.
Background: In the UK and other developed countries the prevalence of asthma symptoms has increased in recent years. This is likely to be the result of increased exposure to environmental factors. A study was undertaken to investigate the association between maternal use of chemical based products in the prenatal period and patterns of wheeze in early childhood.
Methods: In the population based Avon Longitudinal Study of Parents and Children (ALSPAC), the frequency of use of 11 chemical based domestic products was determined from questionnaires completed by women during pregnancy and a total chemical burden (TCB) score was derived. Four mutually exclusive wheezing patterns were defined for the period from birth to 42 months based on parental questionnaire responses (never wheezed, transient early wheeze, persistent wheeze, and late onset wheeze). Multinomial logistic regression models were used to assess the relationship between these wheezing outcomes and TCB exposure while accounting for numerous potential confounding variables. Complete data for analysis was available for 7019 of 13 971 (50%) children.
Results: The mean (SD) TCB score was 9.4 (4.1), range 0–30. Increased use of domestic chemical based products was associated with persistent wheezing during early childhood (adjusted odds ratio (OR) per unit increase of TCB 1.06 (95% confidence interval (CI) 1.03 to 1.09)) but not with transient early wheeze or late onset wheeze. Children whose mothers had high TCB scores (>90th centile) were more than twice as likely to wheeze persistently throughout early childhood than children whose mothers had a low TCB score (<10th centile) (adjusted OR 2.3 (95% CI 1.2 to 4.4)).
Conclusion: These findings suggest that frequent use of chemical based products in the prenatal period is associated with persistent wheezing in young children. Follow up of this cohort is underway to determine whether TCB is associated with wheezing, asthma, and atopy at later stages in childhood.
PMCID: PMC1747149  PMID: 15618582
Pediatric pulmonology  2010;45(9):919-926.
The purpose of the study was to check the hypothesis that early wheezing as reported by mothers would be associated with reduced lung function in 4-year-olds. Study participants were recruited prenatally, as part of a prospective cohort study on the respiratory health of young children exposed to various ambient air pollutants. After delivery, infants were followed over four years and the interviewers visited participants at their home to record respiratory symptoms every three months in the child’s first two years of life and every 6 months in the third and fourth years. In the fourth year of follow-up, children were invited for standard lung function testing by spirometry quantified by FVC, FEV1 and FEV05 levels. Out of 258 children attending spirometry testing 139 performed at least two acceptable exhalation efforts. Cohort children with acceptable spirometric measurements did not differ with respect to wheezing experience and exposure characteristics from those without. The study shows that episodic wheeze was reported in 28.1% of 4-year-olds, 6.5% had transient wheeze and 4.3% had recurrent wheeze. There was an increased frequency of wheezing symptoms and their duration in transient and recurrent wheezers. Adjusted multivariable regression models for gender and height showed that children who reported more than 2 episodes of wheezing at any point over the follow-up had FVC values lower by 120.5 mL (p = 0.016) and FEV1 values lower by 98.3 mL (p = 0.034) compared to those who did not report any wheezing; children experiencing more than 10 wheezing days by age 4 showed FVC deficit of 87.4 mL (p = 0.034) and FEV1 values of 65.7 mL (p = 0.066) The ratios of FEV1/FVC% and FEV05/FVC% were neither associated with wheezing episodes nor wheezing days. In recurrent wheezers lung function decrement amounted to 207 mL of FVC, 175 mL of FEV1 and 104 mL of FEV05. In conclusion, our findings show that wheezing experience during early postnatal life may be associated with lung function deficit of restrictive character in preschool children and detailed history of wheeze in early postnatal life, even though not physician-confirmed, may help define the high risk group of children for poor lung function testing.
PMCID: PMC3691468  PMID: 20672363
9.  Is there an association between wheezing and constipation in preschool children? Explanations from a longitudinal birth cohort 
BMJ Open  2011;1(2):e000237.
To assess whether wheezing and atopic dermatitis were associated with constipation in preschool children and to what extent shared risk factors contribute to this relationship.
