Associations of cord plasma per- and polyfluoroakyl substances (PFAS) with neonatal and child body composition and adiposity: The GUSTO study.

BACKGROUND: The influence of prenatal exposure to per- and poly- fluoroalkyl substances (PFAS) on birth size and offspring adiposity is unclear, especially for the newer, shorter-chained replacement PFAS. METHODS: In the GUSTO multi-ethnic Singaporean mother-offspring cohort, 12 PFAS were measured in 783 cord plasma samples using ultra-performance-liquid chromatography-tandem-mass-spectrometer (UPLC-MS/MS). Outcomes included offspring anthropometry, other indicators of body composition/metabolic health, and MRI-derived abdominal adiposity (subset) at birth and 6 years of age. PFAS were modeled individually, in categories of long-chain and short-chain PFAS, and as scores of three principal components (PC) derived using PC analysis (PC1, PC2, and PC3 reflect predominant exposure patterns to "very-long-PFAS", "long-PFAS", and "short-PFAS", respectively). Associations with outcomes were assessed using multivariable linear regressions, adjusted for important covariates such as maternal sociodemographic and lifestyle factors. RESULTS: Overall, cord PFAS levels showed either no or positive associations (mostly for long-chain PFAS) with birth weight, length and head circumference. In general, PFAS were associated with higher neonatal abdominal adiposity, driven by shorter-chain PFAS. Perfluoroheptanoic acid (PFHpA) was associated with higher volumes of superficial subcutaneous adipose tissue (sSAT) (3.75 [1.13, 6.37] mL per SD increase in PFAS) and internal adipose tissue (IAT) (1.39 [0.41, 2.38] mL). Higher levels of perfluorobutanesulfonic acid (PFBS), short-chain PFAS, and PC3 were associated with higher IAT volume (ß range 1.22-1.41 mL/SD, all P < 0.02), especially in girls. Higher PC3 score was additionally associated with higher sSAT (3.12 [0.45, 5.80] mL) volume. At age 6 years, most observed associations did not persist. No consistent associations were observed between PFAS and whole-body adiposity measures. CONCLUSIONS: Fetal exposure to emerging short-chain PFAS was associated with higher abdominal adiposity at birth but not at age 6 years. Further research is needed to replicate the findings and to determine if these effects may reappear beyond early childhood. Population exposure to newer PFAS and consequent health impact must be monitored.

Environmental exposures in early-life and general health in childhood.

BACKGROUND: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. METHODS: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. FINDINGS: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score. CONCLUSION: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

Development and Evaluation of a Diet Quality Index for Preschool-Aged Children in an Asian population: The Growing Up in Singapore Towards Healthy Outcomes cohort.

BACKGROUND: Diet quality indexes are useful tools to measure diet quality because they compare dietary intakes against recommendations. A dietary quality index for Asian preschool-aged children is lacking. OBJECTIVE: The aims of this study were to develop and evaluate a dietary quality index for preschool-aged children (ie, the DQI-5) based on Singapore dietary recommendations and to examine diet quality in a cohort of 5-year-old children. An additional aim was to assess associations between sociodemographic characteristics and DQI-5 scores. DESIGN: A secondary analysis was conducted using dietary intake of children from the Growing Up in Singapore Towards healthy Outcomes mother-offspring cohort assessed in 2015-2016 using a validated food frequency questionnaire. The sociodemographic data were assessed at recruitment between June 2009 and September 2010. The DQI-5 was evaluated using a construct validity approach, whereby nutrition parameters associated with diet quality were studied. PARTICIPANTS AND SETTING: Participants were 767 Singaporean children aged 5 years of Chinese, Malay, or Indian ethnicity. MAIN OUTCOME MEASURES: The main outcome measures were the DQI-5 scores and the sociodemographic characteristics associated with diet quality. STATISTICAL ANALYSES PERFORMED: Kruskal-Wallis tests were used to evaluate differences in adherence to dietary recommendations across DQI-5 tertiles. Linear multiple regression analysis was performed to identify sociodemographic characteristics that were associated with diet quality in the children. RESULTS: The DQI-5 consists of 12 food and nutrient components, with a minimum score of zero and a maximum score of 110 points. The higher scores indicate a healthier diet, the mean ± SD DQI-5 score for the children was 61.6 ± 13.2. DQI-5 components with low scores included whole grains, vegetables, and fatty acid ratio, whereas total rice and alternatives and milk and dairy products components were overconsumed by 18% and 24.4% of children, respectively. Children with higher scores were more likely to meet dietary recommendations and had higher intake of nutrients such as dietary fiber, iron, vitamin A, and beta carotene. Children whose mothers were of Malay ethnicity and whose mothers had low income, an education below university, and shared primary caregiver responsibilities were more likely to have lower DQI-5 scores. CONCLUSIONS: The DQI-5 scores revealed diets to be low for several components and excessive for a few. The DQI-5 developed for preschool-aged children in Singapore had adequate construct validity.

