A machine-learning exploration of the exposome from preconception in early childhood atopic eczema, rhinitis and wheeze development.

BACKGROUND: Most previous research on the environmental epidemiology of childhood atopic eczema, rhinitis and wheeze is limited in the scope of risk factors studied. Our study adopted a machine learning approach to explore the role of the exposome starting already in the preconception phase. METHODS: We performed a combined analysis of two multi-ethnic Asian birth cohorts, the Growing Up in Singapore Towards healthy Outcomes (GUSTO) and the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohorts. Interviewer-administered questionnaires were used to collect information on demography, lifestyle and childhood atopic eczema, rhinitis and wheeze development. Data training was performed using XGBoost, genetic algorithm and logistic regression models, and the top variables with the highest importance were identified. Additive explanation values were identified and inputted into a final multiple logistic regression model. Generalised structural equation modelling with maternal and child blood micronutrients, metabolites and cytokines was performed to explain possible mechanisms. RESULTS: The final study population included 1151 mother-child pairs. Our findings suggest that these childhood diseases are likely programmed in utero by the preconception and pregnancy exposomes through inflammatory pathways. We identified preconception alcohol consumption and maternal depressive symptoms during pregnancy as key modifiable maternal environmental exposures that increased eczema and rhinitis risk. Our mechanistic model suggested that higher maternal blood neopterin and child blood dimethylglycine protected against early childhood wheeze. After birth, early infection was a key driver of atopic eczema and rhinitis development. CONCLUSION: Preconception and antenatal exposomes can programme atopic eczema, rhinitis and wheeze development in utero. Reducing maternal alcohol consumption during preconception and supporting maternal mental health during pregnancy may prevent atopic eczema and rhinitis by promoting an optimal antenatal environment. Our findings suggest a need to include preconception environmental exposures in future research to counter the earliest precursors of disease development in children.

Clinical predictors of wheeze trajectories and associations with allergy in Asian children.

BACKGROUND: Childhood wheezing is a highly heterogeneous condition with an incomplete understanding of the characteristics of wheeze trajectories, particularly for persistent wheeze. OBJECTIVE: To characterize predictors and allergic comorbidities of distinct wheeze trajectories in a multiethnic Asian cohort. METHODS: A total of 974 mother-child pairs from the prospective Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort were included in this study. Wheeze and allergic comorbidities in the first 8 years of life were assessed using the modified International Study of Asthma and Allergies in Childhood questionnaires and skin prick tests. Group-based trajectory modeling was used to derive wheeze trajectories and regression was used to assess associations with predictive risk factors and allergic comorbidities. RESULTS: There were 4 wheeze trajectories derived, including the following: (1) early-onset with rapid remission from age 3 years (4.5%); (2) late-onset peaking at age 3 years and rapidly remitting from 4 years (8.1%); (3) persistent with a steady increase to age 5 years and high wheeze occurrence until 8 years (4.0%); and (4) no or low wheeze (83.4%). Early-onset wheezing was associated with respiratory infections during infancy and linked to subsequent nonallergic rhinitis throughout childhood. Late-onset and persistent wheeze shared similar origins characterized by parent-reported viral infections in later childhood. However, persistent wheezing was generally more strongly associated with a family history of allergy, parent-reported viral infections in later childhood, and allergic comorbidities as compared with late-onset wheezing. CONCLUSION: The timing of viral infection occurrence may determine the type of wheeze trajectory development in children. Children with a family history of allergy and viral infections in early life may be predisposed to persistent wheeze development and the associated comorbidities of early allergic sensitization and eczema.

Metabolic health status and fecundability in a Singapore preconception cohort study.

