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Isolated extracranial internal carotid artery aneurysms (EICAAs) are rare, accounting for only about .4–4% of all peripheral artery aneurysms. We present a case of an EICAA in a young pregnant patient. To our knowledge, this is the first case being reported of a true EICAA during pregnancy in a multiparous woman. A 25-year-old pregnant patient presented with a pulsatile left neck swelling. Radiological investigations and subsequent surgery during the first trimester confirmed a true saccular left ICA with a maximum diameter of 3.5 cm. She was treated with aneurysm excision and primary anastomosis. She did not have any underlying diseases predisposing to an EICAA. She has been well for 3 years post procedure. It has been postulated that pregnancy could lead to aneurysm development through multiple mechanisms, including hemodynamic, hormonal, and other physiologic changes of pregnancy. Aggressive treatment with surgical intervention is advocated because of the risk of cerebral ischemic complications associated with non-operative treatment, and because satisfactory long-term outcomes can be achieved from surgery.

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring’s epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring’s DNA methylome.

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 110/70mmHg. 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) ¼ 1.72, 95% confidence interval (CI) 1.18-2.52]. High foetoplacental vascular resistance was associated with a 58% higher risk (RR ¼ 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 ¼ 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.

BACKGROUND: Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive. OBJECTIVES: We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production. METHODS: Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26-28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum. RESULTS: Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction in median breastfeeding duration of 2.3 mo. In a model adjusted for maternal prepregnancy BMI and intention to breastfeed, FPG ≥5.1 mmol/L predicted earlier termination of any breastfeeding (adjusted HR: 1.47; 95% CI: 1.04, 2.08) but not full breastfeeding (adjusted HR: 1.08; 0.76, 1.55). 2hPG ≥8.5 mmol/L was not significantly associated with the durations of any (adjusted HR: 0.86; 95% CI: 0.62, 1.19) or full (adjusted HR: 0.85; 95% CI: 0.62, 1.18) breastfeeding. Maternal FPG was significantly and positively associated with breastmilk sodium (adjusted coefficient: 1.28; 95% CI: 1.08, 1.51) and sodium-to-potassium ratio (adjusted coefficient: 1.29; 95% CI: 1.08, 1.54) but not with other measured breastmilk components. CONCLUSIONS: Women with FPG ≥5.1 mmol/L during pregnancy breastfeed for a shorter duration. Future work involving measurement of milk production is needed to determine whether low milk production predicts breastfeeding duration among women with elevated FPG. This trial was registered at www.clinicaltrials.gov as NCT01174875.

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight

Maternal hyperglycemia is associated with disrupted transplacental arachidonic acid (AA) supply and eicosanoid synthesis, which contribute to adverse pregnancy outcomes. Since placental inositol is lowered with increasing glycemia, and since myo-inositol appears a promising intervention for gestational diabetes, we hypothesized that myo-inositol might rectify glucose-induced perturbations in placental AA metabolism. Term placental explants (

Background and AimsFew studies examined influence of carotenoids and vitamin E on blood pressure or hypertension during and after pregnancy. We related perinatal plasma concentrations of individual carotenoids and forms of vitamin E, and their combination, to blood pressure and hypertension at late-pregnancy and 4 years post-pregnancy.Methods and ResultsIn 684 women of the Growing Up in Singapore Towards healthy Outcomes cohort, we quantified plasma carotenoids and vitamin E concentrations at delivery. Systolic and diastolic blood pressure (SBP, 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 carotenoid (CP1: α-, β-carotene, lutein; CP2: zeaxanthin, lycopene, β-cryptoxanthin) and one vitamin E (γ-, δ-, α-tocopherols) patterns were derived. CP1 (1SD score increment) was associated with lower SBP and DBP [β (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 β-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.ConclusionHigher perinatal α-, β-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.