Longitudinal characterization of determinants associated with obesogenic growth patterns in early childhood.

BACKGROUND: Longitudinal assessment of the determinants of obesogenic growth trajectories in childhood can suggest appropriate developmental windows for intervention. METHODS: Latent class growth mixture modelling was used to identify body mass index (BMI) z-score trajectories from birth to age 6 years in 994 children from a prospective mother-offspring cohort (Chinese, Indian and Malay ethnicities) based in Singapore. We evaluated the early-life determinants of the trajectories as well as their associations with cardiometabolic risk markers at age 6 years. RESULTS: Five BMI z-score trajectory patterns were identified, three within the healthy weight range, alongside early-acceleration and late-acceleration obesogenic trajectories. The early-acceleration pattern was characterized by elevated fetal abdominal circumference growth velocity, BMI acceleration immediately after birth and crossing of the obesity threshold by age 2 years. The late-acceleration pattern had normal fetal growth and BMI acceleration after infancy, and approached the obesity threshold by age 6 years. Abdominal fat, liver fat, insulin resistance and odds of pre-hypertension/hypertension were elevated in both groups. Indian ethnicity, high pre-pregnancy BMI, high polygenic risk scores for obesity and shorter breastfeeding duration were common risk factors for both groups. Malay ethnicity and low maternal educational attainment were uniquely associated with early BMI acceleration, whereas nulliparity and obesogenic eating behaviours in early childhood were uniquely associated with late BMI acceleration. CONCLUSION: BMI acceleration starting immediately after birth or after infancy were both linked to early cardiometabolic alterations. The determinants of these trajectories may be useful for developing early risk stratification and intervention approaches to counteract metabolic adversities linked to childhood obesity.

Associations of maternal and foetoplacental factors with prehypertension/hypertension in early childhood.

OBJECTIVE: To evaluate whether characterization of maternal and foetoplacental factors beyond birthweight can enable early identification of children at risk of developing prehypertension/hypertension. METHODS: We recruited 693 mother-offspring dyads from the GUSTO prospective mother-offspring cohort. Prehypertension/hypertension at age 6 years was identified using the simplified paediatric threshold of 110/70 mmHg. We evaluated the associations of pregnancy complications (gestational diabetes, excessive/inadequate gestational weight gain, hypertensive disorders of pregnancy), foetal growth deceleration (decline in foetal abdominal circumference at least 0.67 standard deviations between second and third trimesters), high foetoplacental vascular resistance (third trimester umbilical artery systolic-to-diastolic ratio ≥90th centile), preterm birth, small-for-gestational age and neonatal kidney volumes with risk of prehypertension/hypertension at age 6 years, after adjusting for sex, ethnicity, maternal education and prepregnancy BMI. RESULTS: Pregnancy complications, small-for-gestational age, preterm birth, and low neonatal kidney volume were not associated with an increased risk of prehypertension/hypertension at age 6 years. In contrast, foetal growth deceleration was associated with a 72% higher risk [risk ratio (RR) = 1.72, 95% confidence interval (CI) 1.18-2.52]. High foetoplacental vascular resistance was associated with a 58% higher risk (RR = 1.58, 95% CI 0.96-2.62). Having both these characteristics, relative to having neither, was associated with over two-fold higher risk (RR = 2.55, 95% CI 1.26-5.16). Over 85% of the foetuses with either of these characteristics were born appropriate or large for gestational age. CONCLUSION: Foetal growth deceleration and high foetoplacental vascular resistance may be helpful in prioritizing high-risk children for regular blood pressure monitoring and preventive interventions, across the birthweight spectrum.

