Paediatrics (RCH) - Research Publications
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ItemNo Preview AvailableMaternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming(SPRINGERNATURE, 2023-09)Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (matOSpreg) is linked to offspring mental disorders. Environmental factors contribute to matOSpreg. However, the role of matOSpreg in childhood EBP is unclear. We investigated the associations between (i) matOSpreg and offspring EBP; (ii) social and prenatal environmental factors and matOSpreg; and (iii) social and prenatal factors and childhood EBP and evaluated whether matOSpreg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2'-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (mat8-OHGua36w) was associated with greater offspring total EBP at age four (β = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (β = 0.62, 95% CI (-0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both mat8-OHGua36w and childhood EBP (P-range < 0.001-0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher mat8-OHGua36w (P-range = 0.01-0.05). Higher matOSpreg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by matOSpreg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.
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ItemMaternal gut microbiota during pregnancy and the composition of immune cells in infancy(FRONTIERS MEDIA SA, 2022-09-21)BACKGROUND: Preclinical studies have shown that maternal gut microbiota during pregnancy play a key role in prenatal immune development but the relevance of these findings to humans is unknown. The aim of this prebirth cohort study was to investigate the association between the maternal gut microbiota in pregnancy and the composition of the infant's cord and peripheral blood immune cells over the first year of life. METHODS: The Barwon Infant Study cohort (n=1074 infants) was recruited using an unselected sampling frame. Maternal fecal samples were collected at 36 weeks of pregnancy and flow cytometry was conducted on cord/peripheral blood collected at birth, 6 and 12 months of age. Among a randomly selected sub-cohort with available samples (n=293), maternal gut microbiota was characterized by sequencing the 16S rRNA V4 region. Operational taxonomic units (OTUs) were clustered based on their abundance. Associations between maternal fecal microbiota clusters and infant granulocyte, monocyte and lymphocyte subsets were explored using compositional data analysis. Partial least squares (PLS) and regression models were used to investigate the relationships/associations between environmental, maternal and infant factors, and OTU clusters. RESULTS: We identified six clusters of co-occurring OTUs. The first two components in the PLS regression explained 39% and 33% of the covariance between the maternal prenatal OTU clusters and immune cell populations in offspring at birth. A cluster in which Dialister, Escherichia, and Ruminococcus were predominant was associated with a lower proportion of granulocytes (p=0.002), and higher proportions of both central naïve CD4+ T cells (CD4+/CD45RA+/CD31-) (p<0.001) and naïve regulatory T cells (Treg) (CD4+/CD45RA+/FoxP3low) (p=0.02) in cord blood. The association with central naïve CD4+ T cells persisted to 12 months of age. CONCLUSION: This birth cohort study provides evidence consistent with past preclinical models that the maternal gut microbiota during pregnancy plays a role in shaping the composition of innate and adaptive elements of the infant's immune system following birth.
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ItemEarly life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study(eLIFE SCIENCES PUBL LTD, 2022-05-10)BACKGROUND: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. METHODS: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. RESULTS: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. CONCLUSIONS: Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk. FUNDING: The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women's Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).
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ItemDNA Methylation Profiles of Purified Cell Types in Bronchoalveolar Lavage: Applications for Mixed Cell Paediatric Pulmonary Studies(FRONTIERS MEDIA SA, 2021-12-22)In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type deconvolution, which relies on knowledge of the DNA methylation profiles of purified constituent cell types. These are then used to estimate the cell type proportions of each sample, which can then be incorporated to adjust the association analysis. Bronchoalveolar lavage is commonly used to sample the lung in clinical practice and contains a mixture of different cell types that can vary in proportion across samples, affecting the overall methylation profile. A current barrier to the use of bronchoalveolar lavage in DNA methylation-based research is the lack of reference DNA methylation profiles for each of the constituent cell types, thus making reference-based cell composition estimation difficult. Herein, we use bronchoalveolar lavage samples collected from children with cystic fibrosis to define DNA methylation profiles for the four most common and clinically relevant cell types: alveolar macrophages, granulocytes, lymphocytes and alveolar epithelial cells. We then demonstrate the use of these methylation profiles in conjunction with an established reference-based methylation deconvolution method to estimate the cell type composition of two different tissue types; a publicly available dataset derived from artificial blood-based cell mixtures and further bronchoalveolar lavage samples. The reference DNA methylation profiles developed in this work can be used for future reference-based cell type composition estimation of bronchoalveolar lavage. This will facilitate the use of this tissue in studies examining the role of DNA methylation in lung health and disease.
