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Papers by Vanessa Murphy

Placenta, 2007

Pregnant women with asthma are frequently exposed to synthetic glucocorticoids and glucocorticoid... more Pregnant women with asthma are frequently exposed to synthetic glucocorticoids and glucocorticoids are known to reduce fetal growth. The fetus is normally protected from the harmful effects of maternally derived glucocorticoids by the placental enzyme 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). Whether 11b-HSD2 inactivates the synthetic glucocorticoids used for asthma treatment during pregnancy (budesonide, beclomethasone dipropionate and fluticasone propionate) remains unknown. To investigate the relationship between steroid use during pregnancy and fetal growth and development, pregnant women with (n ¼ 119) and without asthma (n ¼ 84) were followed throughout pregnancy. Data on asthma medication use, neonatal size at birth, placental weight and cord blood cortisol and estriol were collected. Placental tissue samples were collected from non-asthmatic women (n ¼ 8) for metabolism studies. Placental 11b-HSD2 activity was determined using beclomethasone dipropionate, budesonide, fluticasone propionate, prednisolone, dexamethasone and betamethasone as steroid substrates. Steroids and their oxidised metabolites were examined using thin layer chromatography and densitometry. Placental 11b-HSD2 metabolised beclomethasone, prednisolone, dexamethasone and betamethasone, but not budesonide or fluticasone. No association between the use of inhaled steroids for asthma treatment during pregnancy and alterations in neonatal size, placental weight, gestational age at delivery, or umbilical vein estriol concentrations was demonstrated compared to non-asthmatic women. In conclusion, the use of inhaled steroids for asthma treatment does not affect fetal growth, despite differences in placental metabolism by 11b-HSD2.

Nutrients

Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased ... more Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibil...

International Journal of Environmental Research and Public Health

Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the... more Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the offspring. We investigated the association between ambient air pollutants during pregnancy and cell populations in cord blood from babies born to mothers with asthma enrolled in the Breathing for Life Trial. For each patient (n = 91), daily mean ambient air pollutant levels were extracted during their entire pregnancy for sulfur dioxide (SO2), nitric oxide, nitrogen dioxide, carbon monoxide, ozone, particulate matter <10 μm (PM10) or <2.5 μm (PM2.5), humidity, and temperature. Ninety-one cord blood samples were collected, stained, and assessed using fluorescence-activated cell sorting (FACS). Principal Component (PC) analyses of both air pollutants and cell types with linear regression were employed to define associations. Considering risk factors and correlations between PCs, only one PC from air pollutants and two from cell types were statistically significant. PCs from air poll...

International Journal of Environmental Research and Public Health

Wildfires are increasing and cause health effects. The immediate and ongoing health impacts of pr... more Wildfires are increasing and cause health effects. The immediate and ongoing health impacts of prolonged wildfire smoke exposure in severe asthma are unknown. This longitudinal study examined the experiences and health impacts of prolonged wildfire (bushfire) smoke exposure in adults with severe asthma during the 2019/2020 Australian bushfire period. Participants from Eastern/Southern Australia who had previously enrolled in an asthma registry completed a questionnaire survey regarding symptoms, asthma attacks, quality of life and smoke exposure mitigation during the bushfires and in the months following exposure. Daily individualized exposure to bushfire particulate matter (PM2.5) was estimated by geolocation and validated modelling. Respondents (n = 240) had a median age of 63 years, 60% were female and 92% had severe asthma. They experienced prolonged intense PM2.5 exposure (mean PM2.5 32.5 μg/m3 on 55 bushfire days). Most (83%) of the participants experienced symptoms during the...

Paediatric asthma and allergy, 2021

Pediatric Pulmonology, 2020

Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing ... more Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age.

Nutrients, 2020

Low 25-hydroxyvitamin D (25(OH)D) levels are common in pregnancy and associated with adverse mate... more Low 25-hydroxyvitamin D (25(OH)D) levels are common in pregnancy and associated with adverse maternal/neonatal outcomes. In pregnant women with asthma, this study examined the association of lifestyle- and asthma-related factors on 25(OH)D levels and maternal/neonatal outcomes by vitamin D status. Serum 25(OH)D was measured at 16 and 35 weeks gestation in women with asthma (n = 103). Body mass index (BMI), gestational weight gain (GWG), smoking status, inhaled corticosteroid (ICS) use, asthma control, airway inflammation, and exacerbations, and maternal/neonatal outcomes were collected. Baseline and change (Δ) in 25(OH)D were modelled separately using backward stepwise regression, adjusted for season and ethnicity. Maternal/neonatal outcomes were compared between low (25(OH)D < 75 nmol/L at both time points) and high (≥75 nmol/L at one or both time points) vitamin D status. Fifty-six percent of women had low vitamin D status. Obesity was significantly associated with lower baseli...