Perinatal plasma carotenoid and vitamin E concentrations with maternal blood pressure during and after pregnancy.

BACKGROUND AND AIMS: Few studies examined the influence of carotenoids and vitamin E on blood pressure or hypertension during and after pregnancy. We related perinatal plasma concentrations of carotenoids and vitamin E (in individual forms and in combination) to blood pressure and hypertension at late pregnancy and 4 years post-pregnancy. METHODS AND RESULTS: In 684 women of the Growing Up in Singapore Towards Healthy Outcomes cohort, we quantified plasma carotenoids and vitamin E concentrations at delivery. Systolic blood pressure and diastolic blood pressure (SBP and DBP) around 37-39 weeks' gestation were extracted from obstetric records and measured at 4 years post-pregnancy. Principal component analysis derived patterns of carotenoids (CP) and vitamin E. Associations were examined using linear or logistic regressions adjusting for confounders. Two carotenoids (CP1: α-carotene, ß-carotene, and lutein; CP2: zeaxanthin, lycopene, and ß-cryptoxanthin) and one vitamin E (γ-, δ-, and α-tocopherols) patterns were derived. CP1 (1SD score increment) was associated with lower SBP and DBP [ß (95% CI): -2.36 (-3.47, -1.26) and -1.37 (-2.21, -0.53) mmHg] at late pregnancy> and 4 years post-pregnancy [-1.45 (-2.72, -0.18) and -0.99 (-1.98, -0.01) mmHg]. Higher ß-cryptoxanthin concentrations were associated with lower SBP and DBP [-1.50 (-2.49, -0.51) and -1.20 (-1.95, -0.46) mmHg] at late pregnancy. Individual vitamin E and their pattern were not associated with blood pressure or hypertension. CONCLUSION: Higher perinatal α-carotene, ß-carotene, and lutein concentrations are associated with lower blood pressure in women at late pregnancy and post-pregnancy. Foods rich in these carotenoids, such as red-, orange-, and dark-green-colored vegetables, might be beneficial for blood pressure during and after pregnancy.

Newborn body composition and child cardiovascular risk markers: a prospective multi-ethnic Asian cohort study.

BACKGROUND: Early epidemiological studies have associated low birthweight with increased cardiovascular risk. We aimed to examine whether the fat and fat-free components of birthweight have differing relationships with childhood cardiovascular risk markers. METHODS: In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, air displacement plethysmography was conducted within 24 h after delivery in 290 naturally conceived singletons. We investigated associations of newborn cohort-specific standardized z-score of fat mass, fat-free mass, body fat percentage and birthweight on child (at 6 years of age) carotid intima-media thickness, pulse wave velocity, blood pressure, prehypertension/hypertension (>110/70 mmHg) and standardized systolic and diastolic blood pressure (SBP and DBP) trajectories (at 3-6 years of age), taking account of maternal education, height, tobacco exposure, parity, ethnicity, child's sex, gestational age, age at follow-up, and other maternal factors. RESULTS: Clear inverse associations were seen for blood pressure with z-score of fat mass [SBP, ß (95% CI): -1.31 mmHg (-2.57, -0.06); DBP: -0.79 mmHg (-1.74, 0.15)] and body fat percentage [SBP: -1.46 mmHg (-2.73, -0.19); DBP: -0.80 mmHg (-1.75, 0.16)], but not with fat-free mass [SBP: 0.27 mmHg (-1.29, 1.83)]; DBP: -0.14 mmHg (-1.30, 1.03)]. Being in the lowest tertile of fat mass or body fat percentage was associated with higher blood pressure trajectories and prehypertension/hypertension risk [OR (95% CI), fat mass: 4.23 (1.41, 12.68); body fat percentage: 3.22 (1.09, 9.53)] without concomitantly higher overweight/obesity risk. CONCLUSIONS: At birth, low adiposity was associated with increased childhood blood pressure. Low newborn adiposity might serve as a marker of poor fetal growth or suboptimal intrauterine conditions associated with hypertension risk later in life.

