Dietary patterns during pregnancy and maternal and birth outcomes in women with type 1 diabetes: the Environmental Determinants of Islet Autoimmunity (ENDIA) study.

AIMS/HYPOTHESIS: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes. METHODS: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively. RESULTS: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (ß coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes. CONCLUSIONS/INTERPRETATION: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

Prenatal environmental risk factors for autism spectrum disorder and their potential mechanisms.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is globally increasing in prevalence. The rise of ASD can be partially attributed to diagnostic expansion and advocacy efforts; however, the interplay between genetic predisposition and modern environmental exposures is likely driving a true increase in incidence. A range of evidence indicates that prenatal exposures are critical. Infection during pregnancy, gestational diabetes, and maternal obesity are established risk factors for ASD. Emerging areas of research include the effects of maternal use of selective serotonin reuptake inhibitors, antibiotics, and exposure to toxicants during pregnancy on brain development and subsequent ASD. The underlying pathways of these risk factors remain uncertain, with varying levels of evidence implicating immune dysregulation, mitochondrial dysfunction, oxidative stress, gut microbiome alterations, and hormonal disruptions. This narrative review assesses the evidence of contributing prenatal environmental factors for ASD and associated mechanisms as potential targets for novel prevention strategies.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation.

Increasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks' gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother-child pairs were recruited by 28 weeks' gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks' gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks' gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the 'modern wholefoods' and 'processed' maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.

Environmental Determinants of Islet Autoimmunity (ENDIA) longitudinal prospective pregnancy to childhood cohort study of Australian children at risk of type 1 diabetes: parental demographics and birth information.

INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER: ACTRN12613000794707.

Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Physical activity and circulating inflammatory markers and cytokines during pregnancy: A population-based cohort study.

INTRODUCTION: Physical activity (PA) during pregnancy has numerous benefits, which may be mediated via effects on the immune system. However, supportive evidence is inconsistent and is mainly from studies in high-risk groups. We estimated the effect of PA during pregnancy on systemic inflammatory markers and cytokines in mothers recruited in the Barwon infant study. MATERIAL AND METHODS: The Barwon infant study is a prebirth cohort of 1064 mothers recruited in the Barwon Region of Victoria, Australia. Participants reported their previous week's PA at their 28-week antenatal appointment using the International PA Questionnaire. Women were grouped into low, moderate, and high PA categories based on daily duration and weekly frequency of walking, moderate- or vigorous-intensity PA. Women reporting moderate levels of PA, consistent with current recommendations, served as the comparison group. Markers of systemic inflammation, high-sensitivity C-reactive protein (hsCRP), glycoprotein acetyls (GlycA), and 17 cytokines were measured at 28 weeks gestation and log transformed as appropriate. Regression analyses adjusted for maternal smoking, gestational diabetes mellitus, prepregnancy BMI, and household size were performed. RESULTS: Compared to women in the moderate group (n = 371, 42%), women reporting low PA (n = 436, 50%) had 10.1% higher hsCRP (95% CI (3.7% to 16.6%), p < 0.01) while women in high PA (n = 76, 9%) had a 14% higher hsCRP (95% CI (3.1% to 24.8%), p = 0.01). Women in the high PA category had higher interleukin (IL)-4 (q = 0.03) and IL-9 (q = 0.03) levels compared to those in moderate category. Each vigorous MET minute/week was associated with lower GlycA (ß = -0.004, 95% CI (-0.044 to 0.035); p = 0.03). CONCLUSIONS: Low and high PA are each associated with higher hsCRP than moderate PA, suggesting that undertaking the recommended moderate PA during pregnancy decreases systemic inflammation. High PA affects T cell-associated cytokines during pregnancy. Evidence from our study suggests that PA can modulate the immune responses during pregnancy. Studies are now required to assess whether PA during pregnancy impacts maternal and infant clinical outcomes by modifying inflammatory responses.