The Journal of allergy and clinical immunology, Jan 7, 2018

The single-centre double-blind, randomised controlled Managing Asthma in Pregnancy (MAP) trial in... more The single-centre double-blind, randomised controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FeNO) in combination with asthma symptoms (FeNO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (ANZ Clinical Trials Registry, number 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FeNO group. However, the effect of FeNO-guided management on the development of asthma in the offspring is unknown. We sought to investigate the effect of FeNO-guided asthma management during pregnancy on asthma incidence in childhood. 179 mothers consented to participate in the Growing Into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FeNO-guided asthma management on childhood asthma incidence. 140 children (78%) were followed up at 4 to 6 years of a...

7.2 Paediatric Asthma and Allergy, 2016

Background: FeNO-guided asthma management resulted in 50% less exacerbations during pregnancy (Po... more Background: FeNO-guided asthma management resulted in 50% less exacerbations during pregnancy (Powell et al, Lancet 2011) and reduced the prevalence of recurrent bronchiolitis in the first year of life by 90% in their offspring (Mattes et al, Thorax 2014). Objectives: To assess asthma symptoms and diagnosis in a cohort of pre-schoolers born to mothers whose asthma treatment during pregnancy was guided either by symptoms (Clinical group), or FeNO and symptoms (FeNO group). Methods: We followed-up 109 of 146 children (75[PR1] %) seen at 12 months of age for preschool assessment. The ISAAC questionnaire, and interview ascertained symptoms were elicited, and lung function was measured using impulse oscillometry (IOS). Results: Mean age was 5.0 years (3.9-6.9) and 49% were male without difference between groups. Prevalence of wheeze ever (64% vs. 46%, p=0.05), frequent wheezing in the past 12 months (24% vs. 6%, p=0.01), doctor diagnosed asthma (42% vs. 21%, p=0.02) and ED visit for wheeze/asthma (20% vs. 2%, p=0.005) were all significantly lower in children from the FeNO group compared to the Clinical group. IOS was successful in 79 children (72%) and mean Z-score resistance at 5Hz (R5Hz) for children with wheeze ever was 0.74 (95% CI 0.41-1.08) compared to 0.18 (95% CI -0.08-0.43) without wheeze (p=0.01). Children with a doctor diagnosis of asthma had a mean R5Hz Z-score of 0.79 (95% CI 0.35-1.22) compared to 0.28 (95% CI 0.03-0.53, p=0.04) without asthma. No difference in R5Hz was observed between the Clinical and FeNO group. Conclusions: FeNO-guided management of asthma during pregnancy reduces respiratory symptoms and asthma diagnosis in the offspring at preschool age.

BMC pregnancy and childbirth, May 17, 2016

Asthma exacerbations are common during pregnancy and associated with an increased risk of adverse... more Asthma exacerbations are common during pregnancy and associated with an increased risk of adverse perinatal outcomes. Adjusting asthma treatment based on airway inflammation rather than symptoms reduces the exacerbation rate by 50 %. The Breathing for Life Trial (BLT) will test whether this approach also improves perinatal outcomes. BLT is a multicentre, parallel group, randomised controlled trial of asthma management guided by fractional exhaled nitric oxide (FENO, a marker of eosinophilic airway inflammation) compared to usual care, with prospective infant follow-up. Women with physician-diagnosed asthma, asthma symptoms and/or medication use in the previous 12 months, who are 12-22 weeks gestation, will be eligible for inclusion. Women randomised to the control group will have one clinical assessment of their asthma, including self-management education. Any treatment changes will be made by their general practitioner. Women randomised to the intervention group will have clinical ...

Placenta, 2004

Studying the effect of maternal asthma during pregnancy on placental function and fetal developme... more Studying the effect of maternal asthma during pregnancy on placental function and fetal development has highlighted that there is a strong interaction between mother, placenta and fetus and these interactions appear to be sex-specific. This work has found that the female fetus alters maternal asthma during pregnancy by upregulating maternal inflammatory pathways. When asthma-associated inflammatory pathways are not treated with inhaled steroids during pregnancy, the female fetus has reduced growth and adrenal function due to alterations in placental glucocorticoid metabolism. When the mother uses inhaled steroid for the treatment of her asthma during pregnancy, female fetal growth and placental function are comparable to the control population. The growth of the male fetus appears to be unaffected by asthma or inhaled steroid use. These findings indicate there may be different mechanisms regulating placental glucocorticoid and immune mechanisms depending on fetal sex in both asthmatic and non-asthmatic pregnancies.