Associations of maternal periconceptional alcohol consumption with offspring prehypertension/hypertension at age 6 years: the Growing Up in Singapore Towards healthy Outcomes prospective mother-offspring cohort study.

OBJECTIVE: To evaluate the relationship of the levels of maternal alcohol consumption during the 1 year before pregnancy recognition with childhood cardiorenal, metabolic, and neurocognitive health. METHODS: In 1106 women and their children from the Growing Up in Singapore Towards healthy Outcomes mother-offspring cohort, quantity of maternal alcohol consumption in the 12 months prior to pregnancy recognition was categorized as high (≥75th percentile: 1.9 g/day), low (<1.9 g/day), and none, and frequency of alcohol consumption was categorized as high (≥2-3 times/week), low (<2-3 times/week), and none. Offspring MRI-based abdominal fat depot, kidney, and brain volumes, blood pressure, metabolic syndrome score, and cognitive intelligence scores were assessed. Child prehypertension/hypertension at age 6 years was defined using a simplified pediatric threshold of 110/70 mmHg. RESULTS: The average maternal alcohol consumption in the year prior to pregnancy recognition was 2.5 g/day, which is lower than the daily maximal limit of one standard drink (10 g) recommended for women by Singapore's Ministry of Health. After adjusting for participant characteristics, alcohol consumption at least 1.9 g/day was associated with over two-fold higher risk (risk ratio = 2.18, P = 0.013) of child prehypertension and 15% greater kidney growth between early infancy and age 6 years (P = 0.040) compared with abstinence. Alcohol consumption was not associated with metabolic and neurocognitive health at age 6-7 years. The associations with high frequency of alcohol consumption were concordant with those obtained for quantity of alcohol consumption. CONCLUSION: Maternal self-reported alcohol consumption at least 1.9 g/day prior to pregnancy recognition was associated with increased risk of child prehypertension and rapid kidney growth. Our findings highlight the potential detrimental effects of low periconceptional alcohol consumption, below national guidelines on offspring cardiorenal health.

Associations of Maternal Consumption of Dairy Products during Pregnancy with Perinatal Fatty Acids Profile in the EDEN Cohort Study.

Maternal diet is the main source of fatty acids for developing offspring in-utero and in breastfed infants. Dairy products (DP) are important sources of fat in the European population diet. C15:0 and C17:0 fatty acids have been suggested as biomarkers of dairy fat consumption. This study's aim is to describe the associations between maternal DP (milk included) consumption during pregnancy and C15:0, C17:0 and polyunsaturated fatty acid (PUFA) levels in perinatal biofluids. Study populations were composed of 1763, 1337 and 879 French mothers from the EDEN ("Étude des Déterminants pre- et post-natals de la santé de l'ENfant") study, with data on maternal and cord red blood cells' (RBC) membrane and colostrum, respectively. Associations were assessed using linear regression models adjusted for recruitment center, maternal age, healthy dietary pattern or fish consumption. Greater adherence to a "cheese" consumption pattern was associated with lower linoleic acid level in colostrum and higher C15:0 and C17:0 levels but in a less consistent manner for C17:0 across biofluids. Greater adherence to "semi-skimmed milk, yogurt" and "reduced-fat DP" patterns was related to higher docosahexaenoic acid and total n-3 PUFA levels and lower n-6/n-3 long-chain PUFA ratio in maternal and cord RBC. Our results suggest that C15:0 could be a good biomarker of maternal dairy fat consumption in perinatal biofluids.

