Alistair W. Stewart

International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.

The aetiology of asthma and allergic disease remains poorly understood, despite considerable research. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease, by establishing a standardized methodology and facilitating international collaboration. Its specific aims are: 1) to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres, and to make comparisons within and between countries; 2) to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and 3) to provide a framework for further aetiological research into genetic, lifestyle, environmental, and medical care factors affecting these diseases. The ISAAC design comprises three phases. Phase 1 uses core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase 2 will investigate possible aetiological factors, particularly those suggested by the findings of Phase 1. Phase 3 will be a repetition of Phase 1 to assess trends in prevalence.

Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood

BACKGROUND Little is known about the prevalence of atopic eczema outside Northern Europe. OBJECTIVES We sought to describe the magnitude and variation in the prevalence of atopic eczema symptoms throughout the world. METHODS A cross-sectional questionnaire survey was conducted on random samples of schoolchildren aged 6 to 7 years and 13 to 14 years from centers in 56 countries throughout the world. Those children with a positive response to being questioned about the presence of an itchy relapsing skin rash in the last 12 months that had affected their skin creases were considered to have atopic eczema. Children whose atopic eczema symptoms resulted in sleep disturbance for 1 or more nights per week were considered to have severe atopic eczema. RESULTS Complete data was available for 256,410 children aged 6 to 7 years in 90 centers and 458,623 children aged 13 to 14 years in 153 centers. The prevalence range for symptoms of atopic eczema was from less than 2% in Iran to over 16% in Japan and Sweden in the 6 to 7 year age range and less than 1% in Albania to over 17% in Nigeria for the 13 to 14 year age range. Higher prevalences of atopic eczema symptoms were reported in Australasia and Northern Europe, and lower prevalences were reported in Eastern and Central Europe and Asia. Similar patterns were seen for symptoms of severe atopic eczema. CONCLUSIONS Atopic eczema is a common health problem for children and adolescents throughout the world. Symptoms of atopic eczema exhibit wide variations in prevalence both within and between countries inhabited by similar ethnic groups, suggesting that environmental factors may be critical in determining disease expression. Studies that include objective skin examinations are required to confirm these findings.

Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC).

Background: As part of the International Study of Asthma and Allergies in Childhood (ISAAC), prevalence surveys were conducted among representative samples of school children from locations in Europe, Asia, Africa, Australasia, North and South America.

Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme

BACKGROUND Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6-7-year-old children from Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma. METHODS As part of Phase Three of ISAAC, parents or guardians of children aged 6-7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the childs first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression. FINDINGS 205 487 children aged 6-7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6-7 years (OR 1.46 [95% CI 1.36-1.56]). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1.61 [1.46-1.77] and 3.23 [2.91-3.60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6-7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema. INTERPRETATION Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood.

Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood

In Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) time trends in the prevalence of rhinoconjunctivitis symptoms were analysed. Cross‐sectional questionnaire surveys with identical protocols and questionnaires were completed a mean of 7 yr apart in two age groups comprising 498,083 children. In the 13‐ to 14‐yr age group 106 centres in 56 countries participated, and in the 6‐ to 7‐yr age group 66 centres in 37 countries participated. A slight worldwide increase in rhinoconjunctivitis prevalence was observed, but the variations were large among the centres and there was no consistent regional pattern. Prevalence increases in the older children exceeding 1% per year were recorded in 13 centres, including 3 of 9 centres in Africa, 2 of 15 in Asia‐Pacific, 1 of 8 in India, 3 of 15 in Latin America, 3 of 9 in Eastern Europe and 1 of 34 in Western and Northern Europe. Decreasing rhinoconjunctivititis prevalence of similar magnitude was only seen in four centres. The changes were less pronounced in the 6‐ to 7‐yr‐old children and only in one centre did any change exceed 1% per year. The decrease in highest prevalence rates in ISAAC Phase I suggests that the prevalence has peaked in those regions. An increase was recorded in several centres, mostly in low and mid‐income countries. The increases were more pronounced in the older age group, suggesting that environmental influences on the development of allergy may not be limited to early childhood.

Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design Prospective multicentre cohort. Setting Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants 3572 “healthy” nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure Pre-eclampsia defined as ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks’ gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37+0 weeks’ gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks’ gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added. Trial registration ACTRN12607000551493.

Four modifiable and other major risk factors for cot death: the New Zealand study.