A population-based sample of 4651 preschool children was used. At the age of 24, 36 and 48 months, a parental report of functional constipation was available according to the Rome II criteria, and data on atopic dermatitis and wheezing were available using age-adapted questionnaires from the International Study of Asthma and Allergies in Childhood. Stepwise multivariate analyses were performed to assess whether body mass index, infection exposure, food allergy and infant nutrition, and parental stress explained the association between wheezing, atopic dermatitis and constipation.
Out of 4651 children, 12–17% had functional constipation between 24 and 48 months. Symptoms of wheezing decreased from 20% to 12% and atopic dermatitis decreased from 30% to 18% at the age of 24 and 48 months respectively. Between the age of 24 and 48 months, wheezing symptoms were significantly associated with functional constipation (OR 1.17; 1.02 to 1.34) but these results were mainly explained by the child's exposure to infections and use of antibiotics (adjusted odds ratio 1.08; 95% CI 0.95 to 1.24). No significant association was found between symptoms of atopic dermatitis and functional constipation (OR 1.08; 95% CI 0.94 to 1.23).
These findings suggest that functional constipation coexists with wheezing in childhood but is mainly explained by the child's infection exposure and use of antibiotics. Therefore, an independent association between respiratory symptoms and functional bowel disorders as suggested in previous studies is questionable.
Article summary
Article focus
Constipation, wheezing and atopic dermatitis are common symptoms in children.
Functional bowel disorders are linked to asthma and atopy in adults.
Functional bowel disorders, asthma and atopic disease may share common risk-factors that may explain coexistence of these symptoms.
Key messages
Wheezing, but not atopic dermatitis, is associated with functional constipation in preschool children. The association is mainly explained by a history of infection exposure.
Hence, the association between wheezing and functional constipation is not independent. Further research is needed to explore whether this result also applies to the outcome of asthma.
Strengths and limitations of this study
Population-based study population. The study group were not selected according to medical care.
This study addresses a topical area that has not been studied sufficiently and can contribute to the discussion of how asthma or atopy may be associated with functional bowel disorders.
This study took into account multiple shared risk factors of wheezing and constipation to shed light on the suggested association in literature.
Symptoms were available only from parental-reported questionnaires. This may lead to misclassification of the symptoms.
Early wheezing in infancy is not a sufficient predictor of childhood asthma.
No data were available regarding parental concerns of the child's health status. Bias may occur when parents with high concerns are more likely to report symptoms in their child as wheezing, constipation and infectious disease.
No data were available on IgE sensitisation, thus conclusions on the assocation between allergic disease and constipation should be made with caution.
PMCID: PMC3191603  PMID: 22021889
10.  Prenatal Exposure to Bisphenol A and Child Wheeze from Birth to 3 Years of Age 
Environmental Health Perspectives  2012;120(6):916-920.
Background: Bisphenol A (BPA), an endocrine-disrupting chemical that is routinely detected in > 90% of Americans, promotes experimental asthma in mice. The association of prenatal BPA exposure and wheeze has not been evaluated in humans.
Objective: We examined the relationship between prenatal BPA exposure and wheeze in early childhood.
Methods: We measured BPA concentrations in serial maternal urine samples from a prospective birth cohort of 398 mother–infant pairs and assessed parent-reported child wheeze every 6 months for 3 years. We used generalized estimating equations with a logit link to evaluate the association of prenatal urinary BPA concentration with the dichotomous outcome wheeze (wheeze over the previous 6 months).
Results: Data were available for 365 children; BPA was detected in 99% of maternal urine samples during pregnancy. In multivariable analysis, a one-unit increase in log-transformed creatinine-standardized mean prenatal urinary BPA concentration was not significantly associated with child wheeze from birth to 3 years of age, but there was an interaction of BPA concentration with time (p = 0.003). Mean prenatal BPA above versus below the median was positively associated with wheeze at 6 months of age [adjusted odds ratio (AOR) = 2.3; 95% confidence interval (CI): 1.3, 4.1] but not at 3 years (AOR = 0.6; 95% CI: 0.3, 1.1). In secondary analyses evaluating associations of each prenatal BPA concentration separately, urinary BPA concentrations measured at 16 weeks gestation were associated with wheeze (AOR = 1.2; 95% CI: 1.0, 1.5), but BPA concentrations at 26 weeks of gestation or at birth were not.