Breastfeeding may benefit cardiometabolic health of children exposed to increased gestational glycemia in utero.

PURPOSE: There is altered breastmilk composition among mothers with gestational diabetes and conflicting evidence on whether breastfeeding is beneficial or detrimental to their offspring's cardiometabolic health. We aimed to investigate associations between breastfeeding and offspring's cardiometabolic health across the range of gestational glycemia. METHODS: We included 827 naturally conceived, term singletons from a prospective mother-child cohort. We measured gestational (26-28 weeks) fasting plasma glucose (FPG) and 2-h plasma glucose (2 hPG) after an oral glucose tolerance test as continuous variables. Participants were classified into 2 breastfeeding categories (high/intermediate vs. low) according to their breastfeeding duration and exclusivity. Main outcome measures included magnetic resonance imaging (MRI)-measured abdominal fat, intramyocellular lipids (IMCL), and liver fat, quantitative magnetic resonance (QMR)-measured body fat mass, blood pressure, blood lipids, and insulin resistance at 6 years old (all continuous variables). We evaluated if gestational glycemia (FPG and 2 hPG) modified the association of breastfeeding with offspring outcomes after adjusting for confounders using a multiple linear regression model that included a 'gestational glycemia × breastfeeding' interaction term. RESULTS: With increasing gestational FPG, high/intermediate (vs. low) breastfeeding was associated with lower levels of IMCL (p-interaction = 0.047), liver fat (p-interaction = 0.033), and triglycerides (p-interaction = 0.007), after adjusting for confounders. Specifically, at 2 standard deviations above the mean gestational FPG level, high/intermediate (vs. low) breastfeeding was linked to lower adjusted mean IMCL [0.39% of water signal (0.29, 0.50) vs. 0.54% of water signal (0.46, 0.62)], liver fat [0.39% by weight (0.20, 0.58) vs. 0.72% by weight (0.59, 0.85)], and triglycerides [0.62 mmol/L (0.51, 0.72) vs. 0.86 mmol/L (0.75, 0.97)]. 2 hPG did not significantly modify the association between breastfeeding and childhood cardiometabolic risk. CONCLUSION: Our findings suggest breastfeeding may confer protection against adverse fat partitioning and higher triglyceride concentration among children exposed to increased glycemia in utero.

Associations of Childcare Arrangements with Adiposity Measures in a Multi-Ethnic Asian Cohort: The GUSTO Study.

Childcare arrangements shape behavioural patterns that influence the risk of childhood obesity. However, little is known of its influence on childhood obesity in Singapore. We aim to examine the associations between childcare arrangements at the age of 5 years and childhood adiposity at age 6 years. Children from the GUSTO study were grouped into three childcare arrangements at age 5: full-time centre-based childcare (FC), partial centre-based with parental care (PCP), and partial centre-based with non-parents (grandparents and domestic helpers) as caregivers (PCN). Diet, physical activity and sedentary behaviour information were collected at age 5, while anthropometric measurements were collected at age 6. Associations were analysed using multivariable regression models. Among 540 children, those in PCN had higher BMI z-scores (ß: 0.34; 95% CI: 0.01, 0.66), greater sum of skinfold thicknesses (mm) (ß: 3.75; 95% CI: 0.53, 6.97) and were 3.55 times (95% CI: 1.78, 7.05) more likely to be overweight/obese than those in FC. Adiposity measures in PCP children did not differ from those in FC. PCN children were reported to have more screen time and greater fast-food intake. Children in PCN tended to have higher adiposity measures. Greater engagement of non-parental caregivers should be considered in interventions targeting child obesity.

Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach.

Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.

Associations between Infant Dietary Intakes and Liking for Sweetness and Fattiness Sensations in 8-to-12-Year-Old Children.