Nature communications, Jan 23, 2015

Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the ... more Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to preve...

Thorax, 2010

Smoking and severe asthma exacerbations in pregnancy are risk factors for low birth weight babies... more Smoking and severe asthma exacerbations in pregnancy are risk factors for low birth weight babies. No studies have assessed the clinical implications of smoking on asthma exacerbations in pregnancy. Pregnant women with current asthma (n=80) were prospectively assessed at clinic visits (18, 30, 36 weeks), during exacerbations and with fortnightly phone calls. The asthma control questionnaire was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (self-managed). Medications, self-management skills, smoking history, fractional exhaled nitric oxide (FENO), exhaled carbon monoxide (ECO) and lung function were assessed. Pregnant women without asthma (controls, n=46) were assessed prospectively at clinic visits. Women with asthma were more likely to smoke (34% current smokers) than women without asthma (15% current smokers). In women with asthma, the median (IQR) exacerbation rate during pregnancy was 2.0 (1.0-3.0) in current smoker...

BMC Pulmonary Medicine, 2015

Background: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with s... more Background: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with surgical resection or active surveillance. The objective of this study was to comprehensively assess large and small airway function in children with CTM who underwent lobectomy in early life. We hypothesise that sensitive measures of lung function will demonstrate residual impairments in CTM compared to healthy children. Methods: Nitrogen lung clearance index (LCI), reactance and resistance (X5Hz and R5Hz), forced expiratory volume in 1 s and forced vital capacity (FEV1 and FVC) were prospectively measured in 10 children with CTM (mean age/SD: 7.6/1.3) who had undergone surgical resection in early life and in 17 healthy children (mean age/SD: 4.8/0.4). Total lung capacity (TLC) was also conducted in children older than 7 years of age with CTM (n = 8). Results: Mean LCI was 8.0 (95% CI 7.5 to 8.5) in the CTM group and 7.3 (95% CI 7.0 to 7.6) in healthy children (p = 0.016). Mean X5Hz was −0.44kPa/l/s (95% CI −0.58 to −0.31) in the CTM group and −0.31kPa/l/s (95% CI −0.35 to −0.27) in healthy children (p = 0.02). Mean Z score for X5Hz was −2.11 (95% CI −3.59 to −0.63) in the CTM group and −0.11 (95% CI −0.55 to 0.33) in healthy children (p = 0.0008). Mean FEV1 was 1.21 L (95% CI 0.97 to 1.45) in the CTM group and 1.02 L (95% CI 0.90 to 1.15) in healthy children (p = 0.22). Mean % predicted FEV1 was 83% (95% CI 74 to 92) in the CTM group and 97% (95% CI 87 to 107) in healthy children (p < 0.05). Mean % predicted TLC in CTM children was 121.3% (95% CI 88.45 to 154.1). Mean LCI was inversely correlated with height z-scores in the CTM group (rs = −0.88, p = 0.002) but not in healthy children (rs = 0.22, p = 0.4). Conclusions: Children with CTM have impaired lung function as demonstrated by the significant differences in LCI, reactance and FEV1 but not FVC, resistance and TLC. These findings may be of clinical relevance as ventilation inhomogeneities are closely correlated with somatic growth in this study.

Thorax, 2010

Background Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and ha... more Background Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. Methods Pregnant women with mild asthma (n¼52), moderateesevere asthma (n¼71) and without asthma (n¼51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. Results Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p¼0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r¼À0.286, p¼0.017) and, despite a decrease in placental GR mRNA (p¼0.003), placental GRa protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. Conclusions The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or posttranslational modifications.