Pregnancy complications such as maternal hyperglycemia increase perinatal mortality and morbidity, but risks are higher in males than in females. We hypothesized that fetal sex-dependent differences in placental palmitic-acid (PA) and oleic-acid (OA) metabolism influence such risks. Placental explants (n = 22) were incubated with isotope-labeled fatty acids ( 13C-PA or 13C-OA) for 24 or 48 h and the production of forty-seven 13C-PA lipids and thirty-seven 13C-OA lipids quantified by LCMS. Linear regression was used to investigate associations between maternal glycemia, BMI and fetal sex with 13C lipids, and between 13C lipids and birthweight centile. Placental explants from females showed greater incorporation of 13C-OA and 13C-PA into almost all lipids compared to males. Fetal sex also influenced relationships with maternal glycemia, with many 13C-OA and 13C-PA acylcarnitines, 13C-PA-diacylglycerols and 13C-PA phospholipids positively associated with glycemia in females but not in males. In contrast, several 13C-OA triacylglycerols and 13C-OA phospholipids were negatively associated with glycemia in males but not in females. Birthweight centile in females was positively associated with six 13C-PA and three 13C-OA lipids (mainly acylcarnitines) and was negatively associated with eight 13C-OA lipids, while males showed few associations. Fetal sex thus influences placental lipid metabolism and could be a key modulator of the impact of maternal metabolic health on perinatal outcomes, potentially contributing toward sex-specific adaptions in which females prioritize survival.

Context An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. Objective We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. Design, Setting, and Participants A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100*BAT volume/ FDSA volume) was calculated. Main Outcome Measures Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. Results A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), −0.08 (−0.10, −0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, −0.008% (−0.013%, −0.003%); soleus muscle, −0.003% (−0.006%, −0.001%) of water content and lower fatty liver index at 6 years. Conclusions Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.

We examined the associations of gestational diabetes mellitus (GDM) and women’s weight status from pre-pregnancy through post-delivery with the risk of developing dysglycaemia [impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (T2D)] 4–6 years post-delivery. Using Poisson regression with confounder adjustments, we assessed associations of standard categorisations of prospectively ascertained pre-pregnancy overweight and obesity (OWOB), gestational weight gain (GWG) and substantial post-delivery weight retention (PDWR) with post-delivery dysglycaemia (n = 692). Women with GDM had a higher risk of later T2D [relative risk (95% CI) 12.07 (4.55, 32.02)] and dysglycaemia [3.02 (2.19, 4.16)] compared with non-GDM women. Independent of GDM, women with pre-pregnancy OWOB also had a higher risk of post-delivery dysglycaemia. Women with GDM who were OWOB pre-pregnancy and had subsequent PDWR (≥ 5 kg) had 2.38 times (1.29, 4.41) the risk of post-delivery dysglycaemia compared with pre-pregnancy lean GDM women without PDWR. No consistent associations were observed between GWG and later dysglycaemia risk. In conclusion, women with GDM have a higher risk of T2D 4–6 years after the index pregnancy. Pre-pregnancy OWOB and PDWR exacerbate the risk of post-delivery dysglycaemia. Weight management during preconception and post-delivery represent early windows of opportunity for improving long-term health, especially in those with GDM.

The increasing prevalence of gestational diabetes mellitus (GDM) is contributing to the rising global burden of type 2 diabetes (T2D) and intergenerational cycle of chronic metabolic disorders. Primary lifestyle interventions to manage GDM, including second trimester dietary and exercise guidance, have met with limited success due to late implementation, poor adherence and generic guidelines. In this study, we aimed to build a preconception-based GDM predictor to enable early intervention. We also assessed the associations of top predictors with GDM and adverse birth outcomes. Our evolutionary algorithm-based automated machine learning (AutoML) model was implemented with data from 222 Asian multi-ethnic women in a preconception cohort study, Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO). A stacked ensemble model with a gradient boosting classifier and linear support vector machine classifier (stochastic gradient descent training) was derived using genetic programming, achieving an excellent AUC of 0.93 based on four features (glycated hemoglobin A(1c) (HbA(1c)), mean arterial blood pressure, fasting insulin, triglycerides/HDL ratio). The results of multivariate logistic regression model showed that each 1 mmol/mol increase in preconception HbA(1c) was positively associated with increased risks of GDM (p = 0.001, odds ratio (95% CI) 1.34 (1.13-1.60)) and preterm birth (p = 0.011, odds ratio 1.63 (1.12-2.38)). Optimal control of preconception HbA(1c) may aid in preventing GDM and reducing the incidence of preterm birth. Our trained predictor has been deployed as a web application that can be easily employed in GDM intervention programs, prior to conception.