An exposure to sweetened and fatty foods early in life may be involved in high liking later in life. The objective is to investigate the association between dietary exposure to carbohydrate, sugars and fat in infancy, with liking for sweetness, fattiness and fattiness-and-sweetness sensations at 8-to-12-year-old. Analyses were conducted on 759 French children from the EDEN mother-child cohort. Carbohydrate, sugar or fat intake, being a consumer of added sugars or added fats were assessed at 8 and 12 months using 3-day food records. The liking score (0-10) for the different sensations was assessed through an online child-completed questionnaire. Associations were tested by linear regressions adjusted for main confounders and the interaction with sex was tested. None of the early dietary exposure variables was related to fattiness liking. Carbohydrate intake at 8 months was positively but weakly associated with liking for sweetness-and-fattiness. In girls only, carbohydrate intake at 12 months was positively associated with liking for sweetness. Globally, no marked associations were observed between infant dietary exposure to sweet and fat and liking for sweetness and fattiness in young children. The positive link in girls between early carbohydrate exposure and later liking for sweetness needs to be confirmed in further studies.

Increasing nausea and vomiting of pregnancy is associated with sex-dependent differences in early childhood growth: the GUSTO mother-offspring cohort study.

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 ß = 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 .

Maternal height, gestational diabetes mellitus and pregnancy complications.

AIMS: To explore the glucose-overload hypothesis of artefactual gestational diabetes (GDM) diagnosis in shorter women during oral glucose tolerance testing (OGTT), by investigating associations between height and maternal glycemia; and GDM and pregnancy complications in height-groups. METHODS: Women from GUSTO (n = 1100, 2009-2010) and NUH (n = 4068, 2017-2018) cohorts underwent a mid-gestation two and three time-point 75 g 2-hour OGTT, respectively. GDM-related complications (hypertensive disorders of pregnancy, preterm delivery, emergency cesarean section, neonatal intensive care unit admission, macrosomia, birthweight) were compared within shorter and taller groups, dichotomized by ethnic-specific median height. RESULTS: Using WHO-1999 criteria, 18.8% (GUSTO) to 22.9% (NUH) of women were diagnosed with GDM-1999; and by WHO-2013 criteria, 21.9% (NUH) had GDM-2013. Each 5-cm height increment was inversely associated with GDM-1999 (adjusted odds ratio [aOR, 95% CI] = 0.81 [0.76-0.87], 2-h glycemia (adjusted ß [aß, 95% CI] = -0.171 mmol/L [-0.208, -0.135]) and 1-h glycemia (aß = -0.160 mmol/L [-0.207, -0.112]). The inverse association between height and 2-h glycemia was most marked in "Other" ethnicities (Eurasians/Caucasians/mixed/other Asians) and Indians, followed by Chinese, then Malays. Compared with non-GDM, GDM-1999 was associated with preterm delivery (aOR = 1.76 [1.19-2.61]) and higher birthweight (aß = 57.16 g [20.95, 93.38]) only among taller but not shorter women. CONCLUSIONS: Only taller women had an increased odds of GDM-related pregnancy complications. An artefactual GDM diagnosis due to glucose-overload among shorter women is plausible.

Trajectories of Systolic Blood Pressure in Children: Risk Factors and Cardiometabolic Correlates.

