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Abstract Objective We aimed to summarize the association between gestational diabetes mellitus (GDM) and its intergenerational cardiovascular diseases (CVDs) impacts in both mothers and offspring post-delivery in existing literature. Methods PubMed, Embase, Web of Science, and Scopus were utilized for searching publications between January 1980 and June 2024, with data extraction and meta-analysis continuing until 31 July 2024. Based on a predefined PROSPERO protocol, studies published as full-length, English-language journal articles that reported the presence of GDM during pregnancy and its association with any CVD development post-delivery were selected. All studies were evaluated using the Newcastle-Ottawa Scale. Maximally adjusted risk estimates were pooled using random-effects meta-analysis to assess the risk ratio (RR) of GDM, and overall and subtypes of CVDs in both mothers and offspring post-delivery. Results The meta-analysis was based on 38 studies with a total of 77,678,684 participants. The results showed a 46% increased risk (RR 1.46, 95% CI 1.34–1.59) for mothers and a 23% increased risk (1.23, 1.05–1.45) for offspring of developing overall CVDs after delivery, following a GDM-complicated pregnancy. Our subgroup analysis revealed that mothers with a history of GDM faced various risks (20% to 2-fold) of developing different subtypes of CVDs, including cerebrovascular disease, coronary artery disease, heart failure, and venous thromboembolism. Conclusions These findings underscore the heightened risk of developing various CVDs for mothers and offspring affected by GDM, emphasizing the importance of preventive measures even right after birth to mitigate the burden of CVDs in these populations.

Abstract Objective To characterise lifestyle patterns (comprising dietary and movement behaviour aspects) of children in Singapore and examine the correlates of these patterns. Design An observational study approach was used. Children recorded their diet and activities over two weekdays and two weekend days on a validated web-based assessment, My E-Diary for Activities and Lifestyle (MEDAL). Lifestyle patterns were derived using principal component analysis, and the correlations of these with multiple known determinants organised by distal, intermediate, and proximal levels of influence were studied. Setting Children of the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Participants Ten-year-old children (n = 397). Results Three lifestyle patterns, “high snacks and processed food”, “balanced” and “mixed”, were identified. We focused on the more health-promoting “balanced” pattern, characterised by lower screen-viewing and higher consumption of fruits, vegetables, wholegrains, and dairy. Among the distal factors, girls were more adherent to the “balanced” pattern compared to boys, and children of parents with lower education levels were less adherent to this pattern. Among intermediate factors, children of mothers with higher diet quality were more adherent to the “balanced” pattern. Among the proximal factors, engagement in active transport, leisure sports, and educational activities outside of school were positively associated with the “balanced” pattern, whereas screen-viewing while travelling was negatively associated with this pattern. Having siblings, pet ownership, mother’s physical activity, parenting style, parental bonding, child’s outdoor time, and breakfast consumption were not associated with children’s lifestyle patterns. Conclusions These findings provide direction for future interventions by identifying vulnerable groups and contexts that should be prioritised.

BackgroundPhysical activity (PA), sedentary behavior (SB), and sleep are collectively referred to as 24-h movement behaviors, which may be linked to cognitive development in children. However, most of the evidence was based on cross-sectional studies and/or solely relied on parent-reported information on children’s behaviors, and it remains uncertain whether all domains/contexts of PA and SB are similarly associated with executive function and academic achievement.ObjectiveWe investigated the prospective associations of accelerometer-measured 24 h-movement behaviors and domain-specific PA and SB with executive function and academic achievement among school-aged children in Singapore.MethodsThe Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort used a wrist-worn accelerometer (Actigraph-GT3x+) to measure 24 h-movement behaviors data at ages 5.5 and 8 years. Executive function and academic achievement were assessed using NEuroPSYchology (NEPSY) and Wechsler Individual Achievement Tests at ages 8.5 and 9-years, respectively. Compositional data analyses were conducted to explore the associations of 24 h-movement behavior with outcomes, and multiple linear regression models to examine the associations of domain-specific PA and SB with outcomes (n = 432).ResultsAmong 432 children whose parents agreed to cognitive assessments (47% girls and 58% Chinese), the composition of 24 h-movement behaviors at ages 5.5 and 8 years was not associated with executive function and academic achievement. However, higher moderate-to-vigorous PA (MVPA) relative to remaining movement behaviors at age 5.5 years was associated with lower academic achievement [Mean difference (95% confidence interval): −0.367 (−0.726, −0.009) z-score], and reallocating MVPA time to sleep showed higher academic achievement scores [30 min from MVPA to sleep: 0.214 (0.023, 0.404) z-score]. Certain domains of PA and SB, notably organized PA/sports, outdoor play, and reading books were favorably associated with outcomes of interest, while indoor play and screen-viewing were unfavorably associated.ConclusionThe associations between movement behaviors and cognitive outcomes are multifaceted, influenced by specific domains of PA and SB. This study underscores the importance of participation in organized PA/sports, outdoor active play, and reading books, while ensuring adequate sleep and limiting screen viewing, to enhance cognitive outcomes. These findings underscore the need for further research into time-use trade-offs. Such studies could have major implications for revising current guidelines or strategies aimed at promoting healthier 24 h-movement behaviors in children.Study registrationhttps://clinicaltrials.gov/, NCT01174875.

Abstract Background Parental practices and neighbourhood environmental factors may influence children’s movement behaviours. We aimed to investigate the cross-sectional and prospective associations of parental practices and neighbourhood environmental factors with accelerometer-measured 24-hour movement behaviours (24 h-MBs) among school-aged children in Singapore. Methods The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study collected information on dimensions of parental practices and neighbourhood environment at age 5.5 years. Confirmatory factor analyses were performed to generate latent variables and used to compute overall parental practices [involvement in PA + support for PA + control of screen viewing context] and environmental scores [facilities for active play + active mobility facilitators + barriers*-1]. Children wore an accelerometer on their non-dominant wrist for seven consecutive days at ages 5.5 and 8 years. The R-package GGIR 2.6 was used to derive moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), inactivity, and total-sleep (napping+night sleep) minutes per day. Associations were determined using compositional data analysis with multivariate linear regression models, taking into account potential confounders. Results Among 425 children (48% girls, 59% Chinese), higher parental involvement in PA, parental support for PA and overall parental practices were associated with 24 h-MBs at ages 5.5 and 8 years, specifically with greater time spent in MVPA and less time being inactive relative to the remaining movement behaviours. The corresponding mean changes in the overall 24 h-MB for increasing parental practices from lowest to highest scores (− 2 to + 2 z-scores) indicated potential increases of up to 15-minutes in MVPA, 20-minutes in LPA, 5-minutes in sleep duration, and a reduction of 40-minutes in inactivity at age 5.5 years. At age 8 years, this could translate to approximately 15-minutes more of MVPA, 20-minutes more of LPA, a 20-minute reduction in sleep duration, and a 20-minute reduction in inactivity. Parental control of screen viewing contexts and neighbourhood environmental factors were not associated with 24 h-MBs. Conclusions Parental practices but not environmental factors were associated with higher MVPA and lower inactivity among Singaporean children, even at a later age. Further research may provide insights that support development of targeted public health strategies to promote healthier movement behaviours among children. Study registration This study was registered on 4th August 2010 and is available online at ClinicalTrials.gov: NCT01174875.

BackgroundParents experience many challenges during the perinatal period. Mobile app–based interventions and chatbots show promise in delivering health care support for parents during the perinatal period. ObjectiveThis descriptive qualitative process evaluation study aims to explore the perinatal experiences of parents in Singapore, as well as examine the user experiences of the mobile app–based intervention with an in-built chatbot titled Parentbot—a Digital Healthcare Assistant (PDA). MethodsA total of 20 heterosexual English-speaking parents were recruited via purposive sampling from a single tertiary hospital in Singapore. The parents (control group: 10/20, 50%; intervention group: 10/20, 50%) were also part of an ongoing randomized trial between November 2022 and August 2023 that aimed to evaluate the effectiveness of the PDA in improving parenting outcomes. Semistructured one-to-one interviews were conducted via Zoom from February to June 2023. All interviews were conducted in English, audio recorded, and transcribed verbatim. Data analysis was guided by the thematic analysis framework. The COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist was used to guide the reporting of data. ResultsThree themes with 10 subthemes describing parents’ perceptions of their parenting journeys and their experiences with the PDA were identified. The main themes were (1) new babies, new troubles, and new wonders; (2) support system for the parents; and (3) reshaping perinatal support for future parents. ConclusionsOverall, the PDA provided parents with informational, socioemotional, and psychological support and could be used to supplement the perinatal care provided for future parents. To optimize users’ experience with the PDA, the intervention could be equipped with a more sophisticated chatbot, equipped with more gamification features, and programmed to deliver personalized care to parents. Researchers and health care providers could also strive to promote more peer-to-peer interactions among users. The provision of continuous, holistic, and family-centered care by health care professionals could also be emphasized. Moreover, policy changes regarding maternity and paternity leaves, availability of infant care centers, and flexible work arrangements could be further explored to promote healthy work-family balance for parents.

BackgroundThe loss of ancestral microbes, or the “disappearing microbiota hypothesis” has been proposed to play a critical role in the rise of inflammatory and immune diseases in developed nations. The effect of this loss is most consequential during early-life, as initial colonizers of the newborn gut contribute significantly to the development of the immune system.MethodsIn this longitudinal study (day 3, week 3, and month 3 post-birth) of infants of Asian ancestry born in Singapore, we studied how generational immigration status and common perinatal factors affect bifidobacteria and Bifidobacterium longum subsp. infantis (B. infantis) colonization. Cohort registry identifier: NCT01174875.ResultsOur findings show that first-generation migratory status, perinatal antibiotics usage, and cesarean section birth, significantly influenced the abundance and acquisition of bifidobacteria in the infant gut. Most importantly, 95.6% of the infants surveyed in this study had undetectable B. infantis, an early and beneficial colonizer of infant gut due to its ability to metabolize the wide variety of human milk oligosaccharides present in breastmilk and its ability to shape the development of a healthy immune system. A comparative analysis of B. infantis in 12 countries by their GDP per capita showed a remarkably low prevalence of this microbe in advanced economies, especially Singapore.ConclusionThis study provides new insights into infant gut microbiota colonization, showing the impact of generational immigration on early-life gut microbiota acquisition. It also warrants the need to closely monitor the declining prevalence of beneficial microbes such as B. infantis in developed nations and its potential link to increasing autoimmune and allergic diseases.

Early life adversity has been posited to influence the pace of structural neurodevelopment. Most research, however, has relied on cross-sectional data, which do not reveal whether the pace of neurodevelopmental change is accelerated or slowed following early exposures. In a birth cohort study that included neuroimaging data obtained at 4.5, 6, and 7.5 years of age (N = 784), we examined associations among a cumulative measure of perinatal adversity relative to resources, nonlinear trajectories of hippocampal and amygdala volume, and children’s subsequent depressive symptoms at 8.5 years of age. Greater adversity was associated with reduced bilateral hippocampal body volume in early childhood, but also to faster growth in the right hippocampal body across childhood. Further, the association between adversity and childhood depressive symptoms was mediated by faster hippocampal body growth. These findings suggest that perinatal adversity is biologically embedded in hippocampal structure development, including an accelerated pace of change in the right hippocampal body that is implicated in children’s psychopathology risk. In addition, our findings suggest that reduced hippocampal volume is not inconsistent with accelerated hippocampal change; these aspects of structural development may typically co-occur, as smaller regional volumes in early childhood were associated with faster growth across childhood.

Abstract Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β = −0. 141, p-value = 0.024, 95% CI −0. 264 to −0. 018) and a lower WIAT-III mean score at ~9 years (β = −0.222, p-value = 0.001, 95% CI −0.357 to −0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β = −0.172, p-value = 0.002, 95% CI −0.280 to −0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.

Abstract Background Tracking combinations of lifestyle behaviours during childhood (“lifestyle pattern trajectories”) can identify subgroups of children that might benefit from lifestyle interventions aiming to improve health outcomes later in life. However, studies on the critical transition period from early to middle childhood are limited. We aimed to describe lifestyle patterns trajectories in children from 2 to 8 years of age and evaluated their associations with cardiometabolic risk markers at age 8 years in a multi-ethnic Asian cohort. Methods Twelve lifestyle behaviours related to child’s diet, physical activity, screen use, and sleep were ascertained using questionnaires at ages 2, 5, and 8 years. Age-specific lifestyle patterns were derived using principal component analysis and trajectories were determined using group-based multi-trajectory modelling. Child cardiometabolic risk markers were assessed at age 8 years, and associations with trajectories examined using multiple regression, adjusted for confounders. Results Among 546 children, two lifestyle patterns “healthy” and “unhealthy” were observed at ages 2, 5, and 8 years separately. Three trajectory groups from 2 to 8 years were identified: consistently healthy (11%), consistently unhealthy (18%), and mixed pattern (71%). Children in the consistently unhealthy group (vs. mixed pattern) had increased odds of pre-hypertension (OR = 2.96 [95% CI 1.18–7.41]) and higher levels of diastolic blood pressure (β = 1.91 [0.27–3.55] mmHg), homeostasis model assessment of insulin resistance (β = 0.43 [0.13–0.74]), triglycerides (β = 0.11 [0.00-0.22] mmol/L), and metabolic syndrome score (β = 0.85 [0.20–1.49]), but not with BMI z-score or any anthropometric measurements. The consistently healthy group showed no differences in cardiometabolic outcomes compared to the mixed pattern group. Conclusion Three distinct lifestyle pattern trajectories were identified from early to middle childhood. Children in the consistently unhealthy lifestyle group did not have a raised BMI but was associated with several elevated cardiometabolic risk markers. These findings suggest the potential benefits of initiating holistic lifestyle interventions to improve children’s health and well-being from an early age. Trial registration Trial registration number: NCT01174875. Name of registry: ClinicalTrials.gov. URL of registry: https://classic.clinicaltrials.gov/ct2/show/NCT01174875 . Date of registration: August 4, 2010. Date of enrolment of the first participant to the trial: June 2009.

Abstract Background Increasing maternal glycaemia across the continuum during pregnancy may predispose offspring to subsequent cardiometabolic risk later in life. However, evidence of long-term impacts of maternal glycemic status on offspring amino acid (AA) profiles is scarce. We aimed to investigate the association between maternal antenatal glycaemia and offspring mid-childhood amino acid (AA) profiles, which are emerging cardiometabolic biomarkers. Methods Data were drawn from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, a multi-ethnic Asian birth cohort. A subset of 422 mother–child dyads from the GUSTO study, who was followed from early pregnancy to mid-childhood, was included. Mothers underwent an oral glucose tolerance test (OGTT) at 26–28 weeks gestation, with fasting and 2-h plasma glucose concentrations measured and gestational diabetes mellitus (GDM) diagnosed per WHO 1999 guidelines. Offspring fasting plasma samples were collected at mean age 6.1 years, from which AA profiles of nine AAs, alanine, glutamine, glycine, histidine, isoleucine, leucine, valine, phenylalanine, and tyrosine were measured. Total branched-chain amino acids (BCAAs) were calculated as the sum of isoleucine, leucine, and valine concentrations. Multi-variable linear regression was used to estimate the association of maternal glycemic status and offspring mid-childhood AA profiles adjusting for maternal age, ethnicity, maternal education, parity, family history of diabetes, ppBMI, child sex, age and BMI z-scores. Results Approximately 20% of mothers were diagnosed with GDM. Increasing maternal fasting glucose was significantly associated with higher offspring plasma valine and total BCAAs, whereas higher 2-h glucose was significantly associated with higher histidine, isoleucine, valine, and total BCAAs. Offspring born to mothers with GDM had higher valine (standardized mean difference 0.27 SD; 95% CI: 0.01, 0.52), leucine (0.28 SD; 0.02, 0.53), and total BCAAs (0.26 SD; 0.01, 0.52) than their counterparts. Inconsistent associations were found between maternal GDM and other amino acids among offspring during mid-childhood. Conclusions Increasing maternal fasting and post-OGTT glucose concentrations at 26–28 weeks gestation were significantly associated with mid-childhood individual and total BCAAs concentrations. The findings suggest that elevated maternal glycaemia throughout pregnancy, especially GDM, may have persistent programming effects on offspring AA metabolism which were strongly associated with adverse cardiometabolic profiles at mid-childhood.

Abstract Pathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an inflammation-related expression signature, primarily expressed in Hofbauer cells of the term placenta and use expression quantitative trait loci to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we conduct a phenome-wide association study, followed by Mendelian randomization and identify protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth are over-represented within the module. We also identify aspirin as a putative modulator of this inflammation-related signature. Our data support a model where disruption of placental Hofbauer cell function, due to preterm birth or prenatal infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals.

Summary: We investigated the relationship of preconception maternal retinal vasculature and utero-fetoplacental circulation in ensuing pregnancy. Embedded in a hospital-based, prospective preconception cohort, 396 women with a singleton live birth were included for analysis. We assessed retinal vascular caliber during preconception phase and retrieved ultrasonogram results documenting utero-fetoplacental circulatory indices using Doppler ultrasonography and documented them at 18–21 weeks, 24–28 weeks, and 32–34 weeks where available. We performed a modified Poisson regression to estimate the relative risk of utero-fetoplacental abnormalities, adjusting for major confounders including pre-pregnancy and blood pressure. Per 10 μm increment in maternal preconception retinal venules was associated with over two-fold risks in developing notching (Relative risk [RR]: 2.84; 95% confidence interval [CI]: 1.79, 4.81) and ≥95th percentile umbilical artery pulsatility index (2.36; 1.72, 3.23) during mid-to-late pregnancy, respectively. Women with preconception retinal venular widening tended to demonstrate steeper resistance increments in both maternal uterine arteries and fetal umbilical arteries during mid-to-late pregnancy.

BackgroundMaternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation.Methods and findingsIn the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, β-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate ConclusionsOver 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period.Trial registrationClinicalTrials.gov NCT02509988; U1111-1171-8056.

Abstract Background Metabolomic changes during pregnancy have been suggested to underlie the etiology of gestational diabetes mellitus (GDM). However, research on metabolites during preconception is lacking. Therefore, this study aimed to investigate distinctive metabolites during the preconception phase between GDM and non-GDM controls in a nested case–control study in Singapore. Methods Within a Singapore preconception cohort, we included 33 Chinese pregnant women diagnosed with GDM according to the IADPSG criteria between 24 and 28 weeks of gestation. We then matched them with 33 non-GDM Chinese women by age and pre-pregnancy body mass index (ppBMI) within the same cohort. We performed a non-targeted metabolomics approach using fasting serum samples collected within 12 months prior to conception. We used generalized linear mixed model to identify metabolites associated with GDM at preconception after adjusting for maternal age and ppBMI. After annotation and multiple testing, we explored the additional predictive value of novel signatures of preconception metabolites in terms of GDM diagnosis. Results A total of 57 metabolites were significantly associated with GDM, and eight phosphatidylethanolamines were annotated using HMDB. After multiple testing corrections and sensitivity analysis, phosphatidylethanolamines 36:4 (mean difference β: 0.07; 95% CI: 0.02, 0.11) and 38:6 (β: 0.06; 0.004, 0.11) remained significantly higher in GDM subjects, compared with non-GDM controls. With all preconception signals of phosphatidylethanolamines in addition to traditional risk factors (e.g., maternal age and ppBMI), the predictive value measured by area under the curve (AUC) increased from 0.620 to 0.843. Conclusions Our data identified distinctive signatures of GDM-associated preconception phosphatidylethanolamines, which is of potential value to understand the etiology of GDM as early as in the preconception phase. Future studies with larger sample sizes among alternative populations are warranted to validate the associations of these signatures of metabolites and their predictive value in GDM.

Abstract Background Adaptations in lipid metabolism are essential to meet the physiological demands of pregnancy and any aberration may result in adverse outcomes for both mother and offspring. However, there is a lack of population-level studies to define the longitudinal changes of maternal circulating lipids from preconception to postpartum in relation to cardiometabolic risk factors. Methods LC-MS/MS-based quantification of 689 lipid species was performed on 1595 plasma samples collected at three time points in a preconception and longitudinal cohort, Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO). We mapped maternal plasma lipidomic profiles at preconception (N = 976), 26–28 weeks’ pregnancy (N = 337) and 3 months postpartum (N = 282) to study longitudinal lipid changes and their associations with cardiometabolic risk factors including pre-pregnancy body mass index, body weight changes and glycaemic traits. Results Around 56% of the lipids increased and 24% decreased in concentration in pregnancy before returning to the preconception concentration at postpartum, whereas around 11% of the lipids went through significant changes in pregnancy and their concentrations did not revert to the preconception concentrations. We observed a significant association of body weight changes with lipid changes across different physiological states, and lower circulating concentrations of phospholipids and sphingomyelins in pregnant mothers with higher pre-pregnancy BMI. Fasting plasma glucose and glycated haemoglobin (HbA1c) concentrations were lower whereas the homeostatic model assessment of insulin resistance (HOMA-IR), 2-h post-load glucose and fasting insulin concentrations were higher in pregnancy as compared to both preconception and postpartum. Association studies of lipidomic profiles with these glycaemic traits revealed their respective lipid signatures at three physiological states. Assessment of glycaemic traits in relation to the circulating lipids at preconception with a large sample size (n = 936) provided an integrated view of the effects of hyperglycaemia on plasma lipidomic profiles. We observed a distinct relationship of lipidomic profiles with different measures, with the highest percentage of significant lipids associated with HOMA-IR (58.9%), followed by fasting insulin concentration (56.9%), 2-h post-load glucose concentration (41.8%), HbA1c (36.7%), impaired glucose tolerance status (31.6%) and fasting glucose concentration (30.8%). Conclusions We describe the longitudinal landscape of maternal circulating lipids from preconception to postpartum, and a comprehensive view of trends and magnitude of pregnancy-induced changes in lipidomic profiles. We identified lipid signatures linked with cardiometabolic risk traits with potential implications both in pregnancy and postpartum life. Our findings provide insights into the metabolic adaptations and potential biomarkers of modifiable risk factors in childbearing women that may help in better assessment of cardiometabolic health, and early intervention at the preconception period. Trial registration ClinicalTrials.gov, NCT03531658.

Abstract Human brain development starts in the embryonic period. Maternal preconception nutrition and nutrient availability to the embryo may influence brain development at this critical period following conception and early cellular differentiation, thereby affecting offspring neurodevelopmental and behavioural disorder risk. However, studying this is challenging due to difficulties in characterizing preconception nutritional status and few studies have objective neurodevelopmental imaging measures in children. We investigated the associations of maternal preconception circulating blood nutrient-related biomarker mixtures (~15 weeks before conception) with child behavioural symptoms (Child Behaviour Checklist (CBCL), aged 3 years) within the Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) study. The CBCL preschool form evaluates child behaviours based on syndrome scales and Diagnostic and Statistical Manual of Mental Disorders (DSM) oriented scales. These scales consist of internalizing problems, externalizing problems, anxiety problems, pervasive developmental problems, oppositional defiant, etc. We applied data-driven clustering and a method for modelling mixtures (Bayesian kernel machine regression, BKMR) to account for complex, non-linear dependencies between 67 biomarkers. We used effect decomposition analyses to explore the potential mediating role of neonatal (week 1) brain microstructure, specifically orientation dispersion indices (ODI) of 49 cortical and subcortical grey matter regions. We found that higher levels of a nutrient cluster including thiamine, thiamine monophosphate (TMP), pyridoxal phosphate, pyridoxic acid, and pyridoxal were associated with a higher CBCL score for internalizing problems (posterior inclusion probability (PIP) = 0.768). Specifically, thiamine independently influenced CBCL (Conditional PIP = 0.775). Higher maternal preconception thiamine level was also associated with a lower right subthalamic nucleus ODI (P-value = 0.01) while a lower right subthalamic nucleus ODI was associated with higher CBCL scores for multiple domains (P-value

RationalMaternal overweight/obesity and gestational diabetes mellitus (GDM) are associated with an increased risk of their offspring developing overweight/obesity or type 2 diabetes later in life. However, the impacts of maternal overweight/obesity and dysglycemia on human milk (HM) macronutrient composition are not well understood.ObjectiveThrough a double-blind randomised controlled trial, we investigated the effects of maternal supplementation from preconception throughout pregnancy until birth on HM macronutrient concentrations, in association with maternal and infant factors including maternal pre-pregnancy body mass index (BMI) and GDM status. In addition, we aimed to characterise longitudinal changes in HM macronutrients.MethodsThe control supplement contained calcium, iodine, iron, β-carotene, and folic acid. The intervention supplement additionally contained zinc, vitamins B2, B6, B12, and D3, probiotics, and myo-inositol. HM samples were collected across seven time points from 1 week to 12 months from Singapore and/or New Zealand. HM macronutrient concentrations were measured using a MIRIS Human Milk Analyser. Potential differences in HM macronutrient concentrations were assessed using linear mixed models with a repeated measures design.ResultsOverall, HM macronutrient concentrations were similar between control and intervention groups. Among the control group, overweight/obesity and GDM were associated with higher HM fat and energy concentrations over the first 3 months. Such associations were not observed among the intervention group. Of note, mothers with GDM in the intervention group had lower HM fat by 10% (p = 0.049) and energy by 6% (p = 0.029) than mothers with GDM in the control group. Longitudinal changes in HM macronutrient concentrations over 12 months of lactation in New Zealand showed that HM fat and energy decreased in the first 6 months then increased until 12 months. HM lactose gradually decreased from 1 week to 12 months while crude protein decreased from 1 week to 6 months then remained relatively constant until 12 months of lactation.ConclusionMaternal overweight/obesity or GDM were associated with increased HM fat and energy levels. We speculate the intervention taken during preconception and pregnancy altered the impact of maternal BMI or GDM status on HM macronutrient composition. Further studies are required to identify the mechanisms underlying altered HM macronutrient concentration in the intervention group and to determine any long-term effects on offspring health.Clinical trial registrationClinicalTrials.gov, NCT02509988, Universal Trial Number U1111-1171-8056. Registered on 16 July 2015. This is an academic-led study by the EpiGen Global Research Consortium.

Background: Metabolic syndrome score in children assesses the risk of developing cardiovascular disease in future. We aim to probe the role of the caudate in relation to the metabolic syndrome score. Furthermore, using both functional and structural neuroimaging, we aim to examine the interplay between functional and structural measures. Methods: A longitudinal birth cohort study with functional and structural neuroimaging data obtained at 4.5, 6.0 and 7.5 years and metabolic syndrome scores at 8.0 years was used. Pearson correlation and linear regression was used to test for correlation fractional anisotropy (FA) and fractional amplitude of low frequency fluctuations (fALFF) of the caudate with metabolic syndrome scores. Mediation analysis was used to test if later brain measures mediated the relation between earlier brain measures and metabolic syndrome scores. Inhibitory control was also tested as a mediator of the relation between caudate brain measures and metabolic syndrome scores. Results: FA at 4.5 years and fALFF at 7.5 years of the left caudate was significantly correlated with metabolic syndrome scores. Post-hoc mediation analysis showed that fALFF at 7.5 years fully mediated the relation between FA at 4.5 years and metabolic syndrome scores. Inhibitory control was significantly correlated with fALFF at 7.5 years, but did not mediate the relation between fALFF at 7.5 years and metabolic syndrome scores. Conclusions: We found that variations in caudate microstructure at 4.5 years predict later variation in functional activity at 7.5 years. This later variation in functional activity fully mediates the relation between microstructural changes in early childhood and metabolic syndrome scores at 8.0 years.

Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.

Resting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local-global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Yan2023_homotopic).

Dysregulated transplacental lipid transfer and fetal–placental lipid metabolism affect birthweight, as does maternal hyperglycemia. As the mechanisms are unclear, we aimed to identify the lipids in umbilical cord plasma that were most associated with birthweight. Seventy-five Chinese women with singleton pregnancies recruited into the GUSTO mother–offspring cohort were selected from across the glycemic range based on a mid-gestation 75 g oral glucose tolerance test, excluding pre-existing diabetes. Cord plasma samples collected at term delivery were analyzed using targeted liquid-chromatography tandem mass-spectrometry to determine the concentrations of 404 lipid species across 17 lipid classes. The birthweights were standardized for sex and gestational age by local references, and regression analyses were adjusted for the maternal age, BMI, parity, mode of delivery, insulin treatment, and fasting/2 h glucose, with a false discovery-corrected p < 0.05 considered significant. Ten lysophosphatidylcholines (LPCs) and two lysophosphatidylethanolamines were positively associated with the birthweight percentiles, while twenty-four triacylglycerols were negatively associated with the birthweight percentiles. The topmost associated lipid was LPC 20:2 [21.28 (95%CI 12.70, 29.87) percentile increase in the standardized birthweight with each SD-unit increase in log10-transformed concentration]. Within these same regression models, maternal glycemia did not significantly associate with the birthweight percentiles. Specific fetal circulating lysophospholipids and triacylglycerols associate with birthweight independently of maternal glycemia, but a causal relationship remains to be established.

Abstract Background Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood. Methods LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26–28 weeks of gestation (n=752) and 4–5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation. Results Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=−2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=−0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R 2=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specifically associated with decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy. Conclusions In summary, our study provides a detailed landscape of the in utero lipid environment provided by the gestating mother to the growing fetus, and the magnitude of changes in plasma lipidomic profiles from birth to early childhood. We identified the effects of adiposity on the circulating lipid levels in pregnant and non-pregnant women as well as offspring at birth and at 6 years of age. Additionally, the pediatric vs maternal overlap of the circulating lipid phenotype of obesity risk provides intergenerational insights and early opportunities to track and intervene the onset of metabolic adversities. Clinical trial registration This birth cohort is a prospective observational study, which was registered on 1 July 2010 under the identifier NCT01174875 .

Summary: Genomic researchers increasingly utilize commercial cloud service providers (CSPs) to manage data and analytics needs. CSPs allow researchers to grow Information Technology (IT) infrastructure on demand to overcome bottlenecks when combining large datasets. However, without adequate security controls, the risk of unauthorized access may be higher for data stored on the cloud. Additionally, regulators are mandating data access patterns and specific security protocols for the storage and use of genomic data. While CSP provides tools for security and regulatory compliance, building the necessary controls required for cloud solutions is not trivial. Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud-native genomics data repository and analytics platform that implements a “five-safes” framework to provide security and governance controls to data contributors and users, leveraging CSP for sharing and analysis of genomic datasets without the risk of security breaches or running afoul of regulations.

BackgroundPrevious studies have investigated the various effects of parenting on infant developmental outcomes. In particular, parental stress and social support have been found to significantly affect the growth of the newborn. Although many parents today use mobile apps to obtain more support in parenting and perinatal care, few studies have examined how these apps could affect infant development. ObjectiveThis study aimed to examine the effectiveness of the Supportive Parenting App (SPA) in improving infant developmental outcomes during the perinatal period. MethodsThis study adopted a 2-group parallel prospective longitudinal design and recruited 200 infants and their parents (N=400 mothers and fathers). The parents were recruited at 24 weeks of gestation for a randomized controlled trial conducted from February 2020 to July 2022. They were randomly allocated to either the intervention or control group. The infant outcome measures included cognition, language, motor skills, and social-emotional development. Data were collected from the infants when they were aged 2, 4, 6, 9, and 12 months. Linear and modified Poisson regressions were used to analyze the data to examine between- and within-group changes. ResultsAt 9 and 12 months post partum, the infants in the intervention group were found to have better communication and language skills than those in the control group. An analysis of motor development revealed that a larger proportion of the infants in the control group fell under the at-risk category, where they scored approximately 2 SDs below the normative scores. The control group infants scored higher on the problem solving domain at 6 months post partum. However, at 12 months postpartum, the infants in the intervention group performed better on cognitive tasks than those in the control group. Despite not being statistically significant, the intervention group infants were found to have consistently scored better on the social components of the questionnaires than the control group infants. ConclusionsOverall, the infants whose parents had received the SPA intervention tended to fare better in most developmental outcome measures than those whose parents had received standard care only. The findings of this study suggest that the SPA intervention exerted positive effects on the communication, cognition, motor, and socioemotional development of the infants. Further research is needed to improve the content and support provided by the intervention to maximize the benefits gained by infants and their parents. Trial RegistrationClinicalTrials.gov NCT04706442; https://clinicaltrials.gov/ct2/show/NCT04706442

Abstract Background Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. Purpose Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. Methods Ten behavioural variables related to child’s diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5–6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. Results Three broadly similar lifestyle patterns were identified in both cohorts: “discretionary consumption and high screen time”, “fruit, vegetables, and low screen time” and “high outdoor playtime and walking”. The latter two patterns showed small differences between cohorts and sexes. The “discretionary consumption and high screen time” pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. Conclusions Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

We examined the associations of perinatal plasma carotenoids and E vitamers concentrations with glycemia, insulin resistance, and gestational and type 2 diabetes mellitus during pregnancy and post-pregnancy in GUSTO women. Plasma carotenoid and E vitamer concentrations were measured at delivery, and principal component analysis was used to derive the patterns of their concentrations. Fasting and 2 h glucose levels and fasting insulin were measured at 26–28 weeks gestation and 4–6 years post-pregnancy, with the derivation of homeostatic model assessment for insulin resistance (HOMA-IR). In 678 women, two carotenoid patterns (CP1: α- and β-carotene and lutein; CP2: zeaxanthin, lycopene, and β-cryptoxanthin) and one E vitamer pattern (VE: γ-, δ-, and α-tocopherols) were derived. A higher CP1 score (1-SD) was associated with lower gestational fasting glucose (β (95%CI): −0.06 (−0.10, −0.02) mmol/L) and lower gestational (−0.17 (−0.82, 0.01) mmol/L, p = 0.06) and post-pregnancy HOMA-IR (−0.11 (−0.15, −0.08) mmol/L). A higher VE score (1 SD) was associated with higher gestational and post-pregnancy fasting and 2 h glucose (gestational: 0.05 (0.01, 0.08) and 0.08 (0.01, 0.16); post-pregnancy: 0.19 (0.07, 0.31) and 0.24 (0.06, 0.42) mmol/L). Higher α- and β-carotene and lutein may be beneficial for gestational fasting glycemia, but higher vitamin E may increase gestational and post-pregnancy glycemia, although these findings require confirmation in cohorts with prospective longitudinal measurements of these vitamins.

Abstract Background Telomere length (TL) and its attrition are important indicators of physiological stress and biological aging and hence may vary among individuals of the same age. This variation is apparent even in newborns, suggesting potential effects of parental factors and the intrauterine environment on TL of the growing fetus. Methods Average relative TLs of newborns (cord tissue, N = 950) and mothers (buffy coat collected at 26–28 weeks of gestation, N = 892) were measured in a birth cohort. This study provides a comprehensive analysis of the effects of heritable factors, socioeconomic status, and in utero exposures linked with maternal nutrition, cardiometabolic health, and mental well-being on the newborn TL. The association between maternal TL and antenatal maternal health was also studied. Results Longer maternal TL (β = 0.14, P = 1.99E−05) and higher paternal age (β = 0.10, P = 3.73E−03) were positively associated with newborn TL. Genome-wide association studies on newborn and maternal TLs identified 6 genetic variants in a strong linkage disequilibrium on chromosome 3q26.2 (Tag SNP-LRRC34-rs10936600: P meta = 5.95E−08). Mothers with higher anxiety scores, elevated fasting blood glucose, lower plasma insulin-like growth factor-binding protein 3 and vitamin B12 levels, and active smoking status during pregnancy showed a higher risk of giving birth to offspring with shorter TL. There were sex-related differences in the factors explaining newborn TL variation. Variation in female newborn TL was best explained by maternal TL, mental health, and plasma vitamin B12 levels, while that in male newborn TL was best explained by paternal age, maternal education, and metabolic health. Mother’s TL was associated with her own metabolic health and nutrient status, which may have transgenerational effects on offspring TL. Conclusions Our findings provide a comprehensive understanding of the heritable and environmental factors and their relative contributions to the initial setting of TL and programing of longevity in early life. This study provides valuable insights for preventing in utero telomere attrition by improving the antenatal health of mothers via targeting the modifiable factors. Trial registration ClinicalTrials.gov , NCT01174875. Registered on 1 July 2010

BackgroundAdjusting to new or additional parenting responsibilities increases stress and affects parental well-being. Existing research has highlighted both parents’ desire to receive more support. It has also been found that receiving sufficient social support enhances parenting outcomes. With the increasing popularity of mobile health apps, a Supportive Parenting App (SPA) intervention was developed to fulfill the support needs of parents during the perinatal period. ObjectiveThis study aimed to examine the effectiveness of the SPA on parental outcomes during the perinatal period. MethodsA 2-group pretest and repeated posttest randomized controlled trial was conducted wherein 200 couples (N=400 mothers and fathers) were recruited from 2 public health care institutions in Singapore. Parents were randomly assigned to intervention (100/200, 50%) or control (100/200, 50%) groups. The SPA intervention consisted of a mobile app–based psychoeducation and peer support program to support parents from pregnancy to 6 months post partum. The outcome measures included postnatal depression, anxiety, parental bonding, parental self-efficacy, perceived social support, and parenting satisfaction. Data were collected at baseline (at >24 weeks of gestation—age of viability in Singapore) and at the first, second, fourth, sixth, ninth, and 12th month post partum. Linear mixed models were used to compare parental outcomes between the groups, and a linear mixed model for repeated measures was used to examine within-group changes. ResultsParents in the intervention group mostly showed better outcomes compared with those in the control group. Parents in the intervention group had higher perceived social support than those in the control group at the first (effect size=1.59, 95% CI 0.38-2.80; Cohen standardized effect size=1.31; P=.01), second (effect size=1.98, 95% CI 1.09-2.88; Cohen standardized effect size=2.21; P=.003), and fourth (effect size=2.57, 95% CI 1.62-3.51; Cohen standardized effect size=2.72; P=.048) months post partum. However, parents in the intervention group showed significantly poorer parental bonding (effect size=1.67, 95% CI 0.24-3.11; Cohen standardized effect size=1.16; P=.02). The other parental outcomes did not differ significantly between groups. The scores of mothers and fathers also differed significantly for all outcomes except parental self-efficacy. ConclusionsParents in the intervention group generally fared better, especially regarding perceived social support. However, the lack of statistical significance in most outcomes showed the limited effectiveness of the SPA intervention, which may be because of the COVID-19 pandemic. Parental differences in outcome scores suggest that mothers and fathers have different support needs; therefore, interventions should be tailored accordingly. Further improvements and evaluations are needed to examine the effectiveness of the SPA intervention in enhancing parental outcomes. Despite statistically insignificant results, limitations should be considered to further improve mobile health app–based interventions such as SPA, as they could serve as reliable and convenient sources of support for parents. Trial RegistrationClinicaltrails.gov NCT4706442; https://clinicaltrials.gov/ct2/show/NCT04706442

Childhood-onset depression has adverse consequences that are sustained into adulthood, which increases the significance of detection in early childhood. The Children's Depression Inventory (CDI) is used globally in evaluating depressive symptom severity in adolescents, and its second version, the CDI-2, was developed by taking into account advances in childhood depression research. Prior research has reported inconsistencies in its factor structure across populations. In addition, the CDI-2 has not yet been empirically validated with Southeast Asian populations. This study sought to empirically validate the CDI-2's psychometric properties and evaluate its factorial structure with a Singaporean community sample of non-clinical respondents. A total sample of 730 Singaporean children aged between 8.5 and 10.5 years was used. Psychometric properties of the CDI-2, including internal consistency as well as convergent and discriminant validity, were assessed. Factor analyses were conducted to assess the developers' original two-factor structure for a Southeast Asian population. This two-factor structure was not supported in our sample. Instead, the data provided the best fit for a hierarchical two-factor structure with factors namely, socio-emotional problems and cognitive-behavioural problems. This finding suggests that socio-cultural and demographic elements influence interpretation of depressive symptoms and therefore the emerging factor structure of the construct under scrutiny. This study highlights the need to further examine the CDI-2 and ensure that its interpretation is culture-specific. More qualitative work could also bring to light the idiosyncratic understanding of depressive symptomatology, which would then guide culture-specific validation of the CDI-2.

Background: Childhood depression is a highly distinct and prevalent condition with an unknown neurobiological basis. We wish to explore the resting state fMRI data in children for potential associations between neural connectivity and childhood depressive symptoms. Methods: A longitudinal birth cohort study with neuroimaging data obtained at 4.5, 6.0 and 7.5 years of age and the Children Depression Inventory 2 (CDI) administered between 8.5 and 10.5 years was used. The CDI score was used as the dependent variable and tested for correlation, both simple Pearson and network based statistic, with the functional connectivity values obtained from the resting state fMRI. Cross-validated permutation testing with a general linear model was used to validate that the identified functional connections were indeed implicated in childhood depression. Results: Ten functional connections and four brain regions (Somatomotor Area B, Temporoparietal Junction, Orbitofrontal Cortex and Insula) were identified as significantly associated with childhood depressive symptoms for girls at 6.0 and 7.5 years. No significant functional connections were found in girls at 4.5 years or for boys at any timepoint. Network based statistic and permutation testing confirmed these findings. Conclusions: This study revealed significant sex-dependent associations of neural connectivity and childhood depressive symptoms. The regions identified are implicated in speech/language, social cognition and information integration and suggest unique pathways to childhood depressive symptoms.

IntroductionDuring pregnancy and lactation minerals such as zinc are required to support maternal and infant health. Zinc is involved in various cellular processes, with requirements increasing in pregnancy and lactation. In the setting of a randomized trial, we investigated the effects on human milk (HM) zinc concentrations of a micronutrient-containing supplement including zinc in the intervention (but not control) group, started preconception and taken throughout pregnancy until birth. Additionally, we characterized longitudinal changes in HM concentrations of zinc and other minerals (calcium, copper, iodine, iron, magnesium, manganese, phosphorus, potassium, selenium, and sodium).MethodsHM samples were collected across 7 time points from 1 week to 12 months from lactating mothers from Singapore (n = 158) and New Zealand (n = 180). HM minerals were quantified using sector field inductively coupled plasma mass spectrometry. Potential intervention effects on HM mineral concentrations were assessed using linear mixed models with a repeated measures design and time-weighted area-under-the-curve analyses.ResultsOver the first 3 months of lactation, HM zinc concentrations were 11% higher in the intervention group compared to the control group (p = 0.021). Higher HM zinc concentrations were most evident at 6 weeks of lactation. The intervention had no effect on HM concentrations of other minerals, which were not differently supplemented to the control and intervention groups. Temporal changes in HM minerals over 12 months of lactation were studied in the New Zealand mothers; HM zinc and copper concentrations progressively decreased throughout 12 months, while iron, potassium, sodium, and phosphorus decreased until 6 months then plateaued. HM calcium and magnesium initially increased in early lactation and iodine remained relatively constant throughout 12 months. HM manganese and selenium fell over the initial months of lactation, with a nadir at 6 months, and increased thereafter. The contrasting patterns of changes in HM mineral concentrations during lactation may reflect different absorption needs and roles at different stages of infancy.DiscussionOverall, this study indicates that HM zinc concentrations are influenced by maternal supplementation during preconception and pregnancy. Further studies are required to understand the associations between HM zinc and other minerals and both short- and long-term offspring outcomes.Trial registrationClinicalTrials.gov, identifier: NCT02509988, Universal Trial Number U1111-1171-8056. Registered on 16 July 2015. This is an academic-led study by the EpiGen Global Research Consortium.

Abstract 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 .

Abstract Abnormalities of red blood cell (RBC) indices may affect glycated haemoglobin (HbA1c) levels. We assessed the influence of haemoglobin (Hb) and mean corpuscular volume (MCV) on the performance of HbA1c in detecting dysglycaemia among reproductive aged women planning to conceive. Women aged 18–45 years (n = 985) were classified as normal (12 ≤ Hb ≤ 16 g/dL and 80 ≤ MCV ≤ 100 fL) and abnormal (Hb

Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen.

Abstract Background Nausea and vomiting of pregnancy (NVP) is common and underlying mechanisms are poorly understood. Longer-term offspring outcomes are also not well documented. This study aimed to determine if NVP, even in milder forms, is associated with adverse pregnancy and childhood growth outcomes. Methods In the GUSTO prospective mother-offspring cohort, women with singleton pregnancies (n = 1172) recruited in first trimester responded to interviewer-administered questions at 26–28 weeks’ gestation about earlier episodes of NVP since becoming pregnant. Pregnancy outcomes were obtained from medical records. Offspring height and weight measured at 15 time-points between birth to 72 months (m) were standardised for age and sex. Results 58.5% (n = 686) reported mild-moderate vomiting (mNVP), 10.5% (n = 123) severe vomiting (sNVP) and 5.7% (n = 67) severe vomiting with hospitalisation (shNVP). There was no difference in odds of gestational diabetes, hypertensive disorders of pregnancy, labour induction or caesarean section after adjustment for covariates. sNVP was associated with late preterm delivery [34+ 0–36+ 6 weeks’, adjusted OR = 3.04 (95% CI 1.39,6.68)], without increased odds of neonatal unit admission. Compared with no NVP, boys born to mothers with sNVP were longer at birth [adjusted β = 0.38 standard deviations (SDs) (95% CI 0.02,0.73)], remained taller [0.64 SDs (0.23,1.04) at 72 m] and heavier [0.57 SDs (0.05,1.08) at 60 m] without differences in BMI. Conversely, girls born to mothers with shNVP were lighter from 48 m [− 0.52 SDs (− 1.00, − 0.03)] onwards with lower BMI [− 0.61 SDs (− 1.12,-0.09)]. Conditional growth modelling revealed significant sex-divergence in weight-gain at birth-3 m, 6-9 m and 4–5 years. Conclusions Severe NVP was associated with late preterm delivery, and both mild-moderate and severe NVP associated with sex-dependent differences in early childhood growth. Boys whose mothers had NVP were taller and heavier from birth with faster growth in the first year, whereas, girls had poorer weight gain and were lighter by 48 m. As even milder severities of NVP could have long-term impact on offspring growth, further research is needed to determine mechanisms involved and implications on future health. Trial registration Clinicaltrials.gov identifier NCT01174875 .

Abstract 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.

Abstract We aimed to identify serum metabolites related to abnormal glucose metabolism (AGM) among women with gestational diabetes mellitus (GDM). The study recruited 50 women diagnosed with GDM during mid-late pregnancy and 50 non-GDM matchees in a Singapore birth cohort. At the 5-year post-partum follow-up, we applied an untargeted approach to investigate the profiles of serum metabolites among all participants. We first employed OPLS-DA and logistic regression to discriminate women with and without follow-up AGM, and then applied area under the curve (AUC) to assess the incremental indicative value of metabolic signatures on AGM. We identified 23 candidate metabolites that were associated with postpartum AGM among all participants. We then narrowed down to five metabolites [p-cresol sulfate, linoleic acid, glycocholic acid, lysoPC(16:1) and lysoPC(20:3)] specifically associating with both GDM and postpartum AGM. The combined metabolites in addition to traditional risks showed a higher indicative value in AUC (0.92–0.94 vs. 0.74 of traditional risks and 0.77 of baseline diagnostic biomarkers) and R2 (0.67–0.70 vs. 0.25 of traditional risks and 0.32 of baseline diagnostic biomarkers) in terms of AGM indication, compared with the traditional risks model and traditional risks and diagnostic biomarkers combined model. These metabolic signatures significantly increased the AUC value of AGM indication in addition to traditional risks, and might shed light on the pathophysiology underlying the transition from GDM to AGM.

Summary: Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptoms only in mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.

The lack of standardized clinical practice impeding the optimal management of iron deficiency (ID) and iron deficiency anemia (IDA) in women is a global concern, particularly in the Asia-Pacific region. The aim of this study was to determine best practices through a Delphi consensus process. In Round 1, panelists were asked to rate their level of agreement with 99 statements across four domains: identification, diagnosis and assessment, prevention, and treatment of ID/IDA in women. In Round 2, panelists reappraised their ratings in view of the collective feedback and responses to Round 1. After two rounds, consensus (≥85% agreement) was reached for 84% of the Delphi statements. Experts agreed on the role of presenting symptoms and risk factors in prompting assessments of anemia and iron status in women. Experts repeatedly called for prevention, recommending preventive iron supplementation for pregnant women irrespective of anemia prevalence levels, and for non-pregnant adult women, adolescent girls, and perimenopausal women living in areas with a high prevalence of anemia. Experts unanimously agreed to prescribing oral ferrous iron as first-line therapy for uncomplicated ID/IDA. The recommendations and clinical pathway algorithms generated should be used to inform clinical practice and standardize the care of women at risk or presenting with ID/IDA in the Asia-Pacific region.

BackgroundThe increasing prevalence of gestational diabetes mellitus (GDM) is concerning as women with GDM are at high risk of type 2 diabetes (T2D) later in life. The magnitude of this risk highlights the importance of early intervention to prevent the progression of GDM to T2D. Rates of postpartum screening are suboptimal, often as low as 13% in Asian countries. The lack of preventive care through structured postpartum screening in several health care systems and low public awareness are key barriers to postpartum diabetes screening. ObjectiveIn this study, we developed a machine learning model for early prediction of postpartum T2D following routine antenatal GDM screening. The early prediction of postpartum T2D during prenatal care would enable the implementation of effective strategies for diabetes prevention interventions. To our best knowledge, this is the first study that uses machine learning for postpartum T2D risk assessment in antenatal populations of Asian origin. MethodsProspective multiethnic data (Chinese, Malay, and Indian ethnicities) from 561 pregnancies in Singapore’s most deeply phenotyped mother-offspring cohort study—Growing Up in Singapore Towards healthy Outcomes—were used for predictive modeling. The feature variables included were demographics, medical or obstetric history, physical measures, lifestyle information, and GDM diagnosis. Shapley values were combined with CatBoost tree ensembles to perform feature selection. Our game theoretical approach for predictive analytics enables population subtyping and pattern discovery for data-driven precision care. The predictive models were trained using 4 machine learning algorithms: logistic regression, support vector machine, CatBoost gradient boosting, and artificial neural network. We used 5-fold stratified cross-validation to preserve the same proportion of T2D cases in each fold. Grid search pipelines were built to evaluate the best performing hyperparameters. ResultsA high performance prediction model for postpartum T2D comprising of 2 midgestation features—midpregnancy BMI after gestational weight gain and diagnosis of GDM—was developed (BMI_GDM CatBoost model: AUC=0.86, 95% CI 0.72-0.99). Prepregnancy BMI alone was inadequate in predicting postpartum T2D risk (ppBMI CatBoost model: AUC=0.62, 95% CI 0.39-0.86). A 2-hour postprandial glucose test (BMI_2hour CatBoost model: AUC=0.86, 95% CI 0.76-0.96) showed a stronger postpartum T2D risk prediction effect compared to fasting glucose test (BMI_Fasting CatBoost model: AUC=0.76, 95% CI 0.61-0.91). The BMI_GDM model was also robust when using a modified 2-point International Association of the Diabetes and Pregnancy Study Groups (IADPSG) 2018 criteria for GDM diagnosis (BMI_GDM2 CatBoost model: AUC=0.84, 95% CI 0.72-0.97). Total gestational weight gain was inversely associated with postpartum T2D outcome, independent of prepregnancy BMI and diagnosis of GDM (P=.02; OR 0.88, 95% CI 0.79-0.98). ConclusionsMidgestation weight gain effects, combined with the metabolic derangements underlying GDM during pregnancy, signal future T2D risk in Singaporean women. Further studies will be required to examine the influence of metabolic adaptations in pregnancy on postpartum maternal metabolic health outcomes. The state-of-the-art machine learning model can be leveraged as a rapid risk stratification tool during prenatal care. Trial RegistrationClinicalTrials.gov NCT01174875; https://clinicaltrials.gov/ct2/show/NCT01174875

Summary: Background: Few studies have investigated molecular biomarkers of specific executive function (EF) skills in children. We aimed to characterise the prospective associations between metabolome and multiple domains of EF using a bidirectional design. Methods: This study was conducted within a longitudinal birth cohort, the Growing Up in Singapore Towards healthy Outcomes (GUSTO). Circulating levels of 165 metabolites were quantified using a nuclear magnetic resonance based metabolomics platform (n = 457 (∼6yrs) and n = 524 (∼8yrs)). Parent-reported EF was available for 495 children (∼7yrs). Multivariate linear regression was used to assess the metabolite-EF relationships. We examined the role of body composition, dietary factors, and genetics in the metabolite-EF associations. Findings: Higher leucine level (∼6yrs) was associated with poorer EF (∼7yrs, Initiate (P = 0.003) and Working Memory (P = 0.004)). EF (∼7yrs) was not associated with leucine (∼8yrs). Importantly, we found weak evidence for associations of dietary factors (∼5yrs) with leucine (∼6yrs) and EF (∼7yrs). Each copy of C allele in rs1260326 (a leucine-related polymorphism) was associated with higher leucine level and poorer Initiate and Working Memory (P

Background: Allergic sensitization is linked to allergy development, with early sensitization often associated with worse outcomes. We aimed to identify if distinct allergic sensitization trajectories existed within a diverse and multi-ethnic Asian cohort. Methods: We administered modified ISAAC questionnaires in the first 8 years and conducted skin prick testing at ages 18 months, 3, 5 and 8 years in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We used latent class analysis to derive allergic sensitization trajectories, and adjusted odds ratios (AOR) to evaluate predictive risk factors and associations with allergic comorbidities. Results: Among 997 children, three trajectories were identified: early food and mite sensitization (16.2%), late mite sensitization (24.2%) and no/low sensitization (59.6%). Early food and mite sensitization was associated with early eczema by 6 months [AOR (95%CI) 4.67 (1.78–12.28)], increased risk of wheeze by 3–8 years (ARR 1.72–1.99) and eczema in the first 8 years of life (ARR 1.87–2.41). Late mite sensitization was associated with female sex [AOR 0.58 (0.35–0.96)], cesarean section [AOR 0.54 (0.30–0.98)], early eczema by 6 months [AOR 3.40 (1.38–8.42)], and increased risk of eczema by 18 months [ARR 1.47 (1.03–2.08)] and 8 years [ARR 1.35 (1.05–1.73)]. Conclusion: Early onset of eczema and early allergic sensitization were strongly associated. Early sensitization, especially to house dust mites, was associated with increased risks of developing wheeze and eczema, pointing to the importance of developing preventive perinatal interventions and effective therapeutics for sensitized toddlers.

Early differences in reward behavior have been linked to executive functioning development. The nucleus accumbens (NAc) and orbitofrontal cortex (OFC) are activated by reward-related tasks and identified as key nodes of the brain circuit that underlie reward processing. We aimed to investigate the relation between NAc-OFC structural and functional connectivity in preschool children, as well as associations with future reward sensitivity and executive function. We showed that NAc-OFC structural and functional connectivity were not significantly associated in preschool children, but both independently predicted sensitivity to reward in males in a left-lateralized manner. Moreover, significant NAc-OFC structure-function coupling was only found in individuals who performed poorly on executive function tasks in later childhood, but not in the middle- and high-performing groups. As structure-function coupling is proposed to measure functional specialization, this finding suggests premature functional specialization within the reward network, which may impede dynamic communication with other regions, affects executive function development. Our study also highlights the utility of multimodal imaging data integration when studying the effects of reward network functional flexibility in the preschool age, a critical period in brain and executive function development.

Abstract While maternal mental health strongly influences neurodevelopment and health in the offspring, little is known about the determinants of inter-individual variation in the mental health of mothers. Likewise, the in utero biological pathways by which variation in maternal mental health affects offspring development remain to be defined. Previous studies implicate lipids, consistent with a known influence on cognitive and emotional function, but the relevance for maternal mental health and offspring neurodevelopment is unclear. This study characterizes the placental and circulatory lipids in antenatal depression, as well as socio-emotional outcomes in the offspring. Targeted liquid chromatography-mass spectrometry covering 470 lipid species was performed on placenta from 186 women with low (n = 70) or high (n = 116) levels of antenatal depressive symptoms assessed using the Edinburgh Postnatal Depression Scale at 26 weeks’ gestation. Child socio-emotional outcomes were assessed from the Child Behavior Check List (CBCL) at 48 months. Seventeen placental lipid species showed an inverse association with antenatal EPDS scores. Specifically, lower levels of phospholipids containing LC-PUFAs: omega-3 docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-6 arachidonic acid (AA) were significantly associated with depressive symptoms. Additional measurement of LC-PUFA in antenatal plasma samples at mid-gestation confirmed the reduced circulation of these specific fatty acids in mothers. Reduced concentration of the placental phospholipids also predicted poorer socio-emotional outcomes in the offspring. This study provides new insights into the role of the materno-fetal lipid cross-talk as a mechanism linking maternal mental health to that of the offspring. These findings show the potential utility of nutritional approaches among pregnant women with depressive symptoms to reduce offspring risk for later socio-emotional problems.