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ItemOntogeny of circulating lipid metabolism in pregnancy and early childhood - a longitudinal population study(eLIFE SCIENCES PUBL LTD, 2022-03-02)BACKGROUND: There is mounting evidence that in utero and early life exposures may predispose an individual to metabolic disorders in later life; and dysregulation of lipid metabolism is critical in such outcomes. However, there is limited knowledge about lipid metabolism and factors causing lipid dysregulation in early life that could result in adverse health outcomes in later life. We studied the effect of antenatal factors such as gestational age, birth weight, and mode of birth on lipid metabolism at birth; changes in the circulating lipidome in the first 4 years of life and the effect of breastfeeding in the first year of life. From this study, we aim to generate a framework for deeper understanding into factors effecting lipid metabolism in early life, to provide early interventions for those at risk of developing metabolic disorders including cardiovascular diseases. METHODS: We performed comprehensive lipid profiling of 1074 mother-child dyads in the Barwon Infant Study (BIS), a population-based pre-birth cohort and measured 776 distinct lipid features across 39 lipid classes using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We measured lipids in 1032 maternal serum samples at 28 weeks' gestation, 893 cord serum samples at birth, 793, 735, and 511 plasma samples at 6, 12 months, and 4 years, respectively. Cord serum was enriched with long chain poly-unsaturated fatty acids (LC-PUFAs), and corresponding cholesteryl esters relative to the maternal serum. We performed regression analyses to investigate the associations of cord serum lipid species with antenatal factors: gestational age, birth weight, mode of birth and duration of labour. RESULTS: The lipidome differed between mother and newborn and changed markedly with increasing child's age. Alkenylphosphatidylethanolamine species containing LC-PUFAs increased with child's age, whereas the corresponding lysophospholipids and triglycerides decreased. Majority of the cord serum lipids were strongly associated with gestational age and birth weight, with most lipids showing opposing associations. Each mode of birth showed an independent association with cord serum lipids. Breastfeeding had a significant impact on the plasma lipidome in the first year of life, with up to 17-fold increases in a few species of alkyldiaclylglycerols at 6 months of age. CONCLUSIONS: This study sheds light on lipid metabolism in infancy and early childhood and provide a framework to define the relationship between lipid metabolism and health outcomes in early childhood. FUNDING: This work was supported by the A*STAR-NHMRC joint call funding (1711624031).
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ItemMapping Pulmonary and Systemic Inflammation in Preschool Aged Children With Cystic Fibrosis(FRONTIERS MEDIA SA, 2021-10-15)The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b+ granulocytes and increased levels of MIP-1α, MIG, MCP-1, IL-8, and IL-6 in BAL relative to healthy control children. Proportions of systemic neutrophils positively correlated with age in children with CF, whilst systemic CD4 T cells and B cells were inversely associated with age. Inflammatory cells in the BAL from both CF and healthy children expressed higher levels of activation and migration markers relative to their systemic counterparts. This work highlights the utility of multiplex immune profiling and advanced analytical pipelines to understand mechanisms of lung disease in childhood.
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ItemFolate levels in pregnancy and offspring food allergy and eczema(WILEY, 2020-01)BACKGROUND: High folate status in pregnancy has been implicated in the increased prevalence of allergic disease, but there are no published data relating directly measured folate status in pregnancy to challenge-proven food allergy among offspring. The study aim was to examine the association between red blood cell (RBC) folate status in trimester three of pregnancy and allergic disease among offspring. METHODS: Red blood cell folate levels were measured at 28-32 weeks' gestation in a prospective birth cohort (n = 1074). Food allergy outcomes were assessed in 1-year-old infants by skin prick testing and subsequent food challenge. Eczema was assessed by questionnaire and clinical review. High trimester three RBC folate was defined as greater than (>) 1360 nmol/L. Binomial regression was used to examine associations between trimester three RBC folate and allergic outcomes, adjusting for potential confounders. RESULTS: Red blood cell folate levels were measured in 88% (894/1064) of pregnant women. The mean concentration was 1695.6 nmol/L (standard deviation 415.4) with 82% (731/894) >1360 nmol/L. There was no evidence of either linear or non-linear relationships between trimester three RBC folate and allergic outcomes, nor evidence of associations between high RBC folate and food allergy (adjusted risk ratio (aRR) 2.89, 95% CI 0.90-9.35), food sensitization (aRR 1.72, 95% CI 0.85-3.49), or eczema (aRR 0.97, 95% CI 0.67-1.38). CONCLUSION: The majority of pregnant women in this study had high RBC folate levels. There was no evidence of associations between trimester three RBC folate and food allergy, food sensitization, or eczema among the offspring, although larger studies are required.