Conclusions: Mean prenatal BPA was associated with increased odds of wheeze in early life, and the effect diminished over time. Evaluating exposure at each prenatal time point demonstrated an association between wheeze from 6 months to 3 years and log-transformed BPA concentration at 16 weeks gestation only.
PMCID: PMC3385426  PMID: 22334053
bisphenol A; BPA; child; cotinine; prenatal; tobacco; wheeze
11.  Influence of dog ownership and high endotoxin on wheezing and atopy during infancy 
Increased exposure to microbial products early in life may protect from development of atopic disorders in childhood. Few studies have examined the relationship of endotoxin exposure and pet ownership on atopy and wheezing during infancy.
Evaluate relationships among high endotoxin exposure, pet ownership, atopy, and wheezing in high-risk infants.
Infants (n = 532; mean age, 12.5 ± 0.8 months) with at least 1 parent with confirmed atopy were recruited. A complete medical history and skin prick testing to foods and aeroallergens were performed at age 1 year. House dust samples were analyzed for endotoxin.
Prevalences of wheezing were not independently associated with dog or cat ownership or endotoxin levels. Percutaneous reactivity to at least 1 allergen was observed in 28.6% of infants. Univariate analyses showed significant associations of any wheezing, recurrent wheezing, and recurrent wheezing with an event with daycare attendance, number of siblings, respiratory infections, maternal smoking, and history of parental asthma. Logistic regression adjusting for the latter variables showed that recurrent wheezing (odds ratio, 0.4; 95% CI, 0.1–0.9) as well as 2 other wheeze outcomes were significantly reduced in homes with high endotoxin exposure in the presence of 2 or more dogs.
Pet ownership or endotoxin did not independently modify aeroallergen sensitization or wheezing during infancy. However, high endotoxin exposure in the presence of multiple dogs was associated with reduced wheezing in infants. Clinical implications: A home environment with many dogs and high levels of endotoxin may be conducive to reduced wheezing in infancy.
PMCID: PMC2233938  PMID: 17157656
Endotoxin; birth cohort; wheeze; house dust; pet ownership
12.  African ancestry, early life exposures, and respiratory morbidity in early childhood 
Racial disparities persist in early childhood wheezing and cannot be completely explained by known risk factors.
To evaluate the associations of genetic ancestry and self-identified race with early childhood recurrent wheezing, accounting for socio-economic status (SES) and early life exposures.
We studied 1034 children in an urban, multi-racial, prospective birth cohort. Multivariate logistic regression was used to evaluate the association of genetic ancestry as opposed to self-identified race with recurrent wheezing (>3 episodes). Sequential models accounted for demographic, socio-economic factors and early life risk factors. Genetic ancestry, estimated using 150 ancestry informative markers, was expressed in deciles.
Approximately 6.1% of subjects (mean age 3.1 years) experienced recurrent wheezing. After accounting for SES and demographic factors, African ancestry (OR: 1.16, 95% CI: 1.02–1.31) was significantly associated with recurrent wheezing. By self-reported race, hispanic subjects had a borderline decrease in risk of wheeze compared with African Americans (OR: 0.44, 95% CI: 0.19–1.00), whereas white subjects (OR: 0.46, 95% CI: 0.14–1.57) did not have. After further adjustment for known confounders and early life exposures, both African (OR: 1.19, 95% CI: 1.05–1.34) and European ancestry (OR: 0.84, 95% CI: 0.74–0.94) retained a significant association with recurrent wheezing, as compared with self-identified race (ORwhites: 0.31, 95% CI: 0.09–1.14; ORhispanic: 0.47, 95% CI: 0.20–1.08). There were no significant interactions between ancestry and early life factors on recurrent wheezing.
Conclusions and Clinical Relevance
In contrast to self-identified race, African ancestry remained a significant, independent predictor of early childhood wheezing after accounting for early life and other known risk factors associated with lung function changes and asthma. Genetic ancestry may be a powerful way to evaluate wheezing disparities and a proxy for differentially distributed genetic and early life risk factors associated with childhood recurrent wheezing.
PMCID: PMC3656492  PMID: 22093077
early childhood; genetic ancestry; race; wheezing
13.  Prematurity, Chorioamnionitis and the Development of Recurrent Wheezing: a Prospective Birth Cohort Study 
Prematurity (<37 weeks) has been inconsistently associated with asthma and wheezing. Chorioamnionitis may promote both prematurity and inflammatory pathways in infants’ airways.