BACKGROUND: Obesity compromises metabolic health and female fertility, yet not all obese women are similar in metabolic status. The extent to which fecundability is influenced by the metabolic health status of women who are overweight or obese before conception is unknown. OBJECTIVE: This study aimed to: (1) determine the metabolic health status, and (2) examine the association between metabolic health status and fecundability of overweight and obese women trying to conceive in the Singapore PREconception Study of long-Term maternal and child Outcomes cohort study. STUDY DESIGN: We conducted a prospective preconception cohort study of Asian women (Chinese, Malay, and Indian) aged 18 to 45 years trying to conceive who were treated from 2015 to 2017 in KK Women's and Children's Hospital in Singapore (n=834). We defined women to have metabolically unhealthy status if they: (1) met 3 or more modified Joint Interim Statement metabolic syndrome criteria; or (2) had homeostasis model assessment-insulin resistance index ≥2.5. Body mass index was categorized as normal (18.5-22.9 kg/m2), overweight (23-27.4 kg/m2), or obese (≥27.5 kg/m2) on the basis of cutoff points for Asian populations. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrolment. Discrete-time proportional hazards models were used to estimate fecundability odds ratios, with adjustment for confounders and accounting for left truncation and right censoring. RESULTS: Of 232 overweight women, 28 (12.1%) and 25 (10.8%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Of 175 obese women, 54 (30.9%) and 93 (53.1%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Compared with metabolically healthy normal-weight women, lower fecundability was observed in metabolically unhealthy overweight women on the basis of metabolic syndrome criteria (fecundability odds ratios, 0.38 [95% confidence interval, 0.15-0.92]) and homeostasis model assessment-insulin resistance (fecundability odds ratios, 0.68 [95% confidence interval, 0.33-1.39]), with metabolic syndrome criteria showing a stronger association. Metabolically unhealthy obese women showed lower fecundability than the healthy normal-weight reference group by both metabolic syndrome (fecundability odds ratios, 0.35; 95% confidence interval, 0.17-0.72) and homeostasis model assessment-insulin resistance criteria (fecundability odds ratios, 0.43; 95% confidence interval, 0.26-0.71). Reduced fecundability was not observed in overweight or obese women who showed healthy metabolic profiles by either definition. CONCLUSION: Overweight or obesity was not synonymous with having metabolic syndrome or insulin resistance. In our preconception cohort, metabolically unhealthy overweight and obese women showed reduced fecundability, unlike their counterparts who were metabolically healthy. These findings suggest that metabolic health status, rather than simply being overweight and obese per se, plays an important role in fecundability.

Dietary patterns of 5-year-old children and their correlates: findings from a multi-ethnic Asian cohort.

There is limited data on the dietary patterns of 5-year-old children in Asia. The study examined childhood dietary patterns and their maternal and child correlates in a multi-ethnic Asian cohort. Based on caregiver-reported 1-month quantitative FFQ of 777 children from the Growing Up in Singapore Towards healthy Outcomes cohort, cluster analysis identified two mutually exclusive clusters. Children in the 'Unhealthy' cluster (43·9 %) consumed more fries, processed meat, biscuits and ice cream, and less fish, fruits and vegetables compared with those in the 'Healthy' cluster (56·1 %). Children with mothers of lower educational attainment had twice the odds of being assigned to the 'Unhealthy' cluster (adjusted OR (95 % CI) = 2·19 (95 % CI 1·49-3·24)). Children of Malay and Indian ethnicities had higher odds of being assigned to the 'Unhealthy' cluster (adjusted OR = 25·46 (95 % CI 15·40, 42·10) and 4·03 (95 % CI 2·68-6·06), respectively), relative to Chinese ethnicity. In conclusion, this study identified two dietary patterns in children, labelled as the 'Unhealthy' and 'Healthy' clusters. Mothers' educational attainment and ethnicity were two correlates that were associated with the children's assignments to the clusters. These findings can assist in informing health promotion programmes targeted at Asian children.

Tracking of dietary patterns between pregnancy and 6 years post-pregnancy in a multiethnic Asian cohort: the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study.