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ItemMaternal prenatal gut microbiota composition predicts child behaviour(ELSEVIER, 2021-06)BACKGROUND: Murine studies demonstrate that maternal prenatal gut microbiota influences brain development and behaviour of offspring. No human study has related maternal gut microbiota to behavioural outcomes during early life. This study aimed to evaluate relationships between the prenatal faecal microbiota, prenatal diet and childhood behaviour. METHODS: A sub-cohort of 213 mothers and 215 children were selected from a longitudinal pre-birth cohort. Maternal prenatal exposure measures collected during the third trimester included the faecal microbiota (generated using 16S rRNA amplicon sequencing), and dietary intake. The behavioural outcome used the Childhood Behaviour Checklist at age two. Models were adjusted for prenatal diet, smoking, perceived stress, maternal age and sample batch. FINDINGS: We found evidence that the alpha diversity of the maternal faecal microbiota during the third trimester of pregnancy predicts child internalising behaviour at two years of age (-2·74, (-4·71, -0·78), p = 0·01 (Wald test), R2=0·07). Taxa from butyrate-producing families, Lachnospiraceae and Ruminococcaceae, were more abundant in mothers of children with normative behaviour. A healthy prenatal diet indirectly related to decreased child internalising behaviours via higher alpha diversity of maternal faecal microbiota. INTERPRETATION: These findings support animal studies showing that the composition of maternal prenatal gut microbiota is related to offspring brain development and behaviour. Our findings highlight the need to evaluate potential impacts of the prenatal gut microbiota on early life brain development. FUNDING: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980), Murdoch Children's Research Institute, Barwon Health and Deakin University.
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ItemDeserters on the atopic march: Risk factors, immune profile and clinical outcomes of food sensitized-tolerant infants(WILEY, 2020-06)BACKGROUND: A few studies have investigated the antecedents and outcomes of infants who demonstrate IgE sensitization to foods that they clinically tolerate. Improved understanding of this sensitized-tolerant phenotype may inform strategies for the prevention of food allergy. METHODS: In an Australian birth cohort (n = 1074), assembled using an unselected antenatal sampling frame, participants were categorized as nonsensitized (NS), sensitizedtolerant (ST), or food allergic (FA) based on skin prick testing and food challenge at 12 months of age. Environmental exposures were recorded throughout. Cord blood regulatory T-cell populations were measured at birth. Subsequent childhood allergic disease was assessed by parent report, clinical examination, and repeat skin prick testing. RESULTS: The covariates of interest varied between NS (n = 698), ST (n = 27), and FA (n = 61) groups as follows, suggesting that across these measures, the ST group was more similar to the NS than the FA group: family history of eczema NS 44.6%, ST. 44.6%, FA 65.6%; pet ownership at 12 months: NS 71.5%, ST 81.5%, FA 45.8%; eczema during the first 12 months: NS 19%, ST 32%, FA 64%; and aeroallergen sensitization at 4 years: NS 19.1%, ST 28.6%, FA 44.4%. At birth, a higher proportion of activated regulatory T cells was associated with ST (OR = 2.89, 95% CI 1.03-8.16, P = .045). CONCLUSION: Food-sensitized-tolerance in infancy appears to be associated with a similar pattern of exposures, immunity, and outcomes to nonsensitized infants. In addition, we found some evidence that an elevated proportion of activated regulatory T cells at birth was specific to the sensitized-tolerant infants, which may be relevant to suppression of clinical disease.
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ItemGut microbiota composition during infancy and subsequent behavioural outcomes(ELSEVIER, 2020-02)BACKGROUND: Despite intense interest in the relationship between gut microbiota and brain development, longitudinal data from human studies are lacking. This study aimed to investigate the relationship between the composition of gut microbiota during infancy and subsequent behavioural outcomes. METHODS: A subcohort of 201 children with behavioural outcome measures was identified within a longitudinal, Australian birth-cohort study. The faecal microbiota were analysed at 1, 6, and 12 months of age. Behavioural outcomes were measured at 2 years of age. FINDINGS: In an unselected birth cohort, we found a clear association between decreased normalised abundance of Prevotella in faecal samples collected at 12 months of age and increased behavioural problems at 2 years, in particular Internalizing Problem scores. This association appeared independent of multiple potentially confounding variables, including maternal mental health. Recent exposure to antibiotics was the best predictor of decreased Prevotella. INTERPRETATION: Our findings demonstrate a strong association between the composition of the gut microbiota in infancy and subsequent behavioural outcomes; and support the importance of responsible use of antibiotics during early life. FUNDING: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980, 1129813), The Murdoch Children's Research Institute, Barwon Health, Deakin University, Perpetual Trustees, and The Shepherd Foundation. The funders had no involvement in the data collection, analysis or interpretation, trial design, recruitment or any other aspect pertinent to the study.