To investigate the relationship of prematurity and chorioamnionitis with the development of early childhood recurrent wheezing.
The Boston Birth Cohort (n=1096) were followed prospectively from birth to a mean age of 2.2±2 years. Perinatal and postnatal clinical data and placental pathology were collected. The primary outcome was recurrent wheezing (≥2 physician documented episodes). Secondary outcomes included physician diagnosed asthma, food allergy and eczema. Preterm children were grouped by gestational age into moderately (33-36.9 weeks) and very preterm (<33 weeks) with and without chorioamnionitis, and compared to term children without chorioamnionitis (reference group). Chorioamnionitis was diagnosed either by intrapartum fever or by placental histology findings. Logistic regression models were preformed to investigate the independent and joint associations of degree of prematurity and chorioamnionitis.
Prematurity was associated with recurrent wheezing (OR:1.7, 95%CI:1.2-2.6). However, when subjects were grouped by degree of prematurity with or without chorioamnionitis, the highest risk of wheezing (OR:4.0, 95%CI:2.0-8.0) and physician diagnosed asthma (OR:4.4 95%CI:2.2-8.7) was present in the very preterm children with chorioamnionitis. The effect on both wheezing (OR:5.4, 95%CI:2.4-12.0) and asthma (OR:5.2, 95%CI:2.3-11.9) was greater in African Americans. Neither prematurity nor chorioamnionitis were associated with food allergy or eczema.
We found a strong joint effect of prematurity and chorioamnionitis on early childhood wheezing. This effect was stronger in African Americans.
Clinical Implications
Chorioamnionitis may increase the risk of recurrent wheezing in very low birth weight infants.
PMCID: PMC2993062  PMID: 18313129
Chorioamnionitis; prematurity; recurrent wheezing
14.  Early Child Care and Adiposity at Ages 1 and 3 Years 
Pediatrics  2009;124(2):555-562.
The majority of infants in the United States are in non-parental child care, yet little is known about the effect of child care on development of obesity.
To examine the relationship between child care attendance from birth to 6 months and adiposity at 1 and 3 years of age.
We studied 1138 children from a prospective cohort of pregnant women and their offspring. The main exposure was time in child care from birth to 6 months of age, overall and by type of care: (1) child care center; (2) someone else’s home; and (3) child’s own home by nonparent. The main outcomes were weight-for-length (WFL) z score at 1 year and BMI z score at 3 years of age.
A total of 649 (57%) infants attended child care; 17% were cared for in a center, 27% in someone else’s home, and 21% in their own home by a nonparent. After adjustment for confounders, overall time in child care was associated with an increased WFL z score at 1 year and BMI z score at 3 years of age but not skinfold thicknesses. Center and own home care were not associated with the outcomes, but care in someone else’s home was associated with an increase in both the 1- and 3-year outcomes.
Child care in the first 6 months of life, especially in someone else’s home, was associated with an increased WFL z score at 1 year and BMI z score at 3 years of age.
PMCID: PMC3049895  PMID: 19651579
child care; childhood obesity; nutrition; physical activity; infancy
15.  Prevalence and severity of wheezing in the first year of life in the city of Santo André, Brazil☆  
Revista Paulista de Pediatria  2014;32(3):164-170.
To determine the prevalence and the severity of wheezing in the first year of life for infants who live in Santo André, São Paulo, Brazil.
Cross sectional study with the administration of the Estudio Internacional de Sibilancias en Lactantes (EISL), which is a standardized and validated written questionnaire applied to parents and/or guardians of infants aged 12-24 months treated at primary health units, vaccination centers, day care centers, or kindergartens. The questionnaire consisted of questions regarding demographic characteristics, presence of wheezing, respiratory infections, and risk factors. Results were analyzed using the SPSS for Windows, 20.0 (SPSS Inc. - Chicago, Il, United States). Logistic regression was applied to verify variables associated to recurrent wheezing.