PURPOSE: Few studies have described adherence to dietary patterns over time in women of childbearing age. This study aims to describe, examine the stability and changes in dietary patterns between pregnancy and 6 years post-pregnancy and the sociodemographic and lifestyle factors influencing the adherence over time. METHODS: During pregnancy and at 6 years post-pregnancy, 24-h recalls and food frequency questionnaires were collected, respectively, from 709 women. Data on sociodemographic and lifestyle factors were collected via questionnaires. Dietary patterns were identified using principal component analysis and stability assessed using Pearson's correlation coefficients (r) and Cohen's weighted kappa (κ). Associations with sociodemographic characteristics were assessed by multiple logistic regression. RESULTS: The 'Fruits, Vegetables and Legumes' (FVL) and 'Seafood, Noodle, Soup' (SNS) patterns were identified at both time points, with low correlation for the dietary pattern z scores (r 0.2 and 0.3, respectively) and modest agreement in tertile assignment, suggesting poor stability. An 'unhealthy' pattern was only observed at 6 years post-pregnancy. Women who showed increased adherence to FVL pattern had higher educational attainment and exhibited healthy lifestyle behaviours. Women who had gestational diabetes during pregnancy were less likely to decrease adherence to FVL pattern over time. Women who adhered more closely to the 'unhealthy' pattern at 6 years post-pregnancy tended to be younger, of Malay ethnicity, had lower socioeconomic status, were less physically active and had additional pregnancies. CONCLUSIONS: Dietary habits of women became less healthy during the transition from pregnancy to 6 years post-pregnancy. However, results should be interpreted with caution due to the different dietary assessment tools used at the two time points.

Household environmental microbiota influences early-life eczema development.

Exposure to a diverse microbial environment during pregnancy and early postnatal period is important in determining predisposition towards allergy. However, the effect of environmental microbiota exposure during preconception, pregnancy and postnatal life on development of allergy in the child has not been investigated so far. In the S-PRESTO (Singapore PREconception Study of long Term maternal and child Outcomes) cohort, we collected house dust during all three critical window periods and analysed microbial composition using 16S rRNA gene sequencing. At 6 and 18 months, the child was assessed for eczema by clinicians. In the eczema group, household environmental microbiota was characterized by presence of human-associated bacteria Actinomyces, Anaerococcus, Finegoldia, Micrococcus, Prevotella and Propionibacterium at all time points, suggesting their possible contributions to regulating host immunity and increasing the susceptibility to eczema. In the home environment of the control group, putative protective effect of an environmental microbe Planomicrobium (Planococcaceae family) was observed to be significantly higher than that in the eczema group. Network correlation analysis demonstrated inverse relationships between beneficial Planomicrobium and human-associated bacteria (Actinomyces, Anaerococcus, Finegoldia, Micrococcus, Prevotella and Propionibacterium). Exposure to natural environmental microbiota may be beneficial to modulate shed human-associated microbiota in an indoor environment.

The longitudinal association between early-life screen viewing and abdominal adiposity-findings from a multiethnic birth cohort study.

IMPORTANCE: Screen viewing in adults has been associated with greater abdominal adiposity, with the magnitude of associations varying by sex and ethnicity, but the evidence is lacking at younger ages. We aimed to investigate sex- and ethnic-specific associations of screen-viewing time at ages 2 and 3 years with abdominal adiposity measured by magnetic resonance imaging at age 4.5 years. METHODS: The Growing Up in Singapore Towards healthy Outcomes is an ongoing prospective mother-offspring cohort study. Parents/caregivers reported the time their child spent viewing television, handheld devices, and computer screens at ages 2 and 3 years. Superficial and deep subcutaneous and visceral abdominal adipose tissue volumes were quantified from magnetic resonance images acquired at age 4.5 years. Associations between screen-viewing time and abdominal adipose tissue volumes were examined by multivariable linear regression adjusting for confounding factors. RESULTS: In the overall sample (n = 307), greater total screen-viewing time and handheld device times were associated with higher superficial and deep subcutaneous adipose tissue volumes, but not with visceral adipose tissue volumes. Interactions with child sex were found, with significant associations with superficial and deep subcutaneous and visceral adipose tissue volumes in boys, but not in girls. Among boys, the increases in mean (95% CI) superficial and deep subcutaneous and visceral adipose tissue volumes were 24.3 (9.9, 38.7), 17.6 (7.4, 27.8), and 7.8 (2.1, 13.6) mL per hour increase in daily total screen-viewing time, respectively. Ethnicity-specific analyses showed associations of total screen-viewing time with abdominal adiposity only in Malay children. Television viewing time was not associated with abdominal adiposity. CONCLUSION: Greater total screen-viewing time (and in particular, handheld device viewing time) was associated with higher abdominal adiposity in boys and Malay children. Additional studies are necessary to confirm these associations and to examine screen-viewing interventions for preventing excessive abdominal adiposity and its adverse cardiometabolic consequences.