Thorax, 2011

Background Acute respiratory tract infections are common ailments to all individuals and the huma... more Background Acute respiratory tract infections are common ailments to all individuals and the human rhinoviruses (HRVs) cause most of these infections. Pregnant women have increased susceptibility and disease severity to viral infections like influenza and HRVs, as do asthmatics. Successful pregnancy requires immunological modulation to permit fetal tolerance. Objectives To determine whether pregnant women have reduced innate antiviral interferon (IFN) responses to HRV infection compared with non-pregnant women. Methods An in vitro culture system was used, where peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 54 women, including 10 stable asthmatics who were pregnant and 10 who were not pregnant, 10 non-asthmatic women who were pregnant, 10 who were 6monthspostpartumand10whowerenotpregnant.Sampleswerealsocollectedfromfourexacerbatingpregnantasthmatics.PBMCswereculturedwithHRV43andHRV1B.TheantiviralproteinsIFNaandIFNlweremeasuredfromculturesupernatantsbyELISA.ResultsComparedwithhealthynon−pregnantwomen,pregnantwomenhadsignificantlyreducedinnateIFNresponsestoHRVinfection(p<0.02),persisting6 months post partum and 10 who were not pregnant. Samples were also collected from four exacerbating pregnant asthmatics. PBMCs were cultured with HRV43 and HRV1B. The antiviral proteins IFNa and IFNl were measured from culture supernatants by ELISA. Results Compared with healthy non-pregnant women, pregnant women had significantly reduced innate IFN responses to HRV infection (p<0.02), persisting 6monthspostpartumand10whowerenotpregnant.Sampleswerealsocollectedfromfourexacerbatingpregnantasthmatics.PBMCswereculturedwithHRV43andHRV1B.TheantiviralproteinsIFNaandIFNlweremeasuredfromculturesupernatantsbyELISA.ResultsComparedwithhealthynon−pregnantwomen,pregnantwomenhadsignificantlyreducedinnateIFNresponsestoHRVinfection(p<0.02),persisting6 months post partum (p#0.02). Pregnant asthmatics had significantly reduced IFNl responses compared with healthy non-pregnant women (p#0.034), while during current asthma exacerbations a decrease in IFNa (p#0.023) and IFNl (p¼0.007) was observed. Induction by a TLR7 agonist induced a similar pattern of decreased innate IFNs during pregnancy as observed when HRV was the inducing agent. Conclusions Reduced antiviral IFNs during pregnancy and asthma provide an important mechanism for increased susceptibility, morbidity and mortality in pregnant women with respiratory viral infection.

Respirology, 2006

was involved in study design, protocol development, conducting SELDI experiments, data analysis a... more was involved in study design, protocol development, conducting SELDI experiments, data analysis and manuscript preparation. Renee Johnson was involved in protocol development, conducting SELDI experiments, data review and manuscript review. Yung-Chih Wang was involved in protocol development, data review and manuscript review. Karen Akinsanya was involved in protocol development, data review and manuscript review. Peter Gibson was involved in subject characterization, data review and manuscript review. Roger Smith was involved in study design, protocol development, data review and manuscript review. Vicki Clifton was involved in study design, protocol development, data review and manuscript review.

Pediatric Allergy and Immunology, 2013

Background: There are few studies investigating the relationship between respiratory viral infect... more Background: There are few studies investigating the relationship between respiratory viral infection in pregnancy and asthma in the offspring, and none among mothers with asthma. Infants of mothers with asthma are more likely to wheeze and have a higher risk of developing asthma than infants of non-asthmatic mothers. Methods: A prospective cohort study of viral infection in pregnancy was conducted between 2007 and 2009, and a subgroup of infants of mothers with asthma was followed up at 6 and 12 months of age. During common colds, nasal and throat swabs were collected from mothers and respiratory viruses detected by polymerase chain reaction. Respiratory health of infants was assessed by parent-completed questionnaire. Results: Twelve-month-old infants whose mothers had confirmed viral infections in pregnancy (n = 26) reported more frequent wheeze (40% had 4-12 wheeze attacks compared with 0%), sleep disturbed by wheeze (1 night per week or more in 60% vs. 11%), beta agonist treatment for wheeze (27% vs. 0%), prolonged colds (2 wk or longer 31% vs. 0%), more eczema (40% vs. 6.3%), and parent-perceived asthma (32% vs. 0%), compared with infants whose mothers had common colds without laboratory-confirmed viral infection (n = 16). Conclusions: This study demonstrates a relationship between maternal respiratory viral infection in pregnancy and wheezing illness in infants of mothers with asthma. Viral infections are the most common cause of asthma exacerbations in pregnancy, and infants of asthmatic mothers are at increased risk of asthma themselves. Further research is needed to elucidate the mechanisms involved.

The Lancet, 2011

Background Asthma exacerbations during pregnancy are common and can be associated with substantia... more Background Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (F E NO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on F E NO and symptoms would reduce asthma exacerbations. Methods We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks' gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or F E NO concentrations (active intervention group) used to uptitrate (F E NO >29 ppb) or downtitrate (F E NO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting β2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when F E NO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482. Findings 111 women were randomly assigned to the F E NO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the F E NO group than in the control group (0•288 vs 0•615 exacerbations per pregnancy; incidence rate ratio 0•496, 95% CI 0•325-0•755; p=0•001). The number needed to treat was 6. In the F E NO group, quality of life was improved (score on short form 12 mental summary was 56•9 [95% CI 50•2-59•3] in F E NO group vs 54•2 [46•1-57•6] in control group; p=0•037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0•046). Interpretation Asthma exacerbations during pregnancy can be signifi cantly reduced with a validated F E NO-based treatment algorithm.