Among the 1,028 infants studied, 48.5% had one or more episodes of wheezing during the first 12 months of life (wheezing once), and 23.9% had three or more episodes (recurrent wheezing). Nocturnal symptoms, severe breathing difficulty, and visits to the emergency room were observed in 67.3%, 42.4%, and 60.7% of infants, respectively. Among the studied infants, 19.4% were hospitalized, and 11.0% had a medical diagnosis of asthma in the first year of life. Use of β2-agonists, inhaled corticosteroids, oral corticosteroids, and leukotriene receptor antagonists were observed in 88.8%, 21.0%, 54.9%, and 3.2% of children with wheezing, respectively. Use of oral corticosteroids, perception of breathlessness by parents, diagnosis of asthma, pneumonia, and hospitalization for pneumonia were more frequent among infants with recurrent wheezing (p<0.001).
In the city of Santo André, approximately half of infants had at least one episode of wheezing in the first year of life, and almost 25% had recurrent wheezing. Wheezing disorders in Santo André have early onset and high morbidity.
PMCID: PMC4227335  PMID: 25479844
Wheezing; Infants; Epidemiology/prevalence; Asthma
16.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
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.
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).
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
17.  Characterisation of atopic and non-atopic wheeze in 10 year old children 
Thorax  2004;59(7):563-568.
Background: Wheezing occurs in both atopic and non-atopic children. The characteristics of atopic and non-atopic wheeze in children at 10 years of age were assessed and attempts made to identify whether different mechanisms underlie these states.
Methods: Children were seen at birth and at 1, 2, 4 and 10 years of age in a whole population birth cohort study (n = 1456; 1373 seen at 10 years). Information was collected prospectively on inherited and early life environmental risk factors for wheezing. Skin prick testing, spirometry, and methacholine bronchial challenge were conducted at 10 years. Wheezing at 10 years of age was considered atopic or non-atopic depending on the results of the skin prick test. Independent significant risk factors for atopic and non-atopic wheeze were determined by logistic regression.
Results: Atopic (10.9%) and non-atopic (9.7%) wheeze were equally common at 10 years of age. Greater bronchial hyperresponsiveness (p<0.001) and airways obstruction (p = 0.011) occurred in children with atopic wheeze than in those with non-atopic wheeze at 10 years. Children with atopic wheeze more often received treatment (p<0.001) or an asthma diagnosis for their disorder, although current morbidity at 10 years differed little for these states. Maternal asthma and recurrent chest infections at 2 years were independently significant factors for developing non-atopic wheeze. For atopic wheeze, sibling asthma, eczema at 1 year, rhinitis at 4 years, and male sex were independently significant.
Conclusions: Non-atopic wheeze is as common as atopic wheeze in children aged 10 years, but treatment is more frequent in those with atopic wheeze. Different risk factor profiles appear relevant to the presence of atopic and non-atopic wheeze at 10 years of age.
PMCID: PMC1747084  PMID: 15223861
18.  51 Prevalence of Wheezing and Risk Factors Associated to Wheezing in Infants in the First Year of Life, Cuibá, MT, Brazil 
The purpose of this study was to evaluate the prevalence of wheezing and risk factors related to wheezing in infants (12–15 month-old) in the city of Cuiabá, Mato Grosso State, Brazil.
Cross-sectional study by applying a standardized written questionnaire from “Estudio Internacional de sibilancia en lactentes” (EISL) phase III. Parents and/or guardians of infants were interviewed at a primary health care clinic or at home from August 2009 to November 2010. Signed written informe consent was obtained from parents and/or guardians of all subjects. Factors associated to wheezing were studied using bivariate and multivariate analysis (SPSS v.18.0) and expressed as odds ratio (OR) and confidence interval 95% (95% CI).
One thousand sixty parents were interviewed (N = 1060), 27.7% (N = 294) infants had at least one wheezing episode in their first year of life, with onset at 5.8 ± 3.0 months (mean ± standard deviation), and 45.9% (N = 135) had had 3 or more episodes (recurrent wheezing). The use of inhaled β2-agonists, oral corticosteroids or leukotriene receptor antagonist, nocturnal symptoms, respiratory distress, hospitalization and medical diagnose of asthma were significantly more frequent in the group with recurrent wheezing (P < 0.05). Independent risk factors associated with wheezing in the first year of life were: history of previous pneumonia (OR = 10.80; 95% CI, 4.52-25.77); to have more than 6 upper respiratory infections (URI) (OR = 2.95; 95% CI, 2.11-4.14); asthma in sibling (OR = 2.13; 95% CI, 1.18-3.87); asthma in father (OR = 1.98; 95% CI, 1.22-3.23); asthma in mother (OR = 1.62; 95% CI, 1.07-2.43); exposure to paracetamol in the first year of life for URI (OR = 2.13; 95% CI, 1.54-2.95); exposure to moderate air pollution from traffic (OR = 1.59; 95% CI, 1.08-2.33); and a first URI before of third month of age (OR = 1.50; 95% CI, 1.04-2.17).