Atopic dermatitis trajectories to age 8 years in the GUSTO cohort.

BACKGROUND: The heterogeneity of childhood atopic dermatitis (AD) underscores the need to understand latent phenotypes that may inform risk stratification and disease prognostication. OBJECTIVE: To identify AD trajectories across the first 8 years of life and investigate risk factors associated with each trajectory and their relationships with other comorbidities. METHODS: Data were collected prospectively from 1152 mother-offspring dyads in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort from ages 3 months to 8 years. AD was defined based on parent-reported doctor's diagnosis. An unsupervised machine learning technique was used to determine AD trajectories. RESULTS: Three AD trajectories were identified as follows: early-onset transient (6.3%), late-onset persistent (6.3%) and early-onset persistent (2.1%), alongside a no AD/reference group (85.2%). Early-onset transient AD was positively associated with male gender, family history of atopy, house dust mite sensitization and some measures of wheezing. Early-onset persistent AD was associated with antenatal/intrapartum antibiotic use, food sensitization and some measures of wheezing. Late-onset persistent AD was associated with a family history of atopy, some measures of house dust mite sensitization and some measures of allergic rhinitis and wheezing. CONCLUSION AND CLINICAL RELEVANCE: Three AD trajectories were identified in this birth cohort, with different risk factors and prognostic implications. Further work is needed to understand the molecular and immunological origins of these phenotypes.

Trajectories of early-onset rhinitis in the Singapore GUSTO mother-offspring cohort.

BACKGROUND: The natural history of childhood rhinitis is not well described. OBJECTIVE: This study aimed to identify different rhinitis trajectories in early childhood and their predictors and allergic associations. METHODS: Rhinitis symptoms were ascertained prospectively from birth until 6 years using standardized questionnaires in 772 participants. Rhinitis was defined as one or more episodes of sneezing, runny and/or blocked nose >2 weeks duration. Latent trajectories were identified using group-based modelling, and their predictive risk factors and allergic associations were examined. RESULTS: Three rhinitis trajectory groups were identified: 7.6% (n = 59) were termed early transient rhinitis, 8.6% (n = 66) late transient rhinitis, and 6.6% (n = 51) persistent rhinitis. The remaining 77.2% (n = 596) were classified as non-rhinitis/reference group. Early transient rhinitis subjects were more likely of Indian ethnicity, had siblings, reported childcare attendance, early wheezing and eczema in the first 3 years of life. Late transient rhinitis was associated with antenatal exposure to smoking, higher maternal education levels, and wheezing at age 36-72 months. Persistent rhinitis was associated with male gender, paternal and maternal history of atopy, eczema, and house dust mite sensitization. CONCLUSIONS & CLINICAL RELEVANCE: Risk factors for early transient rhinitis involve a combination of genetic and early environmental exposures, whereas late transient rhinitis may relate to maternal factors and early respiratory infections independent of atopy. In contrast, persistent rhinitis is strongly associated with atopic risk and likely represents the typical trajectory associated with allergic disorders. Allergic rhinitis symptoms may commence as early as the first year of life and may inform development of early interventive strategies.

Children of Asian ethnicity in Australia have higher risk of food allergy and early-onset eczema than those in Singapore.

BACKGROUND: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early-life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. METHODS: We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE-mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14-18 months (HealthNuts). Eczema was defined as parent-reported doctor diagnosis. RESULTS: Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P<0.001). Egg introduction was more often delayed (>10 months) in Singapore (63.5%) than Australia (16.3%; P<0.001). Prevalence of early-onset eczema (<6 months) was lower in Singapore (8.4%) than Australia (30.5%) (P<0.001). Children with early-onset eczema were more likely to have food allergy than those without eczema in Australia [aOR 5.11 (2.34-11.14); P<0.001] and Singapore [aOR4.00 (0.62-25.8); P = 0.145]. CONCLUSIONS: Among Asian children, prevalence of early-onset eczema and food allergy was higher in Australia than Singapore. Further research with larger sample sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.

24-hour movement behaviour profiles and their transition in children aged 5.5 and 8 years - findings from a prospective cohort study.