Placenta, 2007

Pregnant women with asthma are frequently exposed to synthetic glucocorticoids and glucocorticoid... more Pregnant women with asthma are frequently exposed to synthetic glucocorticoids and glucocorticoids are known to reduce fetal growth. The fetus is normally protected from the harmful effects of maternally derived glucocorticoids by the placental enzyme 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2). Whether 11b-HSD2 inactivates the synthetic glucocorticoids used for asthma treatment during pregnancy (budesonide, beclomethasone dipropionate and fluticasone propionate) remains unknown. To investigate the relationship between steroid use during pregnancy and fetal growth and development, pregnant women with (n ¼ 119) and without asthma (n ¼ 84) were followed throughout pregnancy. Data on asthma medication use, neonatal size at birth, placental weight and cord blood cortisol and estriol were collected. Placental tissue samples were collected from non-asthmatic women (n ¼ 8) for metabolism studies. Placental 11b-HSD2 activity was determined using beclomethasone dipropionate, budesonide, fluticasone propionate, prednisolone, dexamethasone and betamethasone as steroid substrates. Steroids and their oxidised metabolites were examined using thin layer chromatography and densitometry. Placental 11b-HSD2 metabolised beclomethasone, prednisolone, dexamethasone and betamethasone, but not budesonide or fluticasone. No association between the use of inhaled steroids for asthma treatment during pregnancy and alterations in neonatal size, placental weight, gestational age at delivery, or umbilical vein estriol concentrations was demonstrated compared to non-asthmatic women. In conclusion, the use of inhaled steroids for asthma treatment does not affect fetal growth, despite differences in placental metabolism by 11b-HSD2.

Nutrients

Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased ... more Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibil...

International Journal of Environmental Research and Public Health

Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the... more Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the offspring. We investigated the association between ambient air pollutants during pregnancy and cell populations in cord blood from babies born to mothers with asthma enrolled in the Breathing for Life Trial. For each patient (n = 91), daily mean ambient air pollutant levels were extracted during their entire pregnancy for sulfur dioxide (SO2), nitric oxide, nitrogen dioxide, carbon monoxide, ozone, particulate matter <10 μm (PM10) or <2.5 μm (PM2.5), humidity, and temperature. Ninety-one cord blood samples were collected, stained, and assessed using fluorescence-activated cell sorting (FACS). Principal Component (PC) analyses of both air pollutants and cell types with linear regression were employed to define associations. Considering risk factors and correlations between PCs, only one PC from air pollutants and two from cell types were statistically significant. PCs from air poll...

International Journal of Environmental Research and Public Health

Wildfires are increasing and cause health effects. The immediate and ongoing health impacts of pr... more Wildfires are increasing and cause health effects. The immediate and ongoing health impacts of prolonged wildfire smoke exposure in severe asthma are unknown. This longitudinal study examined the experiences and health impacts of prolonged wildfire (bushfire) smoke exposure in adults with severe asthma during the 2019/2020 Australian bushfire period. Participants from Eastern/Southern Australia who had previously enrolled in an asthma registry completed a questionnaire survey regarding symptoms, asthma attacks, quality of life and smoke exposure mitigation during the bushfires and in the months following exposure. Daily individualized exposure to bushfire particulate matter (PM2.5) was estimated by geolocation and validated modelling. Respondents (n = 240) had a median age of 63 years, 60% were female and 92% had severe asthma. They experienced prolonged intense PM2.5 exposure (mean PM2.5 32.5 μg/m3 on 55 bushfire days). Most (83%) of the participants experienced symptoms during the...

Paediatric asthma and allergy, 2021

Pediatric Pulmonology, 2020

Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing ... more Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age.

Nutrients, 2020

Low 25-hydroxyvitamin D (25(OH)D) levels are common in pregnancy and associated with adverse mate... more Low 25-hydroxyvitamin D (25(OH)D) levels are common in pregnancy and associated with adverse maternal/neonatal outcomes. In pregnant women with asthma, this study examined the association of lifestyle- and asthma-related factors on 25(OH)D levels and maternal/neonatal outcomes by vitamin D status. Serum 25(OH)D was measured at 16 and 35 weeks gestation in women with asthma (n = 103). Body mass index (BMI), gestational weight gain (GWG), smoking status, inhaled corticosteroid (ICS) use, asthma control, airway inflammation, and exacerbations, and maternal/neonatal outcomes were collected. Baseline and change (Δ) in 25(OH)D were modelled separately using backward stepwise regression, adjusted for season and ethnicity. Maternal/neonatal outcomes were compared between low (25(OH)D < 75 nmol/L at both time points) and high (≥75 nmol/L at one or both time points) vitamin D status. Fifty-six percent of women had low vitamin D status. Obesity was significantly associated with lower baseli...