OBJECTIVE: To identify systolic blood pressure (SBP) percentile trajectories in children and to describe the early-life risk factors and cardiometabolic correlates of those trajectories. STUDY DESIGN: Using age-, sex-, and height-specific SBP percentiles based on the American Academy of Pediatrics reference, we examined SBP trajectories using latent class mixed models from ages 3 to 8 years (n = 844) from the Growing Up in Singapore Towards healthy Outcomes-study, a Singaporean mother-offspring cohort study. We analyzed associations between SBP trajectories and early-life risk factors using multinomial logistic regression and differences across trajectories in cardiometabolic outcomes using multiple linear regression. RESULTS: Children were classified into 1 of 4 SBP percentile trajectories: "low increasing" (15%), "high stable" (47%), "high decreasing" (20%), and "low stable" (18%). Maternal hypertension during early pregnancy was a predictor of the "high stable" and "low increasing" SBP trajectories. Rapid child weight gain in the first 2 years of life was only associated with the "high stable" trajectory. Compared with children in the "low stable" trajectory, children in the "high stable" SBP trajectory had greater body mass index z scores, sum of skinfold thicknesses, waist circumference from ages 3 to 8 years, and abdominal adipose tissue (milliliters) at 4.5 years (adjusted mean difference [95% CI]: superficial and deep subcutaneous abdominal adipose tissue: 115.2 [48.1-182.3] and 85.5 [35.2-135.8]). Their fat mass (kilograms) (1.3 [0.6-2.0]), triglyceride levels (mmol/L) (0.10 [0.02-0.18]), and homeostasis model assessment of insulin resistance (0.28 [0.11 0.46]) at age 6 years were also greater but not their arterial thickness and stiffness. CONCLUSIONS: Reducing maternal blood pressure during pregnancy and infant weight gain in the first 2 years of life might help to prevent the development of high SBP.

Neonatal amygdala microstructure mediates the relationship between gestational glycemia and offspring adiposity.

INTRODUCTION: To determine if variations in the neonatal amygdala mediate the association between maternal antenatal glycemia and offspring adiposity in early childhood. RESEARCH DESIGN AND METHODS: 123 non-obese pregnant women with no pregnancy complications aside from gestational diabetes underwent a 75 g 2-hour oral glucose tolerance test at 26-28 weeks' gestation. Volume and fractional anisotropy (FA) of the neonatal amygdala (5-17 days old) were measured by MRI. The Body Mass Index (BMI) z-scores and sum of skinfold thickness (subscapular and triceps) of these children were tracked up to 60 months of age (18, 24, 36, 48, 54 and 60 months). RESULTS: Maternal fasting glucose levels were positively associated with the offspring's sum of skinfold thickness at age 48 months (ß=3.12, 95% CI 0.18 to 6.06 mm) and 60 months (ß=4.14, 95% CI 0.46 to 7.82 mm) and BMI z-scores at 48 months (ß=0.94, 95% CI 0.03 to 1.85), 54 months (ß=0.74, 95% CI 0.12 to 1.36) and 60 months (ß=0.74, 95% CI 0.08 to 1.39). Maternal fasting glucose was negatively associated with the offspring's FA of the right amygdala (ß=-0.019, 95% CI -0.036 to -0.003). Right amygdala FA was negatively associated with the sum of skinfold thickness in the offspring at age 48 months (ß=-56.95, 95% CI -98.43 to -15.47 mm), 54 months (ß=-46.18, 95% CI -88.57 to -3.78 mm), and 60 months (ß=-53.69, 95% CI -105.74 to -1.64 mm). The effect sizes mediated by right amygdala FA between fasting glucose and sum of skinfolds were estimated at ß=5.14 (95% CI 0.74 to 9.53) mm (p=0.022), ß=4.40 (95% CI 0.08 to 8.72) (p=0.049) mm and ß=4.56 (95% CI -0.17 to 9.29) mm (p=0.059) at 48, 54 and 60 months, respectively. CONCLUSIONS: In the offspring of non-obese mothers, gestational fasting glucose concentration is negatively associated with neonatal right amygdala FA and positively associated with childhood adiposity. Neonatal right amygdala FA may be a potential mediator between maternal glycemia and childhood adiposity.

Cardiometabolic Profile of Different Body Composition Phenotypes in Children.