The prevalence of wheezing episodes among one year-old infants living in Cuiabá was high and early in life. Risk factors for wheezing are similar to risk factors for asthma. Exposure to paracetamol was associated with wheezing but more researches are required to clarify this potential association.
PMCID: PMC3512833
19.  Is Early Life Wheeze Associated with Lung Function at Age 6 Years? 
The incidence of wheeze is unknown and the role of early life wheeze in subsequent health is not clearly understood. Our goal was to calculate the age-specific incidence of wheeze and determine whether wheezing at particular times in early life was predictive of abnormal airway hyperresponsiveness (AHR), percent predicted FEV1 and current asthma at age 6 years.
Using data from a birth cohort study with annual report of wheezing (Childhood Allergy Study) and spirometry and methacholine challenge at age 6 years, the age-specific incidence of wheeze was determined using Kaplan-Meier estimates. Logistic and linear regression models were used to assess the associations between the presence of age-specific wheezing and the outcomes of current asthma, AHR and percent predicted FEV1 at age 6 years.
The 6-year cumulative incidence of wheezing was higher for boys (66.2%, 95% CI 59.8%, 72.6%) than girls (47.6% 95% CI 41.4%, 53.8%). There was no age when wheezing was more strongly associated with either AHR or percent predicted FEV1 at 6 years. Only wheeze in the fifth year among males and in females, both wheezing in the fourth and fifth years were positively predictive of current asthma at age 6. This is likely due to the definition of current asthma (ever doctor diagnosis and either medication or symptoms in last year). Eczema, parental asthma history and total cord blood IgE did not affect these associations.
Wheezing at any particular time in early life may not be predictive of early childhood lung function.
PMCID: PMC3737567  PMID: 19205282
20.  Evaluation of Airway Reactivity and Immune Characteristics as Risk Factors for Wheezing Early in Life 
Childhood asthma is most often characterized by recurrent wheezing, airway hyper-reactivity, and atopy; however, our understanding of these relationships from early in life remains unclear. Respiratory illnesses and atopic sensitization early in life may produce an interaction between innate and acquired immune responses leading to airway inflammation and heightened airway reactivity.
We hypothesized that pre-morbid airway reactivity and immunologic characteristics of infants without prior episodes of wheezing would be associated with subsequent wheezing during 1-year follow-up.
116 infants with chronic dermatitis were enrolled prior to episodes of wheezing. Airway reactivity, allergen-specific IgE, cytokine production by stimulated peripheral blood mononuclear cells (PBMCs), and percentages of dendritic cells were measured upon entry and airway reactivity was reassessed at 1-year follow-up. Linear regression models were used to evaluate predictor’s effect on continuous outcomes.
milk and/or egg sensitization was associated with heightened airway reactivity prior to wheezing and after the onset of wheezing; however, these factors were not associated with an increased risk of wheezing. There was an interaction between initial airway reactivity and wheezing as a determinant of airway reactivity at follow-up. In addition, cytokine production by stimulated PBMCs was a risk factor for wheezing, while increased percentages of conventional dendritic cells were protective for wheezing.
Our data in a selected cohort of infants support a model with multiple risk factors for subsequent wheezing that are independent of initial airway reactivity; however, the etiologic factors that produce wheezing very early in life may contribute to heightened airway reactivity.
PMCID: PMC2935911  PMID: 20816184
infants; wheezing; airway reactivity; atopy; dermatitis; cytokines; dendritic cells; food allergy
Thorax  2013;68(4):372-379.
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
22.  Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population 
Thorax  2002;57(5):388-392.