The Journal of allergy and clinical immunology, Jan 7, 2018

The single-centre double-blind, randomised controlled Managing Asthma in Pregnancy (MAP) trial in... more The single-centre double-blind, randomised controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FeNO) in combination with asthma symptoms (FeNO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (ANZ Clinical Trials Registry, number 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FeNO group. However, the effect of FeNO-guided management on the development of asthma in the offspring is unknown. We sought to investigate the effect of FeNO-guided asthma management during pregnancy on asthma incidence in childhood. 179 mothers consented to participate in the Growing Into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FeNO-guided asthma management on childhood asthma incidence. 140 children (78%) were followed up at 4 to 6 years of a...

7.2 Paediatric Asthma and Allergy, 2016

Background: FeNO-guided asthma management resulted in 50% less exacerbations during pregnancy (Po... more Background: FeNO-guided asthma management resulted in 50% less exacerbations during pregnancy (Powell et al, Lancet 2011) and reduced the prevalence of recurrent bronchiolitis in the first year of life by 90% in their offspring (Mattes et al, Thorax 2014). Objectives: To assess asthma symptoms and diagnosis in a cohort of pre-schoolers born to mothers whose asthma treatment during pregnancy was guided either by symptoms (Clinical group), or FeNO and symptoms (FeNO group). Methods: We followed-up 109 of 146 children (75[PR1] %) seen at 12 months of age for preschool assessment. The ISAAC questionnaire, and interview ascertained symptoms were elicited, and lung function was measured using impulse oscillometry (IOS). Results: Mean age was 5.0 years (3.9-6.9) and 49% were male without difference between groups. Prevalence of wheeze ever (64% vs. 46%, p=0.05), frequent wheezing in the past 12 months (24% vs. 6%, p=0.01), doctor diagnosed asthma (42% vs. 21%, p=0.02) and ED visit for wheeze/asthma (20% vs. 2%, p=0.005) were all significantly lower in children from the FeNO group compared to the Clinical group. IOS was successful in 79 children (72%) and mean Z-score resistance at 5Hz (R5Hz) for children with wheeze ever was 0.74 (95% CI 0.41-1.08) compared to 0.18 (95% CI -0.08-0.43) without wheeze (p=0.01). Children with a doctor diagnosis of asthma had a mean R5Hz Z-score of 0.79 (95% CI 0.35-1.22) compared to 0.28 (95% CI 0.03-0.53, p=0.04) without asthma. No difference in R5Hz was observed between the Clinical and FeNO group. Conclusions: FeNO-guided management of asthma during pregnancy reduces respiratory symptoms and asthma diagnosis in the offspring at preschool age.

BMC pregnancy and childbirth, May 17, 2016

Asthma exacerbations are common during pregnancy and associated with an increased risk of adverse... more Asthma exacerbations are common during pregnancy and associated with an increased risk of adverse perinatal outcomes. Adjusting asthma treatment based on airway inflammation rather than symptoms reduces the exacerbation rate by 50 %. The Breathing for Life Trial (BLT) will test whether this approach also improves perinatal outcomes. BLT is a multicentre, parallel group, randomised controlled trial of asthma management guided by fractional exhaled nitric oxide (FENO, a marker of eosinophilic airway inflammation) compared to usual care, with prospective infant follow-up. Women with physician-diagnosed asthma, asthma symptoms and/or medication use in the previous 12 months, who are 12-22 weeks gestation, will be eligible for inclusion. Women randomised to the control group will have one clinical assessment of their asthma, including self-management education. Any treatment changes will be made by their general practitioner. Women randomised to the intervention group will have clinical ...

Placenta, 2004

Studying the effect of maternal asthma during pregnancy on placental function and fetal developme... more Studying the effect of maternal asthma during pregnancy on placental function and fetal development has highlighted that there is a strong interaction between mother, placenta and fetus and these interactions appear to be sex-specific. This work has found that the female fetus alters maternal asthma during pregnancy by upregulating maternal inflammatory pathways. When asthma-associated inflammatory pathways are not treated with inhaled steroids during pregnancy, the female fetus has reduced growth and adrenal function due to alterations in placental glucocorticoid metabolism. When the mother uses inhaled steroid for the treatment of her asthma during pregnancy, female fetal growth and placental function are comparable to the control population. The growth of the male fetus appears to be unaffected by asthma or inhaled steroid use. These findings indicate there may be different mechanisms regulating placental glucocorticoid and immune mechanisms depending on fetal sex in both asthmatic and non-asthmatic pregnancies.