Barriers and enablers to antenatal care attendance for women referred to social work services in a Victorian regional hospital: A qualitative descriptive study.

BACKGROUND: Women referred to social work services during pregnancy are more likely to experience social disadvantage than those who are not, resulting in reduced antenatal care attendance. Lack of antenatal care engagement leads to poor identification and management of concerns that can have immediate and long-term health consequences for women and their babies. Identifying the barriers and enablers to antenatal care attendance for women referred to social work services is important for designing models of care that promote effective engagement. AIMS: This study aimed to explore the barriers and enablers to antenatal care attendance by women referred to social work services from the perspectives of women, and clinicians who provide antenatal healthcare. METHODS: A qualitative descriptive study using constructivist grounded theory methods was undertaken. Ten women referred to social work services and 11 antenatal healthcare providers were purposively recruited for interviews from a regional maternity service in Victoria, Australia. FINDINGS: Continuity of care and healthcare providers partnering with women were central to effective engagement with antenatal care services. Three interrelated concepts were identified: 1) experiences of the hospital environment and access to care; 2) perceptions of care influence engagement, and 3) motivations for regularly attending services. CONCLUSIONS: Continuity of care is essential for supporting women referred to social work services to attend antenatal appointments. Women are better equipped to overcome other barriers to antenatal service attendance when they have a strong partnership with clinicians involved in their care.

Cord blood lipid correlation network profiles are associated with subsequent attention-deficit/hyperactivity disorder and autism spectrum disorder symptoms at 2 years: a prospective birth cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. METHODS: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. FINDINGS: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. INTERPRETATION: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. FUNDING: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.

Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming.

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 (ß = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (ß = 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.

Defining the lipid profiles of human milk, infant formula, and animal milk: implications for infant feeding.

Background: Breastfed infants have lower disease risk compared to formula-fed infants, however, the mechanisms behind this protection are unknown. Human milk has a complex lipidome which may have many critical roles in health and disease risk. However, human milk lipidomics is challenging, and research is still required to fully understand the lipidome and to interpret and translate findings. This study aimed to address key human milk lipidome knowledge gaps and discuss possible implications for early life health. Methods: Human milk samples from two birth cohorts, the Barwon Infant Study (n = 312) and University of Western Australia birth cohort (n = 342), were analysed using four liquid chromatography-mass spectrometry (LC-MS) methods (lipidome, triacylglycerol, total fatty acid, alkylglycerol). Bovine, goat, and soy-based infant formula, and bovine and goat milk were analysed for comparison. Composition was explored as concentrations, relative abundance, and infant lipid intake. Statistical analyses included principal component analysis, mixed effects modelling, and correlation, with false discovery rate correction, to explore human milk lipidome longitudinal trends and inter and intra-individual variation, differences between sample types, lipid intakes, and correlations between infant plasma and human milk lipids. Results: Lipidomics analysis identified 979 lipids. The human milk lipidome was distinct from that of infant formula and animal milk. Ether lipids were of particular interest, as they were significantly higher, in concentration and relative abundance, in human milk than in formula and animal milk, if present in the latter samples at all. Many ether lipids were highest in colostrum, and some changed significantly through lactation. Significant correlations were identified between human milk and infant circulating lipids (40% of which were ether lipids), and specific ether lipid intake by exclusively breastfed infants was 200-fold higher than that of an exclusively formula-fed infant. Conclusion: There are marked differences between the lipidomes of human milk, infant formula, and animal milk, with notable distinctions between ether lipids that are reflected in the infant plasma lipidome. These findings have potential implications for early life health, and may reveal why breast and formula-fed infants are not afforded the same protections. Comprehensive lipidomics studies with outcomes are required to understand the impacts on infant health and tailor translation.

Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression.