BACKGROUND: Time spent in movement behaviours, including physical activity (PA), sedentary behaviour (SB) and sleep, across the 24-h day may have distinct health consequences. We aimed to describe 24-h movement behaviour (24 h-MB) profiles in children and how profile membership changed from age 5.5 to 8 years. METHODS: Children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort were asked to wear an accelerometer (ActiGraph-GT3X+) on their wrist for seven consecutive days at ages 5.5 and 8 years to measure 24 h-MB patterns. Time spent in night sleep, inactivity (proxy for SB), light PA, moderate PA (MPA), and vigorous PA (VPA) per day were calculated using the R-package GGIR 2.0. Using latent profile analyses (n = 442) we identified 24 h-MB profiles, which were given animal names to convey key characteristics. Latent transition analyses were used to describe the profile membership transition from ages 5.5 to 8 years. Associations with sex and ethnicity were examined. RESULTS: We identified four profiles, "Rabbits" (very high-MPA/VPA, low-inactivity and average-night-sleep), "Chimpanzees" (high-MPA, low-inactivity and average-night-sleep), "Pandas" (low-PA, high-inactivity and high-night-sleep) and "Owls" (low-PA, high-inactivity and low-night-sleep), among children at both time points. At ages 5.5 and 8 years, the majority of children were classified into profiles of "Chimpanzees" (51 and 39%, respectively) and "Pandas" (24 and 37%). Half of the sample (49%), particularly "Rabbits", remained in the same profile at ages 5.5 and 8 years: among children who changed profile the predominant transitions occurred from "Chimpanzees" (27%) and "Owls" (56%) profiles to "Pandas". Sex, but not ethnicity, was associated with profile membership: compared to girls, boys were more likely to be in the "Rabbits" profile (adjusted OR [95% CI]: 3.6 [1.4, 9.7] and 4.5 [1.8, 10.9] at ages 5.5 and 8 years, respectively) and less likely to be in the "Pandas" profile (0.5 [0.3, 0.9] and 0.4 [0.2, 0.6]) at both ages. CONCLUSIONS: With increasing age about half the children stayed in the same of four 24 h-MB profiles, while the predominant transition for the remaining children was towards lower PA, higher inactivity and longer sleep duration. These findings can aid development and implementation of public health strategies to promote better health. STUDY REGISTRATION: This study was registered on 4th August 2010 and is available online at ClinicalTrials.gov: NCT01174875 .

Cohort profile: Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO).

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18-45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases.

Fecundability in reproductive aged women at risk of sexual dysfunction and associated risk factors: a prospective preconception cohort study.

BACKGROUND: Female sexual dysfunction (FSD) is a prevalent problem, affecting up to 41% of reproductive aged women worldwide. However, the association between female sexual function (FSF) and fecundability in women attempting to conceive remains unclear. We aimed 1) to examine the association between FSF in reproductive-aged preconception Asian women and fecundability, as measured by time-to-pregnancy in menstrual cycles, and 2) to examine lifestyle and behavioral factors associated with FSF. METHODS: From the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) prospective cohort, we evaluated FSF using the 6-item Female Sexual Function Index (FSFI-6) and ascertained time-to-pregnancy within a year of baseline assessment. We estimated fecundability ratio (FR) and 95% confidence interval (CI) using the discrete-time proportional hazards model, accounting for left-truncation and right censoring. We used multivariable logistic and linear regression models to identify potential factors related to FSF. RESULTS: Among 513 participants, 58.9% had low FSF as defined by a total FSFI-6 score at or below the median value of 22. Compared to women with high FSF, those with low FSF had a 27% reduction in fecundability (FR 0.73; 95% CI 0.54, 0.99), with adjustment for age, ethnicity, education, parity and body mass index. Overall, the FRs generally reduced with decreasing FSFI-6 scores. Physical activity, obesity, absence of probable depression and anxiety were independently associated with reduced odds of low FSF and increased FSFI-6 scores, after adjusting for sociodemographic characteristics. CONCLUSIONS: Low FSF is associated with a longer time-to-pregnancy. Early evaluation and optimization of FSF through increased physical activity and optimal mental health may help to improve female fecundity. The finding of obese women having improved FSF remains uncertain which warrants further investigations on plausibly mechanisms. In general, the current finding highlights the importance of addressing FSF in preconception care service for general women, which is currently lacking as part of the fertility promotion effort in the country.