Background: Abnormal premorbid lung function is a risk factor for subsequent wheezing in children with one or no atopic parent. This study was undertaken to establish whether early lung function in high risk infants (both parents atopic) was a risk factor for respiratory symptoms in infancy and to examine the influence of maternal asthma, smoking, and allergen exposure during pregnancy on any association.
Methods: Infants were recruited from the NAC Manchester Asthma and Allergy Study cohort at birth. Partial forced expiratory flow volume technique under sedation was carried out to determine maximal flow at FRC (V'maxFRC). Children were followed prospectively and parents completed a standard respiratory questionnaire at one year of age.
Results: Sixty nine term infants (34 boys; 88% mothers non-smokers; no household pets) underwent respiratory function testing. Size adjusted V'maxFRC was significantly lower in infants who had recurrent wheeze during the first year of life (mean 1.3 ml/s/cm, 95% CI 0.99 to 1.60) than in those who did not (mean 2.03 ml/s/cm, 95% CI 1.71 to 2.36; p=0.01). V'maxFRC was also significantly lower in infants who had recurrent cough symptoms. In multivariate regression analysis, when adjusted for age at test, sex, maternal asthma, smoking and maternal mattress Der 1 levels, a lower size adjusted V'maxFRC score remained strongly associated with wheezing (OR 0.37, 95% CI 0.18 to 0.77, p=0.007). Maternal smoking also remained an independent risk factor (OR 29.85, 95% CI 2.46 to 362.5, p=0.008).
Conclusion: Significantly diminished lung function was present in high risk infants who subsequently wheezed and coughed. This was independent of maternal exposure to mite allergen, asthma, and smoking during pregnancy.
PMCID: PMC1746314  PMID: 11978912
23.  Socioeconomic and Sociodemographic Factors Associated with Asthma Related Outcomes in Early Childhood: The Generation R Study 
PLoS ONE  2013;8(11):e78266.
Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied.
The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models.
At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18–2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24–2.15, aOR = 1.85, 95% CI:1.11–3.09, aOR = 1.58, 95% CI:1.24–2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained.
This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We encourage further studies on underlying pathways and public health intervention programs, focusing on reducing socioeconomic or sociodemographic inequalities in asthma.
PMCID: PMC3823924  PMID: 24244299
24.  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.
To investigate the association between the duration of exclusive breast feeding and the development of asthma related outcomes in children at age 6 years.
Prospective cohort study.
Western Australia.
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.
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).
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
25.  Prevalence and clinical characteristics of wheezing in children in the first year of life, living in Cuiabá, Mato Grosso, Brazil☆  
Revista Paulista de Pediatria  2014;32(4):313-319.
To evaluate the prevalence and the clinical characteristics of wheezing in infants aged 12 to 15 months in the city of Cuiabá, Mato Grosso State, Midwest Brazil.
Parents and/or guardians of infants were interviewed and completed a written standardized questionnaire of the Estudio Internacional de Sibilancia en Lactantes (EISL) - phase 3 at primary healthcare clinics at the same day of children vaccination or at home, from August of 2009 to November of 2010.
1,060 parents and/or guardians completed the questionnaire, and 514 (48.5%) infants were male. Among the studied infants, 294 (27.7%) had at least one episode of wheezing during the first year of life, beggining at 5.8±3.0 months of age, with a predominance of male patients. The prevalence of occasional wheezing (<3 episodes of wheezing) was 15.0% and recurrent wheezing (≥3 episodes) was 12.7%. Among the infants with recurrent wheezing, the use of inhaled β2-agonist, oral corticosteroid, leukotriene receptor antagonist, as well as night symptoms, respiratory distress, and hospitalization due to severe episodes were significantly more frequent. Physician-diagnosed asthma was observed in 28 (9.5%) of the wheezing infants. Among the wheezing infants, 80 (27.7%) were diagnosed with pneumonia, of whom 33 (11.2%) required hospitalization; neverthless, no differences between occasional and recurrent wheezing infants were found.
The prevalence of recurrent wheezing and physician-diagnosed asthma in infants were lower compared with those observed in other Brazilian studies. Recurrent wheezing had early onset and high morbity.
PMCID: PMC4311784  PMID: 25510994
Infant; Respiratory sounds; Asthma; Prevalence

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