BACKGROUND: Pre-pregnancy obesity is an emerging risk factor for perinatal depression. However, the underlying mechanisms remain unclear. We investigated the association between pre-pregnancy body mass index (BMI) and perinatal depressive symptoms in a large population-based pre-birth cohort, the Barwon Infant Study. We also assessed whether the levels of circulating inflammatory markers during pregnancy mediated this relationship. METHODS: Depressive symptoms were assessed in 883 women using the Edinburgh Postnatal Depression Scale (EPDS) and psychological stress using the Perceived Stress Scale (PSS) at 28 weeks gestation and 4 weeks postpartum. Glycoprotein acetyls (GlycA), high-sensitivity C-reactive protein (hsCRP) and cytokines were assessed at 28 weeks gestation. We performed regression analyses, adjusted for potential confounders, and investigated mediation using nested counterfactual models. RESULTS: The estimated effect of pre-pregnancy obesity (BMI ≥ 30 kg/m2) on antenatal EPDS scores was 1.05 points per kg/m2 increase in BMI (95% CI: 0.20, 1.90; p = 0.02). GlycA, hsCRP, interleukin (IL) -1ra and IL-6 were higher in women with obesity, compared to healthy weight women, while eotaxin and IL-4 were lower. Higher GlycA was associated with higher EPDS and PSS scores and partially mediated the association between pre-pregnancy obesity and EPDS/PSS scores in unadjusted models, but this association attenuated upon adjustment for socioeconomic adversity. IL-6 and eotaxin were negatively associated with EPDS/PSS scores, however there was no evidence for mediation. CONCLUSIONS: Pre-pregnancy obesity increases the risk of antenatal depressive symptoms and is also associated with systemic inflammation during pregnancy. While discrete inflammatory markers are associated with antenatal depressive symptoms and perceived stress, their role in mediating the effects of pre-pregnancy obesity on antenatal depression requires further investigation.

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

The distribution of dietary choline intake and serum choline levels in Australian women during pregnancy and associated early life factors.

BACKGROUND: Maternal dietary choline has a central role in foetal brain development and may be associated with later cognitive function. However, many countries are reporting lower than recommended intake of choline during pregnancy. METHODS: Dietary choline was estimated using food frequency questionnaires in pregnant women participating in population-derived birth cohort, the Barwon Infant Study (BIS). Dietary choline is reported as the sum of all choline-containing moieties. Serum total choline-containing compounds (choline-c), phosphatidylcholine and sphingomyelin were measured using nuclear magnetic resonance metabolomics in the third trimester. The main form of analysis was multivariable linear regression. RESULTS: The mean daily dietary choline during pregnancy was 372 (standard deviation (SD) 104) mg/day. A total of 236 women (23%) had adequate choline intake (440 mg/day) based on the Australian and New Zealand guidelines, and 27 women (2.6%) took supplemental choline ([Formula: see text] 50 mg/dose) daily during pregnancy. The mean serum choline-c in pregnant women was 3.27 (SD 0.44) mmol/l. Ingested choline and serum choline-c were not correlated (R2) = - 0.005, p = 0.880. Maternal age, maternal weight gain in pregnancy, and a pregnancy with more than one infant were associated with higher serum choline-c, whereas gestational diabetes and environmental tobacco smoke during preconception and pregnancy were associated with lower serum choline-c. Nutrients or dietary patterns were not associated with variation in serum choline-c. CONCLUSION: In this cohort, approximately one-quarter of women met daily choline recommendations during pregnancy. Future studies are needed to understand the potential impact of low dietary choline intake during pregnancy on infant cognition and metabolic intermediaries.

Gut microbiota maturity mediates the protective effect of siblings on food allergy.