Abstract New Zealands high mortality rate from sudden infant death syndrome (SIDS) prompted the development of the New Zealand Cot Death Study. A report of the analysis of the data from the first year has been published. This report now gives the major identified risk factors from the full 3 year data set. In this case‐control study there were 485 infants who died from SIDS in the post‐neonatal age group, and 1800 control infants, who were a representative sample of all hospital births in the study region. Obstetric records were examined and parental interviews were completed in 97.5% and 86.9% of subjects, respectively. As expected many risk factors for SIDS were confirmed including: lower socio‐economic status, unmarried mother, young mother, younger school‐leaving age of mother, younger age of mother at first pregnancy, late attendance at antenatal clinic, non‐attendance at antenatal classes, Maori, greater number of previous pregnancies, the further south the domicile, winter, low birthweight, short gestation, male infant and admission to a special care baby unit. In addition, however, we identified four risk factors that are potentially amenable to modification. These were the prone sleeping position of the baby (odds ratio (OR) = 3.70; 95% confidence interval (Cl) = 2.91, 4.70); bed sharing (OR = 2.70; 95% Cl = 2.02, 3.62); maternal smoking of 1–9 cigarettes per day (OR = 3.47; 95% Cl = 2.50, 4.83), 10–19 cigarettes per day (OR = 3.94; 95% Cl = 2.87, 5.41) or more than 20 cigarettes per day (OR = 5.90; 95% Cl = 4.20, 8.31); and not breast feeding (OR = 2.39; 95% Cl = 1.88, 3.04). After controlling for all of the above variables, the relative risks associated with prone sleeping position (OR = 4.84). sharing bed (OR = 2.02), maternal smoking (OR = 1.79) and not breast feeding (OR = 1.89) were still statistically significant. Population‐attributable risk calculations suggest that these four risk factors may account for 82% of deaths from SIDS. The SIDS mortality rate may fall to less than 0.7/1000 live births if all parents stop putting their infants down to sleep in the prone position, do not sleep with their baby, do not smoke, and breast feed their infants.

International trends in stroke mortality: 1970-1985.

We compared the pattern of cerebrovascular disease (stroke) mortality in men and women aged 40-69 years in 27 countries during 1970-1985 with the decline in coronary heart disease mortality during the same period. Stroke mortality rates declined in 21 and 25 countries for men and women, respectively. In 23 countries the decline in stroke mortality in women was greater than that in men. Countries with the highest rates of stroke mortality are also those with the least favorable secular trend. The rate of decline for stroke mortality is greater than that for coronary heart disease mortality in those countries that experienced a decline in both categories. International comparisons of risk factor levels over time are required to explain the striking differences between countries.

Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study

Objectives To compare pregnancy outcomes between women who stopped smoking in early pregnancy and those who either did not smoke in pregnancy or continued to smoke. Design Prospective cohort study. Setting Auckland, New Zealand and Adelaide, Australia. Participants 2504 nulliparous women participating in the Screening for Pregnancy Endpoints (SCOPE) study grouped by maternal smoking status at 15 (±1) week’s gestation. Main outcome measures Spontaneous preterm birth and small for gestational age infants (birth weight <10th customised centile). We compared odds of these outcomes between stopped smokers and non-smokers, and between current smokers and stopped smokers, using logistic regression, adjusting for demographic and clinical risk factors. Results 80% (n=1992) of women were non-smokers, 10% (n=261) had stopped smoking, and 10% (n=251) were current smokers. We noted no differences in rates of spontaneous preterm birth (4%, n=88 v 4%, n=10; adjusted odds ratio 1.03, 95% confidence interval l0.49 to 2.18; P=0.66) or small for gestational age infants (10%, n=195 v 10%, n=27; 1.06, 0.67 to 1.68; P=0.8) between non-smokers and stopped smokers. Current smokers had higher rates of spontaneous preterm birth (10%, n=25 v 4%, n=10; 3.21, 1.42 to 7.23; P=0.006) and small for gestational age infants (17%, n=42 v 10%, n=27; 1.76, 1.03 to 3.02; P=0.03) than stopped smokers. Conclusion In women who stopped smoking before 15 weeks’ gestation, rates of spontaneous preterm birth and small for gestational age infants did not differ from those in non-smokers, indicating that these severe adverse effects of smoking may be reversible if smoking is stopped early in pregnancy.

The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three: A global synthesis

This ISAAC Phase Three synthesis provides summarised information on the main findings of the study, regional tables and figures related to the prevalence and severity of current symptoms of asthma, rhinoconjunctivitis and eczema in the main regions of the world. The large number of surveyed children (≈1,200,000), the large number of centres (233) and countries (98) that participated in ISAAC Phase Three makes this study the most comprehensive survey of these diseases ever undertaken. Globally, the prevalence for current asthma, rhinoconjunctivitis and eczema in the 13-14-year age group was 14.1%, 14.6% and 7.3%, respectively. In the 6-7-year age group the prevalence for current asthma, rhinoconjunctivitis and eczema was 11.7%, 8.5% and 7.9%, respectively. The study shows a wide variability in the prevalence and severity of asthma, rhinoconjunctivitis and eczema which occurs not just between regions and countries but between centres in the same country and centres in the same city. This study definitively establishes that the prevalence of those diseases can be very high in non-affluent centres with low socioeconomic conditions. The large variability also suggests a crucial role of local environment characteristics to determine the differences in prevalence between one place and another. Thus, ISAAC Phase Three has provided a large body of epidemiological information on asthma, rhinoconjunctivitis and eczema in childhood from contrasting environments which is expected to yield new clues about the aetiology of those conditions and reasons for their marked global variability.