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 (≥75 thpercentile: 1.9 g/day), low (

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 β [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 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.

Background In women without diabetes, little is known about the consequences of hyperglycemia during pregnancy for the offspring’s cardiovascular structure and function. Objective To investigate the association of maternal glycemia during pregnancy with cardiovascular risk markers in their children in GUSTO, a Singaporean birth cohort study. Methods Around 26 weeks’ gestation, a 75 g oral glucose tolerance test was performed and fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPPG) concentrations were measured. Gestational diabetes mellitus (GDM) was defined using WHO 1999 diagnostic criteria. At 6 years of age, we measured the child’s carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), and blood pressure (BP). Association of maternal glycemia during pregnancy with cardiovascular risk markers in their children were analyzed using multiple linear and logistic regressions. Results Analysis were performed on 479 mother–child dyads. Higher maternal FPG was associated with higher cIMT and, in males, with a higher cfPWV in the offspring (adjusted β [CI 95%], cIMT: 0.08 per 10mm increase [0.02; 0.15], cfPWV: 0.36 m/s [0.01; 0.70]). Higher 2-hour PPPG was associated with higher cfPWV and AIx. Gestational diabetes mellitus was associated with higher AIx. No association was found between maternal glycemia and their offspring blood pressure. Conclusions among mothers without pre-existing diabetes, higher glycemia during pregnancy was associated with mild structural and functional vascular changes in their children at 6 years of age across a continuum. These results support the necessity to monitor maternal glycemia during pregnancy even in the absence of pre-existing diabetes or diagnosed GDM.

Objectives The increasing prevalence of advanced maternal age (AMA) coupled with poor sleep quality among pregnant women makes it important to study their association with perinatal outcomes. However, little is known about the interaction of AMA and maternal antenatal sleep on perinatal outcomes. Here, we examined whether associations between AMA and perinatal outcomes are modified by antenatal sleep quality. Participants Data were collected from 446 women, with a singleton pregnancy and no pregnancy complications, who participated in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study. Measurements Participants completed the Pittsburgh Sleep Quality Index (PSQI) at 26-28 weeks gestation and had perinatal outcome data collected upon delivery. Interactions between AMA and maternal sleep quality on perinatal outcomes were investigated and where significant, analyses were further stratified by maternal age. All analyses were adjusted for maternal BMI at 26-28 weeks gestation, ethnicity, and maternal education. Results Neonates of mothers of AMA and poor sleep quality (PSQI score >5) had increased odds of stay in the neonatal intensive care unit (adjusted odds ratio = 3.53, 95% CI: −1.21 to 10.27) and shorter birth length (adjusted mean difference = −1.05 cm, 95% CI: −1.82 to −0.20), as compared with women of AMA and good sleep quality (PSQI score ≤5). In women Conclusion Poor sleep quality in women of AMA was associated with neonatal health outcomes. Improving maternal antenatal sleep may potentially improve perinatal outcomes in offspring of women of AMA.

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, β (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.

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 (26-28weeks) fasting plasma glucose (FPG) and 2-hour plasma glucose (2hrPG) 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 & 2hrPG) modified the association of breastfeeding with offspring outcomes after adjusting for confounders using a multiple linear regression model that included a ‘gestational glycemia x 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 (0.62mmol/L [0.51,0.72] vs. 0.86mmol/L [0.75,0.97]). 2hrPG 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.