BACKGROUND: The mechanisms underlying the protective effect of older siblings on allergic disease remain unclear but may relate to the infant gut microbiota. OBJECTIVE: We sought to investigate whether having older siblings decreases the risk of IgE-mediated food allergy by accelerating the maturation of the infant gut microbiota. METHODS: In a birth cohort assembled using an unselected antenatal sampling frame (n = 1074), fecal samples were collected at 1 month, 6 months, and 1 year, and food allergy status at 1 year was determined by skin prick test and in-hospital food challenge. We used 16S rRNA gene amplicon sequencing to derive amplicon sequence variants. Among a random subcohort (n = 323), microbiota-by-age z scores at each time point were calculated using fecal amplicon sequence variants to represent the gut microbiota maturation over the first year of life. RESULTS: A greater number of siblings was associated with a higher microbiota-by-age z score at age 1 year (ß  = 0.15 per an additional sibling; 95% CI, 0.05-0.24; P = .003), which was in turn associated with decreased odds of food allergy (odds ratio, 0.45; 95% CI, 0.33-0.61; P < .001). Microbiota-by-age z scores mediated 63% of the protective effect of siblings. Analogous associations were not observed at younger ages. CONCLUSIONS: The protective effect of older siblings on the risk of developing IgE-mediated food allergy during infancy is substantially mediated by advanced maturation of the gut microbiota at age 1 year.

Understanding the pathways between prenatal and postnatal factors and overweight outcomes in early childhood: a pooled analysis of seven cohorts.

BACKGROUND/OBJECTIVES: Childhood overweight and obesity are influenced by a range of prenatal and postnatal factors. Few studies have explored the integrative pathways linking these factors and childhood overweight. This study aimed to elucidate the integrative pathways through which maternal pre-pregnancy body mass index (BMI), infant birth weight, breastfeeding duration, and rapid weight gain (RWG) during infancy are associated with overweight outcomes in early childhood from ages 3 to 5 years. SUBJECTS/METHODS: Pooled data from seven Australian and New Zealand cohorts were used (n = 3572). Generalized structural equation modelling was used to examine direct and indirect associations of maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration, and RWG during infancy with child overweight outcomes (BMI z-score and overweight status). RESULTS: Maternal pre-pregnancy BMI was directly associated with infant birth weight (ß 0.01, 95%CI 0.01, 0.02), breastfeeding duration ≥6 months (OR 0.92, 95%CI 0.90, 0.93), child BMI z-score (ß 0.03, 95%CI 0.03, 0.04) and overweight status (OR 1.07, 95%CI 1.06, 1.09) at ages 3-5 years. The association between maternal pre-pregnancy BMI and child overweight outcomes was partially mediated by infant birth weight, but not RWG. RWG in infancy exhibited the strongest direct association with child overweight outcomes (BMI z-score: ß 0.72, 95%CI 0.65, 0.79; overweight status: OR 4.49, 95%CI 3.61, 5.59). Infant birth weight was implicated in the indirect pathways of maternal pre-pregnancy BMI with RWG in infancy, breastfeeding duration, and child overweight outcomes. The associations between breastfeeding duration (≥6 months) and lower child overweight outcomes were fully mediated by RWG in infancy. CONCLUSIONS: Maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration and RWG in infancy act in concert to influence early childhood overweight. Future overweight prevention interventions should target RWG in infancy, which showed the strongest association with childhood overweight; and maternal pre-pregnancy BMI, which was implicated in several pathways leading to childhood overweight.

Age-dependent associations of human milk oligosaccharides with body size and composition up to 4 years of age.

BACKGROUND: Human milk oligosaccharides (HMOs) are major components of human milk that may mediate its beneficial effects on infant growth. OBJECTIVES: To investigate relationships between HMO concentrations in milk at 6 wk postpartum and anthropometry to 4 y of age in human milk-fed infants. METHODS: Milk samples were collected from 292 mothers at 6 wk (median 6.0 wk; range 3.3, 11.1] postpartum in a longitudinal, population-derived cohort. Of the infants, 171 were exclusively human milk-fed to 3 mo of age and 127 to 6 mo. Concentrations of 19 HMOs were quantified using high-performance liquid chromatography. Maternal secretor status (n = 221 secretors) was determined from 2'-fucosyllactose (2'FL) concentration. We calculated z-scores for child weight, length, head circumference, summed triceps and subscapular skinfold thicknesses, and weight-for-length at 6 wk, 6 mo, 12 mo, and 4 y. We investigated associations of secretor status and each HMO measure with change from birth for each z-score using linear mixed-effects models. RESULTS: Maternal secretor status was not associated with anthropometric z-scores up to 4 y of age. Several HMOs were associated with z-scores at 6 wk and 6 mo, predominantly within secretor status subgroups. Higher levels of 2'FL were associated with greater weight [ß = 0.91 increase in z-score per SD increase log-2'FL, 95% CI (0.17, 1.65)] and length [ß = 1.22, (0.25, 2.20)] in children born to secretor mothers, but not body composition measures. Higher lacto-N-tetraose was associated with greater weight [ß = 0.22, (0.02, 0.41)] and length (ß = 0.30, (0.07, 0.53)] among children born to nonsecretor mothers. Several HMOs were associated with anthropometric measures at 12 mo and 4 y of age. CONCLUSIONS: Milk HMO composition at 6 wk postpartum is associated with several anthropometry measures up to 6 mo of age in a potential secretor status-specific manner, with largely different HMOs associating with anthropometry from 12 mo to 4 y of age.

Modifiable factors associated with pediatric asthma readmissions: a multi-center linked cohort study.

OBJECTIVES: To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use. METHODS: We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively. RESULTS: Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47, p = 0.05. None of the hospital or home environmental factors appeared to be associated with hospital readmissions. CONCLUSIONS: Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

A Long-Term Evaluation of Facebook for Recruitment and Retention in the ENDIA Type 1 Diabetes Pregnancy-Birth Cohort Study.

BACKGROUND: The Environmental Determinants of Islet Autoimmunity (ENDIA) study is an Australia-wide pregnancy-birth cohort study following children who have a first-degree relative with type 1 diabetes (ACTRN1261300794707). A dedicated ENDIA Facebook page was established in 2013 with the aim of enhancing recruitment and supporting participant retention through dissemination of study information. To measure the impact of Facebook, we evaluated the sources of referral to the study, cohort demographics, and withdrawal rates. We also investigated whether engagement with Facebook content was associated with specific post themes. METHODS: Characteristics of Facebook versus conventional recruits were compared using linear, logistic, and multinomial logistic regression models. Logistic regression was used to determine the risk of study withdrawal. Data pertaining to 794 Facebook posts over 7.5 years were included in the analysis. RESULTS: Facebook was the third largest source of referral (300/1511; 19.9%). Facebook recruits were more frequently Australian-born (P < .001) enrolling postnatally (P = .01) and withdrew from the study at a significantly lower rate compared with conventional recruits (4.7% vs 12.3%; P < .001) after a median of follow-up of 3.3 years. Facebook content featuring stories and images of participants received the highest engagement even though <20% of the 2337 Facebook followers were enrolled in the study. CONCLUSIONS: Facebook was a valuable recruitment tool for ENDIA. Compared with conventional recruits, Facebook recruits were three times less likely to withdraw during long-term follow-up and had different sociodemographic characteristics. Facebook content featuring participants was the most engaging. These findings inform social media strategies for future cohort and type 1 diabetes studies. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN1261300794707.

Increased maternal non-oxidative energy metabolism mediates association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and offspring autism spectrum disorder symptoms in early life: A birth cohort study.

Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study (BIS), a population-based birth cohort of 1,074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord serum at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured in 596 and 674 children by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) prospective associations between higher prenatal di-(2-ethylhexyl) phthalate (DEHP) levels and upregulation of maternal non-oxidative energy metabolism pathways, and (ii) prospective associations between upregulation of these pathways and increased offspring ASD symptoms at 2 and 4 years of age. Counterfactual mediation analyses indicated that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. These results highlight the importance of the prenatal period and suggest that further investigation of maternal energy metabolism as a molecular mediator of the adverse impact of prenatal environmental exposures such as phthalates is warranted.