A J W Henderson

Paracetamol use in pregnancy and wheezing in early childhood

Background: We recently reported links between frequent paracetamol (acetaminophen) use and wheezing and asthma in adults and children, but data are lacking on possible effects of prenatal exposure on wheezing in early childhood. Methods: In the population based Avon Longitudinal Study of Parents and Children (ALSPAC) women were asked twice during pregnancy (at 18–20 weeks and 32 weeks) about their usage of paracetamol and aspirin. Six months after birth, and at yearly intervals thereafter, mothers were asked about wheezing and eczema symptoms in their child. The effects of paracetamol and aspirin use in pregnancy on the risk in the offspring of wheezing at 30–42 months (n=9400) and eczema at 18–30 months (n=10 216) and on their risk of different wheezing patterns (defined by presence or absence of wheezing at <6 months and at 30–42 months) were examined. Results: Paracetamol was taken frequently (most days/daily) by only 1% of women. After controlling for potential confounders, frequent paracetamol use in late pregnancy (20–32 weeks), but not in early pregnancy (<18–20 weeks), was associated with an increased risk of wheezing in the offspring at 30–42 months (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41); p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24 to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30–42 months was attributable to this exposure. Frequent paracetamol use in pregnancy was not associated with an increased risk of eczema. Frequent aspirin use in pregnancy was associated with an increased risk of wheezing only at <6 months. Conclusions: Frequent use of paracetamol in late pregnancy may increase the risk of wheezing in the offspring, although such an effect could explain only about 1% of the population prevalence of wheezing in early childhood.

Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema

It has been suggested that foetal nutrition might influence the inception of wheezing and atopic disorders in childhood but specific nutrients have not been implicated. In the Avon Longitudinal Study of Parents and Children umbilical cord samples were assayed for trace elements and minerals, and mothers were asked about wheezing and eczema in their children. Associations of cord concentrations of selenium, zinc, copper, manganese, magnesium, iron, lead and mercury with wheezing at 30–42 months, with wheezing patterns defined by the presence or absence of transient infant, later onset or persistent wheezing at 0–6 months and 30–42 months, respectively (n=2,044), and with eczema at 18–30 months (n=2,173), were analysed. Cord selenium was negatively associated with persistent wheeze (adjusted odds ratio (OR) per doubling concentration: 0.67). Cord iron was negatively associated with later onset wheeze (OR: 0.86) and with eczema (OR: 0.90). Children with high cord concentrations of selenium and iron were less likely than those with low concentrations to wheeze transiently in infancy. The level of foetal exposure to selenium and iron may possibly influence the risk of wheezing and eczema in early childhood although, in view of the multiple analyses carried out, it is possible that the main findings occurred by chance.

Dietary patterns in pregnancy and respiratory and atopic outcomes in childhood

Background: Studies of the relation between maternal diet in pregnancy and respiratory and atopic outcomes in the offspring have focused on the effects of individual nutrients and foods rather than dietary patterns. A study was undertaken to determine whether dietary patterns in pregnancy are related to childhood asthma and related outcomes. Methods: In a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), dietary patterns in pregnancy previously identified using principal components analysis (“health conscious”, “traditional”, “processed”, “vegetarian” and “confectionery”) were related to early wheezing phenotypes and eczema; wheezing, hay fever, eczema, doctor-diagnosed asthma, atopy and total IgE at 7 years; lung function and bronchial responsiveness at 8–9 years. In regression models, confounders were controlled for using propensity scores. Results: Univariately, the “health conscious” pattern was positively associated with eczema, total IgE, forced expiratory volume in 1 s and forced expiratory flow and negatively associated with early wheezing and asthma (unadjusted odds ratios per standard deviation increase in pattern score for early persistent wheeze and asthma: 0.78 (95% CI 0.70 to 0.87), p = 7.3×10−6, N = 8886 and 0.90 (95% CI 0.84 to 0.97), p = 0.007, N = 7625, respectively). The “processed” pattern was positively associated with early wheezing and negatively associated with atopy and forced vital capacity. On controlling for confounders, the effects were substantially attenuated and became non-significant (adjusted odds ratios for the associations of the “health conscious” pattern with early persistent wheeze and asthma: 1.00 (0.86 to 1.16), p = 0.99 and 0.95 (0.86 to 1.04), p = 0.27, respectively). Conclusions: In this cohort, dietary patterns in pregnancy did not predict asthma and related outcomes in the offspring after controlling for confounders.