Comparative epidemiology of gestational diabetes in ethnic Chinese from Shanghai birth cohort and growing up in Singapore towards healthy outcomes cohort.

BACKGROUND: Gestational diabetes mellitus (GDM) has been associated with adverse health outcomes for mothers and offspring. Prevalence of GDM differs by country/region due to ethnicity, lifestyle and diagnostic criteria. We compared GDM rates and risk factors in two Asian cohorts using the 1999 WHO and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. METHODS: The Shanghai Birth Cohort (SBC) and the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort are prospective birth cohorts. Information on sociodemographic characteristics and medical history were collected from interviewer-administered questionnaires. Participants underwent a 2-h 75-g oral glucose tolerance test at 24-28 weeks gestation. Logistic regressions were performed. RESULTS: Using the 1999 WHO criteria, the prevalence of GDM was higher in GUSTO (20.8%) compared to SBC (16.6%) (p = 0.046). Family history of hypertension and alcohol consumption were associated with higher odds of GDM in SBC than in GUSTO cohort while obesity was associated with higher odds of GDM in GUSTO. Using the IADPSG criteria, the prevalence of GDM was 14.3% in SBC versus 12.0% in GUSTO. A history of GDM was associated with higher odds of GDM in GUSTO than in SBC, while being overweight, alcohol consumption and family history of diabetes were associated with higher odds of GDM in SBC. CONCLUSIONS: We observed several differential risk factors of GDM among ethnic Chinese women living in Shanghai and Singapore. These findings might be due to heterogeneity of GDM reflected in diagnostic criteria as well as in unmeasured genetic, lifestyle and environmental factors.

Implication of gut microbiota in the association between infant antibiotic exposure and childhood obesity and adiposity accumulation.

BACKGROUND: In animal studies early life antibiotic exposure causes metabolic abnormalities including obesity through microbiota disruption, but evidence from human studies is scarce. We examined involvement of gut microbiota in the associations between infant antibiotic exposure and childhood adiposity. METHODS: Infant antibiotic exposure in the first year of life was ascertained using parental reports during interviewer-administered questionnaires. Primary outcomes were childhood obesity [body mass index (BMI) z-score > 95th percentile] and adiposity [abdominal circumference (AC) and skinfold (triceps + subscapular (SST)) measurements] determined from ages 15-60 months. At age 24 months, when the gut microbiota are more stable, stool samples (n = 392) were collected for the gut microbiota profiling using co-abundancy networks. Associations of antibiotic exposure with obesity and adiposity (n = 1016) were assessed using multiple logistic and linear mixed effects regressions. Key bacteria associated with antibiotics exposure were identified by partial redundancy analysis and multivariate association with linear models. RESULTS: Antibiotic exposure was reported in 38% of study infants. In a fully adjusted model, a higher odds of obesity from 15-60 months of age was observed for any antibiotic exposure [OR(95% CI) = 1.45(1.001, 2.14)] and exposure to ≥3 courses of antibiotics [2.78(1.12, 6.87)]. For continuous adiposity indicators, any antibiotic exposure was associated with higher BMI z-score in boys [ß = 0.15(0.01, 0.28)] but not girls [ß = -0.04(-0.19, 0.11)] (P interaction = 0.026). Similarly, exposure to ≥3 courses of antibiotics was associated with higher AC in boys [1.15(0.05, 2.26) cm] but not girls [0.57(-1.32, 2.45) cm] (P interaction not significant). Repeated exposure to antibiotics was associated with a significant reduction (FDR-corrected P values < 0.05) in a microbial co-abundant group (CAG) represented by Eubacterium hallii, whose proportion was negatively correlated with childhood adiposity. Meanwhile, a CAG represented by Tyzzerella 4 was positively correlated with the repeated use of antibiotics and childhood adiposity. CONCLUSIONS: Infant antibiotic exposure was associated with disruption of the gut microbiota and the higher risks of childhood obesity and increased adiposity.

Determinants of intramyocellular lipid accumulation in early childhood.