Nature communications, Jan 23, 2015

Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the ... more Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to preve...

Thorax, 2010

Smoking and severe asthma exacerbations in pregnancy are risk factors for low birth weight babies... more Smoking and severe asthma exacerbations in pregnancy are risk factors for low birth weight babies. No studies have assessed the clinical implications of smoking on asthma exacerbations in pregnancy. Pregnant women with current asthma (n=80) were prospectively assessed at clinic visits (18, 30, 36 weeks), during exacerbations and with fortnightly phone calls. The asthma control questionnaire was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (self-managed). Medications, self-management skills, smoking history, fractional exhaled nitric oxide (FENO), exhaled carbon monoxide (ECO) and lung function were assessed. Pregnant women without asthma (controls, n=46) were assessed prospectively at clinic visits. Women with asthma were more likely to smoke (34% current smokers) than women without asthma (15% current smokers). In women with asthma, the median (IQR) exacerbation rate during pregnancy was 2.0 (1.0-3.0) in current smoker...

BMC Pulmonary Medicine, 2015

Background: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with s... more Background: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with surgical resection or active surveillance. The objective of this study was to comprehensively assess large and small airway function in children with CTM who underwent lobectomy in early life. We hypothesise that sensitive measures of lung function will demonstrate residual impairments in CTM compared to healthy children. Methods: Nitrogen lung clearance index (LCI), reactance and resistance (X5Hz and R5Hz), forced expiratory volume in 1 s and forced vital capacity (FEV1 and FVC) were prospectively measured in 10 children with CTM (mean age/SD: 7.6/1.3) who had undergone surgical resection in early life and in 17 healthy children (mean age/SD: 4.8/0.4). Total lung capacity (TLC) was also conducted in children older than 7 years of age with CTM (n = 8). Results: Mean LCI was 8.0 (95% CI 7.5 to 8.5) in the CTM group and 7.3 (95% CI 7.0 to 7.6) in healthy children (p = 0.016). Mean X5Hz was −0.44kPa/l/s (95% CI −0.58 to −0.31) in the CTM group and −0.31kPa/l/s (95% CI −0.35 to −0.27) in healthy children (p = 0.02). Mean Z score for X5Hz was −2.11 (95% CI −3.59 to −0.63) in the CTM group and −0.11 (95% CI −0.55 to 0.33) in healthy children (p = 0.0008). Mean FEV1 was 1.21 L (95% CI 0.97 to 1.45) in the CTM group and 1.02 L (95% CI 0.90 to 1.15) in healthy children (p = 0.22). Mean % predicted FEV1 was 83% (95% CI 74 to 92) in the CTM group and 97% (95% CI 87 to 107) in healthy children (p < 0.05). Mean % predicted TLC in CTM children was 121.3% (95% CI 88.45 to 154.1). Mean LCI was inversely correlated with height z-scores in the CTM group (rs = −0.88, p = 0.002) but not in healthy children (rs = 0.22, p = 0.4). Conclusions: Children with CTM have impaired lung function as demonstrated by the significant differences in LCI, reactance and FEV1 but not FVC, resistance and TLC. These findings may be of clinical relevance as ventilation inhomogeneities are closely correlated with somatic growth in this study.

Thorax, 2010

Background Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and ha... more Background Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. Methods Pregnant women with mild asthma (n¼52), moderateesevere asthma (n¼71) and without asthma (n¼51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. Results Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p¼0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r¼À0.286, p¼0.017) and, despite a decrease in placental GR mRNA (p¼0.003), placental GRa protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. Conclusions The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or posttranslational modifications.