Association of duration of television viewing in early childhood with the subsequent development of asthma

Objective: To investigate whether duration of television (TV) viewing in young children is associated with subsequent development of asthma. Methods: Children taking part in the Avon Longitudinal Study of Parents and Children (ALSPAC) with no wheeze up to the age of 3.5 years and follow-up data at 11.5 years of age took part in a prospective longitudinal cohort study. The main outcome measure was asthma, defined as doctor-diagnosed asthma by 7.5 years of age with symptoms and/or treatment in the previous 12 months at 11.5 years of age. Parental report of hours of TV viewing per day by the children was ascertained at 39 months. Results: In children with no symptoms of wheeze at 3.5 years of age and follow-up data at 11.5 years of age, the prevalence of asthma was 6% (185/3065). Increased TV viewing at 3.5 years was associated with increased prevalence of asthma at 11.5 years of age (p for linear trend = 0.0003). Children who watched television for >2 h/day were almost twice as likely to develop asthma by 11.5 years of age as those watching TV for 1–2 h/day (adjusted odds ratio 1.8 (95% CI 1.2 to 2.6)). Conclusion: Longer duration of TV viewing in children with no symptoms of wheeze at 3.5 years of age was associated with the development of asthma in later childhood.

Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function

It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed.

Maternal Nrf2 and gluthathione-S-transferase polymorphisms do not modify associations of prenatal tobacco smoke exposure with asthma and lung function in school-aged children

Background Maternal smoking during pregnancy has detrimental effects on the respiratory health of infants and children. Polymorphisms of antioxidant genes including glutathione-S-transferases (GSTs) have been proposed as candidates for asthma and reduced lung function in children. Methods Women enrolled in the Avon Longitudinal Study of Parents and Children reported smoking habits during pregnancy. Asthma status in their children was established at age 7.5 years from parental reports and lung function was measured by spirometry at age 8.5 years. Maternal and child DNA were genotyped for deletions of GSTM1 and GSTT1 and functional polymorphisms of GSTP1 and Nrf2 genes. Associations of prenatal tobacco smoke exposure with asthma and lung function in children were stratified by maternal genotype. Results In 6606 children, maternal smoking during pregnancy was negatively associated with maximal mid expiratory flow (FEF25-75) (−0.05 SD units, 95% CI −0.07 to −0.03, p<0.001). There was little evidence for interactions between maternal smoking and any maternal genotype considered on childrens asthma or lung function. Maternal smoking was associated with reduced childhood FEF25-75 only in mother-child pairs (n=1227) with both copies of GSTM1 deleted (−0.08 SD units, 95% CI −0.14 to −0.02, p=0.01) or (n=2313) at least one copy of GSTT1 present (−0.05 SD units, 95% CI −0.09 to 0, p=0.03). Conclusion This study confirms a detrimental effect of intrauterine tobacco smoke exposure on childhood lung function but no strong evidence of modification by maternal genotype for important antioxidant genes. Adverse effects of fetal exposure to tobacco smoke on the respiratory health of children may be mediated by pathways other than oxidative stress.

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

BACKGROUND The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.

Higher systolic blood pressure with normal vascular function measurements in preterm-born children

Preterm birth, low birth weight and poor foetal nutrition have been linked to cardiovascular disease, but the underlying mechanisms remain unclear. We explored prematurity and vascular function by studying a UK cohort of 14 049 children and conducting a systematic review.

Maternal age of menarche is not associated with asthma or atopy in prepubertal children

Background: Maternal sex hormones in pregnancy can theoretically influence the developing fetal immune system and modulate the subsequent development of atopic disorders. Early onset of menarche has been linked to increased oestrogen levels in adult women. A study was undertaken to examine the association between early onset menarche in pregnant women and asthma and atopic status of their children at 7 years of age. Methods: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal birth cohort study in which pregnant women, resident in Avon (UK), were recruited on the basis of an expected date of delivery between 1 April 1991 and 31 December 1992. Maternal age at menarche was assessed from prenatal questionnaires administered to the women. Clinical outcomes in the children were based on mothers’ responses to self-completion questionnaires and included asthma, eczema, and hay fever. The atopic status of the child was objectively assessed by skin prick tests to a panel of common aeroallergens at the age of 7 years. Analyses used multivariable logistic regression with a diverse range of possible confounders. Results: Complete data were available on 5765 woman and child pairs. The prevalence of ever reported asthma to 7 years was 20.4%, eczema 58.6%, hay fever 12.1%, and atopy (defined as any positive (>2 mm weal) response) was present in 20.6%. There were no significant differences in mean age of menarche between mothers of children with and without each of the primary outcomes. Adjusted odds ratios (95% CI) for the latest age of menarche (16+ years) compared with the lowest (<12 years) reference group were 1.41 (1.00 to 1.99) for asthma, 0.98 (0.73 to 1.91) for eczema, 0.95 (0.62 to 1.44) for hay fever, and 0.98 (0.68 to 1.42) for atopy. Conclusion: No consistent association was found between maternal age at menarche and asthma, eczema, hay fever or atopy in their children during early childhood.

A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults.

Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics.