Yap-Seng Chong

Cohort Profile: Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study

Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore Institute for Clinical Sciences, Agency for Science and Technology Research (A*STAR), Brenner Centre for Molecular Medicine, Singapore, Liggins Institute, University of Auckland, Auckland, New Zealand, Medical Research Council Lifecourse Epidemiology Unit, Southampton, UK, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK, Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore and KK Women’s and Children’s Hospital, Singapore

Antenatal education and postnatal support strategies for improving rates of exclusive breast feeding: randomised controlled trial

Objective To investigate whether antenatal breast feeding education alone or postnatal lactation support alone improves rates of exclusive breast feeding compared with routine hospital care. Design Randomised controlled trial. Setting A tertiary hospital in Singapore. Participants 450 women with uncomplicated pregnancies. Main outcome measures Primary outcomes were rates of exclusive breast feeding at discharge from hospital and two weeks, six weeks, three months, and six months after delivery. Secondary outcomes were rates of any breast feeding. Results Compared with women who received routine care, women in the postnatal support group were more likely to breastfeed exclusively at two weeks (relative risk 1.82, 95% confidence interval 1.14 to 2.90), six weeks (1.85, 1.11 to 3.09), three months (1.87, 1.03 to 3.41), and six months (2.12, 1.03 to 4.37) postnatally. Women receiving antenatal education were more likely to breast feed exclusively at six weeks (1.73, 1.04 to 2.90), three months (1.92, 1.07 to 3.48), and six months (2.16, 1.05 to 4.43) postnatally. The numbers needed to treat to achieve one woman exclusively breast feeding at six months were 11 (6 to 80) for postnatal support and 10 (6 to 60) for antenatal education. Women who received postnatal support were more likely to exclusively or predominantly breast feed two weeks after delivery compared with women who received antenatal education (1.53, 1.01 to 2.31). The rate of any breastfeeding six weeks after delivery was also higher in the postnatal support group compared with women who received routine care (1.16, 1.02 to 1.31). Conclusions Antenatal breast feeding education and postnatal lactation support, as single interventions based in hospital both significantly improve rates of exclusive breast feeding up to six months after delivery. Postnatal support was marginally more effective than antenatal education. Trial registration Clinical Trials NCT00270920.

Dynamics of Infant Gut Microbiota Are Influenced by Delivery Mode and Gestational Duration and Are Associated with Subsequent Adiposity

ABSTRACT  We found that the relatively simple microbiota of young infants shifts predictably to a more mature anaerobic microbiota during infancy and the dynamics of this shift are influenced by environmental factors. In this longitudinal study of 75 infants, we demonstrate high interindividual variability within the normal range of birth outcomes, especially in the rate of microbiota progression. Most had acquired a microbiota profile high in Bifidobacterium and Collinsella by 6 months of age, but the time point of this acquisition was later in infants delivered by caesarean section and those born after a shorter duration of gestation. Independently of the delivery mode and gestation duration, infants who acquired a profile high in Bifidobacterium and Collinsella at a later age had lower adiposity at 18 months of age. IMPORTANCE  This study shows that the acquisition of the early microbiota is strongly influenced by environmental factors such as the delivery mode and duration of gestation, even in healthy neonates. The composition of the early microbiota has been linked with long-lasting effects on health and disease. Here we show that the rate of acquisition of certain microbiota predicts adiposity at 18 months of age and so potentially the risk of later obesity. This study shows that the acquisition of the early microbiota is strongly influenced by environmental factors such as the delivery mode and duration of gestation, even in healthy neonates. The composition of the early microbiota has been linked with long-lasting effects on health and disease. Here we show that the rate of acquisition of certain microbiota predicts adiposity at 18 months of age and so potentially the risk of later obesity.

Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth.

BACKGROUND Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development. METHODS Our study recruited Asian mothers at 10 to 13 weeks pregnancy and assessed maternal depression at 26 weeks gestation using the Edinburgh Postnatal Depression Scale. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 157 nonsedated, 6- to 14-day-old newborns and then analyzed to extract the volume, fractional anisotropy, and axial diffusivity values of the amygdala. RESULTS Adjusting for household income, maternal age, and smoking exposure, postconceptual age at magnetic resonance imaging, and birth weight, we found significantly lower fractional anisotropy (p = .009) and axial diffusivity (p = .028), but not volume (p = .993), in the right amygdala in the infants of mothers with high compared with those with low-normal Edinburgh Postnatal Depression Scale scores. CONCLUSIONS The results reveal a significant relation between antenatal maternal depression and the neonatal microstructure of the right amygdala, a brain region closely associated with stress reactivity and vulnerability for mood anxiety disorders. These findings suggest the prenatal transmission of vulnerability for depression from mother to child and that interventions targeting maternal depression should begin early in pregnancy.

Prenatal maternal depression alters amygdala functional connectivity in 6-month-old infants.

Prenatal maternal depression is associated with alterations in the neonatal amygdala microstructure, shedding light on the timing for the influence of prenatal maternal depression on the brain structure of the offspring. This study aimed to examine the association between prenatal maternal depressive symptomatology and infant amygdala functional connectivity and to thus establish the neural functional basis for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Twenty-four infants were included in this study with both structural magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) at 6 months of age. Maternal depression was assessed at 26 weeks of gestation and 3 months after delivery using the Edinburgh Postnatal Depression Scale. Linear regression was used to identify the amygdala functional networks and to examine the associations between prenatal maternal depressive symptoms and amygdala functional connectivity. Our results showed that at 6 months of age, the amygdala is functionally connected to widespread brain regions, forming the emotional regulation, sensory and perceptual, and emotional memory networks. After controlling for postnatal maternal depressive symptoms, infants born to mothers with higher prenatal maternal depressive symptoms showed greater functional connectivity of the amygdala with the left temporal cortex and insula, as well as the bilateral anterior cingulate, medial orbitofrontal and ventromedial prefrontal cortices, which are largely consistent with patterns of connectivity observed in adolescents and adults with major depressive disorder. Our study provides novel evidence that prenatal maternal depressive symptomatology alters the amygdalas functional connectivity in early postnatal life, which reveals that the neuroimaging correlates of the familial transmission of phenotypes associated with maternal mood are apparent in infants at 6 months of age.

Measuring the methylome in clinical samples: Improved processing of the Infinium Human Methylation450 BeadChip Array

The Infinium Human Methylation450 BeadChip ArrayTM (Infinium 450K) is an important tool for studying epigenetic patterns associated with disease. This array offers a high-throughput, low cost alternative to more comprehensive sequencing-based methodologies. Here we compare data generated by interrogation of the same seven clinical samples by Infinium 450K and reduced representation bisulfite sequencing (RRBS). This is the largest data set comparing Infinium 450K array to the comprehensive RRBS methodology reported so far. We show good agreement between the two methodologies. A read depth of four or more reads in the RRBS data was sufficient to achieve good agreement with Infinium 450K. However, we observe that intermediate methylation values (20–80%) are more variable between technologies than values at the extremes of the bimodal methylation distribution. We describe careful processing of Infinium 450K data to correct for known limitations and batch effects. Using methodologies proposed by others and newly implemented and combined in this report, agreement of Infinium 450K data with independent techniques can be vastly improved.

Maternal anxiety and infants' hippocampal development: timing matters.

Exposure to maternal anxiety predicts offspring brain development. However, because children’s brains are commonly assessed years after birth, the timing of such maternal influences in humans is unclear. This study aimed to examine the consequences of antenatal and postnatal exposure to maternal anxiety upon early infant development of the hippocampus, a key structure for stress regulation. A total of 175 neonates underwent magnetic resonance imaging (MRI) at birth and among them 35 had repeated scans at 6 months of age. Maternal anxiety was assessed using the State-Trait Anxiety Inventory (STAI) at week 26 of pregnancy and 3 months after delivery. Regression analyses showed that antenatal maternal anxiety did not influence bilateral hippocampal volume at birth. However, children of mothers reporting increased anxiety during pregnancy showed slower growth of both the left and right hippocampus over the first 6 months of life. This effect of antenatal maternal anxiety upon right hippocampal growth became statistically stronger when controlling for postnatal maternal anxiety. Furthermore, a strong positive association between postnatal maternal anxiety and right hippocampal growth was detected, whereas a strong negative association between postnatal maternal anxiety and the left hippocampal volume at 6 months of life was found. Hence, the postnatal growth of bilateral hippocampi shows distinct responses to postnatal maternal anxiety. The size of the left hippocampus during early development is likely to reflect the influence of the exposure to perinatal maternal anxiety, whereas right hippocampal growth is constrained by antenatal maternal anxiety, but enhanced in response to increased postnatal maternal anxiety.

The Influence of Birth Size on Intelligence in Healthy Children

OBJECTIVE. Birth parameters have been hypothesized to have an influence on IQ. However, studies within the range of normal birth size have been sparse. With this study we examined the associations between birth length, birth weight, head circumference, and gestational age within the normal birth size range in relation to childhood IQ in Asian children. METHODS. A cohort of 1979 of 2913 Asian children aged 7 to 9 years, recruited from 3 schools in Singapore, were followed yearly from 1999 onward. Birth parameters were recorded by health personnel. Childhood IQ was measured with the Ravens Standard Progressive Matrices at ages 8 to 12. RESULTS. The mean IQ score across the sample (n = 1645) was 114.2. After controlling for multiple confounders for every 1-cm increment in birth length, 1 kg in birth weight, or 1 cm in head circumference, there was a corresponding increase in IQ of 0.49 points (P for trend < .001), 2.19 points (P for trend = .007) and .62 points (P for trend = .003), respectively. These associations persisted even after exclusion of premature children and children with extreme weights and head circumferences. CONCLUSIONS. Longer birth length, higher birth weight, or larger head circumferences within the normal birth size range are associated with higher IQ scores in Asian children. Our results suggest that antenatal factors reflected in altered rates of growth but within the normative range of pregnancy experiences play a role in generating cognitive potential. This has implications for targeting early intervention and preventative programs.

Structural connectivity asymmetry in the neonatal brain

Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-world characteristics were exhibited, but did not differ between the two hemispheres, suggesting that neighboring brain regions connect tightly with each other, and that one region is only a few paths away from any other region within each hemisphere. Moreover, the neonatal brain showed greater structural efficiency in the left hemisphere than that in the right. In neonates, brain regions involved in motor, language, and memory functions play crucial roles in efficient communication in the left hemisphere, while brain regions involved in emotional processes play crucial roles in efficient communication in the right hemisphere. These findings suggest that even at birth, the topology of each cerebral hemisphere is organized in an efficient and compact manner that maps onto asymmetric functional specializations seen in adults, implying lateralized brain functions in infancy.

Unravelling the Mystery of Stem/Progenitor Cells in Human Breast Milk

Background Mammary stem cells have been extensively studied as a system to delineate the pathogenesis and treatment of breast cancer. However, research on mammary stem cells requires tissue biopsies which limit the quantity of samples available. We have previously identified putative mammary stem cells in human breast milk, and here, we further characterised the cellular component of human breast milk. Methodology/Principal Findings We identified markers associated with haemopoietic, mesenchymal and neuro-epithelial lineages in the cellular component of human breast milk. We found 2.6±0.8% (mean±SEM) and 0.7±0.2% of the whole cell population (WCP) were found to be CD133+ and CD34+ respectively, 27.8±9.1% of the WCP to be positive for Stro-1 through flow-cytometry. Expressions of neuro-ectodermal stem cell markers such as nestin and cytokeratin 5 were found through reverse-transcription polymerase chain reaction (RT-PCR), and in 4.17±0.2% and 0.9±0.2% of the WCP on flow-cytometry. We also established the presence of a side-population (SP) (1.8±0.4% of WCP) as well as CD133+ cells (1.7±0.5% of the WCP). Characterisation of the sorted SP and non-SP, CD133+ and CD133- cells carried out showed enrichment of CD326 (EPCAM) in the SP cells (50.6±8.6 vs 18.1±6.0, P-value  = 0.02). However, culture in a wide range of in vitro conditions revealed the atypical behaviour of stem/progenitor cells in human breast milk; in that if they are present, they do not respond to established culture protocols of stem/progenitor cells. Conclusions/Significance The identification of primitive cell types within human breast milk may provide a non-invasive source of relevant mammary cells for a wide-range of applications; even the possibility of banking ones own stem cell for every breastfeeding woman.