BACKGROUND/OBJECTIVES: Accumulation of lipid droplets inside skeletal muscle fibers (intramyocellular lipids or IMCL) with increasing obesity has been linked to skeletal muscle insulin resistance and risk of type 2 diabetes in both adults and prepubertal children. We aimed to evaluate the associations of race, genotype, prenatal factors, and postnatal factors with IMCL in early childhood. SUBJECTS/METHODS: This study was a secondary analysis performed on the GUSTO birth cohort. Soleus muscle IMCL of 392 children at 4.5 years of age was measured by magnetic resonance spectroscopy, of which usable imaging data were obtained from 277 children (137 Chinese, 87 Malays, and 53 Indians). Metabolic assessments (fasting glucose, insulin, and HOMA-IR) were performed at age 6. RESULTS: The mean IMCL level at 4.5 years was 0.481 ± 0.279% of water resonance (mean ± sd). Corroborating with results from adults, Indian children had the highest IMCL levels compared with Malay and Chinese children. Among the prenatal factors, the rate of gestational weight gain (GWG rate) was associated with offspring IMCL (B = 0.396 (0.069, 0.724); p = 0.018). Both race and GWG rate continued to be associated with offspring IMCL even after accounting for current offspring BMI. Postnatally, IMCL was associated with shorter breastfeeding duration (B = 0.065 (0.001, 0.128); p = 0.045) and conditional relative weight gain between ages 2 and 3 (B = 0.052 (0.012, 0.093); p = 0.012). The associations with postnatal factors were attenuated after adjusting for current offspring BMI. IMCL was positively associated with offspring BMI (B = 0.028 (0.012, 0.044); p = 0.001). IMCL levels were not associated with fasting glucose, fasting insulin, and HOMA-IR at age 6. CONCLUSION: This study provides evidence that IMCL accumulation occurs in early childhood and that developmental factors and race are associated with it. We also show that early childhood IMCL accumulation is well tolerated, suggesting that the adverse associations between IMCL and insulin resistance may emerge at older ages.

Longitudinal assessment of antibiotic resistance gene profiles in gut microbiomes of infants at risk of eczema.

BACKGROUND: While there is increasing knowledge about the gut microbiome, the factors influencing and the significance of the gut resistome are still not well understood. Infant gut commensals risk transferring multidrug-resistant antibiotic resistance genes (ARGs) to pathogenic bacteria. The rapid spread of multidrug-resistant pathogenic bacteria is a worldwide public health concern. Better understanding of the naïve infant gut resistome may build the evidence base for antimicrobial stewardship in both humans and in the food industry. Given the high carriage rate of extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in Asia, we aimed to evaluate community prevalence, dynamics, and longitudinal changes in antibiotic resistance gene (ARG) profiles and prevalence of ESBL-producing E. coli and K. pneumoniae in the intestinal microbiome of infants participating in the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study, a longitudinal cohort study of pregnant women and their infants. METHODS: We analysed ARGs in the first year of life among 75 infants at risk of eczema who had stool samples collected at multiple timepoints using metagenomics. RESULTS: The mean number of ARGs per infant increased with age. The most common ARGs identified confer resistance to aminoglycoside, beta-lactam, macrolide and tetracycline antibiotics; all infants harboured these antibiotic resistance genes at some point in the first year of life. Few ARGs persisted throughout the first year of life. Beta-lactam resistant Escherichia coli and Klebsiella pneumoniae were detected in 4 (5.3%) and 32 (42.7%) of subjects respectively. CONCLUSION: In this longitudinal cohort study of infants living in a region with high endemic antibacterial resistance, we demonstrate that majority of the infants harboured several antibiotic resistance genes in their gut and showed that the infant gut resistome is diverse and dynamic over the first year of life.

Timeliness of Childhood Vaccination Coverage: the Growing Up in Singapore Towards Healthy Outcomes Study.