Thorax, 2011

Background Acute respiratory tract infections are common ailments to all individuals and the huma... more Background Acute respiratory tract infections are common ailments to all individuals and the human rhinoviruses (HRVs) cause most of these infections. Pregnant women have increased susceptibility and disease severity to viral infections like influenza and HRVs, as do asthmatics. Successful pregnancy requires immunological modulation to permit fetal tolerance. Objectives To determine whether pregnant women have reduced innate antiviral interferon (IFN) responses to HRV infection compared with non-pregnant women. Methods An in vitro culture system was used, where peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 54 women, including 10 stable asthmatics who were pregnant and 10 who were not pregnant, 10 non-asthmatic women who were pregnant, 10 who were 6monthspostpartumand10whowerenotpregnant.Sampleswerealsocollectedfromfourexacerbatingpregnantasthmatics.PBMCswereculturedwithHRV43andHRV1B.TheantiviralproteinsIFNaandIFNlweremeasuredfromculturesupernatantsbyELISA.ResultsComparedwithhealthynon−pregnantwomen,pregnantwomenhadsignificantlyreducedinnateIFNresponsestoHRVinfection(p<0.02),persisting6 months post partum and 10 who were not pregnant. Samples were also collected from four exacerbating pregnant asthmatics. PBMCs were cultured with HRV43 and HRV1B. The antiviral proteins IFNa and IFNl were measured from culture supernatants by ELISA. Results Compared with healthy non-pregnant women, pregnant women had significantly reduced innate IFN responses to HRV infection (p<0.02), persisting 6monthspostpartumand10whowerenotpregnant.Sampleswerealsocollectedfromfourexacerbatingpregnantasthmatics.PBMCswereculturedwithHRV43andHRV1B.TheantiviralproteinsIFNaandIFNlweremeasuredfromculturesupernatantsbyELISA.ResultsComparedwithhealthynon−pregnantwomen,pregnantwomenhadsignificantlyreducedinnateIFNresponsestoHRVinfection(p<0.02),persisting6 months post partum (p#0.02). Pregnant asthmatics had significantly reduced IFNl responses compared with healthy non-pregnant women (p#0.034), while during current asthma exacerbations a decrease in IFNa (p#0.023) and IFNl (p¼0.007) was observed. Induction by a TLR7 agonist induced a similar pattern of decreased innate IFNs during pregnancy as observed when HRV was the inducing agent. Conclusions Reduced antiviral IFNs during pregnancy and asthma provide an important mechanism for increased susceptibility, morbidity and mortality in pregnant women with respiratory viral infection.

Respirology, 2006

was involved in study design, protocol development, conducting SELDI experiments, data analysis a... more was involved in study design, protocol development, conducting SELDI experiments, data analysis and manuscript preparation. Renee Johnson was involved in protocol development, conducting SELDI experiments, data review and manuscript review. Yung-Chih Wang was involved in protocol development, data review and manuscript review. Karen Akinsanya was involved in protocol development, data review and manuscript review. Peter Gibson was involved in subject characterization, data review and manuscript review. Roger Smith was involved in study design, protocol development, data review and manuscript review. Vicki Clifton was involved in study design, protocol development, data review and manuscript review.

Pediatric Allergy and Immunology, 2013

Background: There are few studies investigating the relationship between respiratory viral infect... more Background: There are few studies investigating the relationship between respiratory viral infection in pregnancy and asthma in the offspring, and none among mothers with asthma. Infants of mothers with asthma are more likely to wheeze and have a higher risk of developing asthma than infants of non-asthmatic mothers. Methods: A prospective cohort study of viral infection in pregnancy was conducted between 2007 and 2009, and a subgroup of infants of mothers with asthma was followed up at 6 and 12 months of age. During common colds, nasal and throat swabs were collected from mothers and respiratory viruses detected by polymerase chain reaction. Respiratory health of infants was assessed by parent-completed questionnaire. Results: Twelve-month-old infants whose mothers had confirmed viral infections in pregnancy (n = 26) reported more frequent wheeze (40% had 4-12 wheeze attacks compared with 0%), sleep disturbed by wheeze (1 night per week or more in 60% vs. 11%), beta agonist treatment for wheeze (27% vs. 0%), prolonged colds (2 wk or longer 31% vs. 0%), more eczema (40% vs. 6.3%), and parent-perceived asthma (32% vs. 0%), compared with infants whose mothers had common colds without laboratory-confirmed viral infection (n = 16). Conclusions: This study demonstrates a relationship between maternal respiratory viral infection in pregnancy and wheezing illness in infants of mothers with asthma. Viral infections are the most common cause of asthma exacerbations in pregnancy, and infants of asthmatic mothers are at increased risk of asthma themselves. Further research is needed to elucidate the mechanisms involved.

The Lancet, 2011

Background Asthma exacerbations during pregnancy are common and can be associated with substantia... more Background Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (F E NO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on F E NO and symptoms would reduce asthma exacerbations. Methods We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks' gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or F E NO concentrations (active intervention group) used to uptitrate (F E NO >29 ppb) or downtitrate (F E NO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting β2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when F E NO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482. Findings 111 women were randomly assigned to the F E NO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the F E NO group than in the control group (0•288 vs 0•615 exacerbations per pregnancy; incidence rate ratio 0•496, 95% CI 0•325-0•755; p=0•001). The number needed to treat was 6. In the F E NO group, quality of life was improved (score on short form 12 mental summary was 56•9 [95% CI 50•2-59•3] in F E NO group vs 54•2 [46•1-57•6] in control group; p=0•037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0•046). Interpretation Asthma exacerbations during pregnancy can be signifi cantly reduced with a validated F E NO-based treatment algorithm.