Adopting a healthy diet during and after pregnancy is important for women’s cardiometabolic health. We related changes in diet quality from pregnancy to 6 years postpregnancy to cardiometabolic markers 8 years postpregnancy. In 652 women from the GUSTO cohort, we assessed dietary intakes at 26–28 weeks’ gestation and 6 years postpregnancy using 24 h recall and a food frequency questionnaire, respectively; diet quality was scored using a modified Healthy Eating Index for Singaporean women. Diet quality quartiles were derived; stable, large/small improvement/decline in diet quality as no change, >1 or 1 quartile increase/decrease. Fasting triglyceride (TG), total-, high- and low-density-lipoprotein cholesterol (TC, HDL- and LDL-C), glucose and insulin were measured 8 years postpregnancy; homeostatic model assessment for insulin resistance (HOMA-IR) and TG: HDL-C ratio were derived. Linear regressions examined changes in diet quality quartiles and cardiometabolic markers. Compared to a stable diet quality, a large improvement was associated with lower postpregnancy TG [−0.17 (−0.32, −0.01) mmol/L], TG: HDL-C ratio [−0.21 (−0.35, −0.07) mmol/L], and HOMA-IR [−0.47 (−0.90, −0.03)]; a large decline was associated with higher postpregnancy TC and LDL-C [0.25 (0.02, 0.49); 0.20 (0.004, 0.40) mmol/L]. Improving or preventing a decline in diet quality postpregnancy may improve lipid profile and insulin resistance.

BackgroundThe cost-effectiveness of interventions has attracted increasing interest among researchers. Although web-based and home-based psychoeducational interventions have been developed to improve first-time mothers’ postnatal health outcomes, very limited studies have reported their cost-effectiveness. ObjectiveThe aim of this study was to evaluate the cost-effectiveness of web-based and home-based postnatal psychoeducational interventions for first-time mothers during the early postpartum period. MethodsA randomized controlled 3-group pretest and posttest design was adopted, and cost-effectiveness analysis from the health care’s perspective was conducted. A total of 204 primiparas were recruited from a public tertiary hospital in Singapore from October 2016 to August 2017 who were randomly allocated to the web-based intervention (n=68), home-based intervention (n=68), or control (n=68) groups. Outcomes of maternal parental self-efficacy, social support, postnatal depression, anxiety, and health care resource utilization were measured using valid and reliable instruments at baseline and at 1 month, 3 months, and 6 months after childbirth. The generalized linear regression models on effectiveness and cost were used to assess the incremental cost-effectiveness ratios of the web-based and home-based intervention programs compared to routine care. Projections of cumulative cost over 5 years incurred by the 3 programs at various coverage levels (ie, 10%, 50%, and 100%) were also estimated. ResultsThe web-based intervention program dominated the other 2 programs (home-based program and routine care) with the least cost (adjusted costs of SGD 376.50, SGD 457.60, and SGD 417.90 for web-based, home-based, and control group, respectively; SGD 1=USD 0.75) and the best improvements in self-efficacy, social support, and psychological well-being. When considering the implementation of study programs over the next 5 years by multiplying the average cost per first-time mother by the estimated average number of first-time mothers in Singapore during the 5-year projection period, the web-based program was the least costly program at all 3 coverage levels. Based on the 100% coverage, the reduced total cost reached nearly SGD 7.1 million and SGD 11.3 million when compared to control and home-based programs at the end of the fifth year, respectively. ConclusionsThe web-based approach was promisingly cost-effective to deliver the postnatal psychoeducational intervention to first-time mothers and could be adopted by hospitals as postnatal care support. Trial RegistrationISRCTN registry ISRCTN45202278; https://www.isrctn.com/ISRCTN45202278

BackgroundIncreasing evidence suggests that maternal distress is a risk factor for development of respiratory infections and allergic diseases in the offspring. We aim to evaluate the link between maternal distress during critical periods in early life, namely the preconception, pregnancy and postnatal periods, and development of respiratory infections and allergic diseases in the offspring from the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohort.MethodsMaternal perceived distress was evaluated using validated questionnaires including Beck Depression Inventory-II (BDI-II) administered during three time periods: preconception (three months apart at four timepoints), pregnancy (during each trimester) and postnatal (3 and 6 months post-delivery). Child eczema, rhinitis and wheeze outcomes were evaluated using a modified ISAAC questionnaire at ages 3, 6, 12, and 18 months. Child allergic sensitization was determined by skin prick testing at 18 months.ResultsAmong 332 mother-child pairs studied, higher maternal distress during preconception and pregnancy increased the risks of wheeze development in the first 18 months; for example, preconception and pregnancy BDI-II scores ≥20 were associated with increased risks of wheeze by 18 months [adjusted risk ratios 3.2 (95%CI 1.1–9.4) and 2.5 (1.0–5.9), respectively]. Emotional and practical support from family during preconception decreased the risks of offspring wheeze. No associations were observed between maternal distress and offspring eczema, rhinitis and allergic sensitization.ConclusionMaternal distress during critical early life periods was associated with offspring wheeze in the first 18 months of life. Supporting maternal mental health even before pregnancy could reduce the risk of offspring wheeze.

BackgroundEpidemiological studies suggest a link between eczema and attention deficit hyperactivity disorder (ADHD), but underlying mechanisms have not been examined.ObjectiveWe aim to investigate the association between eczema and subsequent ADHD symptoms in the Growing Up in Singapore Towards healthy Outcomes cohort and explore the role of pro-inflammatory cytokines and gut microbiome.MethodsThe modified International Study of Asthma and Allergies in Childhood questionnaire and Computerized Diagnostic Interview Schedule for Children Version IV were administered to assess reported eczema within the first 18 months and presence of ADHD symptoms at 54 months, respectively. Skin prick testing at 18 months, cytokines in maternal blood during pregnancy and cord blood and the mediating role of the gut microbiome at 24 months were assessed.ResultsAfter adjusting for confounders, eczema with or without a positive skin prick test was associated with doubling the risk of ADHD symptoms. No differences in maternal and cord blood cytokines were observed in children with and without eczema, or children with and without ADHD. Gut microbiome dysbiosis was observed in children with eczema and children with ADHD. Children with eczema also had lower gut bacterial Shannon diversity. However, the relationship between eczema and ADHD was not mediated by gut microbiome.ConclusionEarly life eczema diagnosis is associated with a higher risk of subsequent ADHD symptoms in children. We found no evidence for underlying inflammatory mechanism or mediation by gut microbiome dysbiosis. Further research should evaluate other mechanisms underlying the link between eczema and ADHD.Clinical Trial Registration[https://clinicaltrials.gov/ct2/show/NCT01174875], identifier [NCT01174875].

Abstract We investigated whether adding anthropometric measures to HbA1c would have stronger discriminative ability over HbA1c alone in detecting dysglycemia (diabetes and prediabetes) among Asian women trying to conceive. Among 971 Singaporean women, multiple regression models and area under receiver-operating characteristic (AUROC) curves were used to analyze associations of anthropometric (weight, height, waist/hip circumferences, 4-site skinfold thicknesses) and HbA1c z-scores with dysglycemia (fasting glucose ≥6.1 mmol/L with 2-hour glucose ≥7.8 mmol/l). The prevalence of dysglycemia was 10.9%. After adjusting for sociodemographic/medical history, BMI (Odds Ratio [OR] = 1.62 [95%CI 1.32–1.99]), waist-to-height ratio (OR = 1.74 [1.39–2.17]) and total skinfolds (OR = 2.02 [1.60–2.55]) showed the strongest associations with dysglycemia but none outperformed HbA1c (OR = 4.09 [2.81–5.94]). After adjustment for history, adding BMI, waist-to-height ratio and total skinfolds (anthropometry trio) as continuous variables to HbA1c (AUROC = 0.80 [95%CI 0.75–0.85]) performed similarly to HbA1c alone (AUROC = 0.79 [0.74–0.84]). However, using clinically-defined thresholds without considering history, as in common clinical practice, BMI ≥ 23 kg/m2 + HbA1c ≥ 5.7% (AUROC = 0.70 [0.64–0.75]) and anthropometry trio + HbA1c ≥ 5.7% (AUROC = 0.71 [0.65–0.76]) both outperformed HbA1c ≥ 5.7% alone (AUROC = 0.61 [0.57–0.65]). In a two-stage strategy, incorporating BMI ≥ 23 kg/m2 alongside HbA1c ≥ 5.7% into first-stage screening to identify high risk women for subsequent oral glucose tolerance testing improves dysglycemia detection in Asian women preconception.

Abstract 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.