CONTEXT: Cardiometabolic profiles of different body composition phenotypes are poorly characterized in young children, where it is well established that high adiposity is unfavorable, but the role of lean mass is unclear. OBJECTIVE: We hypothesized that higher lean mass attenuates cardiometabolic risk in children with high fat mass. METHODS: In 6-year-old children (n = 377) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective birth cohort, whole-body composition was measured by quantitative magnetic resonance, a novel validated technology. Based on fat mass index (FMI) and lean mass index (LMI), 4 body composition phenotypes were derived: low FMI-low LMI (LF-LL), low FMI-high LMI (LF-HL), high FMI-low LMI (HF-LL), high FMI-high LMI (HF-HL). MAIN OUTCOME MEASURES: Body mass index (BMI) z-score, fasting plasma glucose, insulin resistance, metabolic syndrome risk score, fatty liver index, and blood pressure. RESULTS: Compared with the LF-HL group, children in both high FMI groups had increased BMI z-score (HF-HL: 1.43 units 95% CI [1.11,1.76]; HF-LL: 0.61 units [0.25,0.96]) and metabolic syndrome risk score (HF-HL: 1.64 [0.77,2.50]; HF-LL: 1.28 [0.34,2.21]). The HF-HL group also had increased fatty liver index (1.15 [0.54,1.77]). Girls in HF-HL group had lower fasting plasma glucose (-0.29 mmol/L [-0.55,-0.04]) and diastolic blood pressure (-3.22 mmHg [-6.03,-0.41]) than girls in the HF-LL group. No similar associations were observed in boys. CONCLUSION: In a multi-ethnic Asian cohort, lean mass seemed to protect against some cardiometabolic risk markers linked with adiposity, but only in girls. The FMI seemed more important than lean mass index in relation to cardiometabolic profiles of young children.

High placental inositol content associated with suppressed pro-adipogenic effects of maternal glycaemia in offspring: the GUSTO cohort.

BACKGROUND/OBJECTIVES: Maternal glycaemia promotes fetal adiposity. Inositol, an insulin sensitizer, has been trialled for gestational diabetes prevention. The placenta has been implicated in how maternal hyperglycaemia generates fetal pathophysiology, but no studies have examined whether placental inositol biology is altered with maternal hyperglycaemia, nor whether such alterations impact fetal physiology. We aimed to investigate whether the effects of maternal glycaemia on offspring birthweight and adiposity at birth differed across placental inositol levels. METHODS: Using longitudinal data from the Growing Up in Singapore Towards healthy Outcomes cohort, maternal fasting glucose (FPG) and 2-hour plasma glucose (2hPG) were obtained in pregnant women by a 75-g oral glucose tolerance test around 26 weeks' gestation. Relative placental inositol was quantified by liquid chromatography-mass spectrometry. Primary outcomes were birthweight (n = 884) and abdominal adipose tissue (AAT) volumes measured by neonatal MRI scanning in a subset (n = 262) of term singleton pregnancies. Multiple linear regression analyses were performed. RESULTS: Placental inositol was lower in those with higher 2hPG, no exposure to tobacco smoke antenatally, with vaginal delivery and shorter gestation. Positive associations of FPG with birthweight (adjusted ß [95% CI] 164.8 g [109.1, 220.5]) and AAT (17.3 ml [11.9, 22.6] per mmol glucose) were observed, with significant interactions between inositol tertiles and FPG in relation to these outcomes (p < 0.05). Stratification by inositol tertiles showed that each mmol/L increase in FPG was associated with increased birthweight and AAT volume among cases within the lowest (birthweight = 174.2 g [81.2, 267.2], AAT = 21.0 ml [13.1, 28.8]) and middle inositol tertiles (birthweight = 202.0 g [103.8, 300.1], AAT = 19.7 ml [9.7, 29.7]). However, no significant association was found among cases within the highest tertile (birthweight = 81.0 g [-21.2, 183.2], AAT = 0.8 ml [-8.4, 10.0]). CONCLUSIONS: High placental inositol may protect the fetus from the pro-adipogenic effects of maternal glycaemia. Studies are warranted to investigate whether prenatal inositol supplementation can increase placental inositol and reduce fetal adiposity.