Studies investigating timeliness for childhood vaccination are limited especially in Asia. We examined the timeliness of vaccine administration and associated factors among infant and young children in Singapore. A total of 782 children born between November 2009 and July 2011 from a prospective cohort in Singapore were studied. Vaccination records from birth to 24 months of age were obtained from the National Immunization Registry of Singapore. Multivariable logistic regression models were performed. By 2 years of age, 92.8% of children in our cohort experienced a delay in receiving 1 or more vaccine doses according to the recommended national immunization schedule. When vaccinations were reviewed by series for each vaccine, 15.6% received all vaccine series outside the recommended age ranges. Factors associated with receiving vaccination series outside the recommended ages included maternal aged ≤ 35 years (OR 2.00; 95% CI 1.09, 3.66), Malay (1.71; 1.01, 2.89) or Indian ethnicity (2.06; 1.19, 3.59), low monthly household income (1.91; 1.14, 3.18), having at least four children (3.46; 1.62, 7.38) and private (3.42; 1.80, 6.48) and multiple vaccination providers (3.91; 1.23, 12.48). These findings show an unacceptably high proportion of children experienced a delay in the receipt of their vaccinations. The identification of several demographic, socioeconomic, health-seeking behavioural and vaccine provider factors provides opportunities for targeted interventions to enhance the timeliness of childhood vaccination in Singapore.

Effects of Migration on Allergic Diseases.

Studies in migrant populations provide vital opportunities to investigate the role of environmental factors in the pathogenesis of allergic disorders. Differences in allergy prevalence have been observed between migrants and native-born subjects living in the same geographical location. Immigrants who migrate from less affluent countries with lower allergy prevalence tend to have a lower prevalence of allergic disorders compared to native-born residents of the more affluent host country. The patterns of allergic disease prevalence also differ between first- and second-generation migrants. The timing of migration in relation to birth, age at migration, and duration of residence in the host country also influence one's atopic risk. A complex interplay of multiple environmental, socioeconomic, and cultural factors is likely responsible for these observed differences. Further research into the roles of various risk factors in modulating differences in allergic disease prevalence between migrant and native populations will enhance our understanding of the complex gene-environment interactions involved in the pathogenesis of allergic disorders.

High Maternal Circulating Cotinine During Pregnancy is Associated With Persistently Shorter Stature From Birth to Five Years in an Asian Cohort.

BACKGROUND: Self-reported maternal active smoking has been associated with reduced offspring birth length and shorter stature in early and late childhood. OBJECTIVE: To use circulating cotinine as an objective biomarker to investigate the association between smoking and environmental tobacco smoke (ETS) exposure in pregnancy and longitudinal measures of offspring length/height from birth to 60 months. METHODS: In 969 maternal-offspring dyads from the GUSTO cohort, maternal plasma cotinine at 26-28 weeks' gestation was measured by LC/MS/MS and categorized into four groups: Group 1: cotinine <0.17 ng/mL (the assay's detection limit) and no ETS exposure; Group 2: cotinine <0.17 ng/mL but self-reported ETS; Group 3: cotinine 0.17-13.99 ng/mL (ETS or light smoking); Group 4: cotinine ≥14 ng/mL (active smoking). RESULTS: Adjusting for infant sex, gestational age at birth, ethnicity, maternal age, education, parity, BMI, and height, Group 4 offspring were shorter at birth [z-score ß = -0.42 SD units (SDs) (95% CI = -0.77 to -0.06)] than Group 1 offspring. Group 4 offspring continued to be shorter at older ages, with similar effect sizes at 3 months [-0.57 SDs (-0.95 to -0.20)], 36 months [-0.53 SDs (-0.92 to -0.15)], 48 months [-0.43 SDs (-0.81 to -0.04)], and 60 months [-0.57 SDs (-0.96 to -0.17)]. Associations were particularly marked in boys. No significant differences in stature were observed in Groups 2 or 3 compared with Group 1. CONCLUSIONS: This Asian longitudinal study associated high prenatal cotinine with persistently shorter stature in offspring from birth and into early childhood, whilst low prenatal cotinine levels and ETS exposure showed no such association. IMPLICATIONS: Little is known about the long-term effects of prenatal tobacco exposure on offspring stature in Asia where passive smoking is common. This study has used an objective biomarker to reveal that the association of prenatal tobacco exposure with offspring length/height mainly occurs at a high maternal cotinine level of greater than 14 ng/mL in pregnancy, consistent with active smoking, but no significant associations were found with lower cotinine levels, consistent with passive smoking. Encouraging women to quit smoking prior to or during pregnancy may avert the long-term negative impact on their child's height despite appreciable prenatal ETS exposure.