AimsThe heterogeneity in Gestational Diabetes Mellitus (GDM) risk factors among different populations impose challenges in developing a generic prediction model. This study evaluates the predictive ability of existing UK NICE guidelines for assessing GDM risk in Singaporean women, and used machine learning to develop a non-invasive predictive model.MethodsData from 909 pregnancies in Singapore’s most deeply phenotyped mother-offspring cohort study, Growing Up in Singapore Towards healthy Outcomes (GUSTO), was used for predictive modeling. We used a CatBoost gradient boosting algorithm, and the Shapley feature attribution framework for model building and interpretation of GDM risk attributes.ResultsUK NICE guidelines showed poor predictability in Singaporean women [AUC:0.60 (95% CI 0.51, 0.70)]. The non-invasive predictive model comprising of 4 non-invasive factors: mean arterial blood pressure in first trimester, age, ethnicity and previous history of GDM, greatly outperformed [AUC:0.82 (95% CI 0.71, 0.93)] the UK NICE guidelines.ConclusionsThe UK NICE guidelines may be insufficient to assess GDM risk in Asian women. Our non-invasive predictive model outperforms the current state-of-the-art machine learning models to predict GDM, is easily accessible and can be an effective approach to minimize the economic burden of universal testing & GDM associated healthcare in Asian populations.

Key Points Question Is there an association between gestational weight gain (GWG) and adverse infant outcomes among women across body mass index (BMI) categories? Findings In this cohort study of 15.8 million mother-infant dyads, infant morbidity and mortality risks showed U-shaped associations with GWG. Inadequate GWG and weight loss were associated with increased risks across BMI categories, but the effect sizes were smaller among women with obesity. Meaning In this study, extreme GWG ranges were associated with increased risks of infant morbidity and mortality across BMI categories, suggesting that prenatal weight loss or weight maintenance should not be encouraged., Importance The associations of gestational weight gain (GWG) with infant morbidity and mortality are unclear, and the existing recommendations for GWG have not been stratified by the severity of obesity. Objectives To identify optimal GWG ranges associated with reduced risks of infant morbidity and mortality across maternal body mass index (BMI) categories. Design, Setting, and Participants This retrospective cohort study used US nationwide, linked birth and infant death data between 2011 and 2015 to assess the associations of GWG in 2.0-kg groups with infant morbidity and mortality and identified optimal GWG ranges associated with reduced risks of both outcomes, using multivariable logistic regression models. Statistical analysis was performed from February 11 to October 14, 2021. Exposure Gestational weight gain equivalent to 40 weeks. Main Outcomes and Measures The 2 main outcomes were (1) significant morbidity of the newborn infant, defined as any presence of assisted ventilation, admission to the neonatal intensive care unit, surfactant therapy, antibiotic therapy, or seizures; and (2) infant mortality younger than 1 year of age (, This cohort study uses US nationwide, linked birth and infant death data to identify optimal gestational weight gain ranges associated with reduced risks of infant morbidity and mortality across maternal body mass index categories.

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

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with

The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.

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

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.

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.

Purpose To explore the associations between type of milk feeding (the “nutrients”) and mode of breast milk feeding (the “nursing”) with child cognition. Methods Healthy children from the GUSTO (Growing Up in Singapore Toward healthy Outcomes) cohort participated in repeated neurodevelopmental assessments between 6 and 54 months. For “nutrients”, we compared children exclusively bottle-fed according to type of milk received: formula only (n = 296) vs some/all breast milk (n = 73). For “nursing”, we included only children who were fully fed breast milk, comparing those fed directly at the breast (n = 59) vs those fed partially/completely by bottle (n = 63). Results Compared to infants fed formula only, those who were bottle-fed breast milk demonstrated significantly better cognitive performance on both the Bayley Scales of Infant and Toddler Development (Third Edition) at 2 years [adjusted mean difference (95% CI) 1.36 (0.32, 2.40)], and on the Kaufman Brief Intelligence Test (Second Edition) at 4.5 years [7.59 (1.20, 13.99)]. Children bottle-fed breast milk also demonstrated better gross motor skills at 2 years than those fed formula [1.60 (0.09, 3.10)]. Among infants fully fed breast milk, those fed directly at the breast scored higher on several memory tasks compared to children bottle-fed breast milk, including the deferred imitation task at 6 months [0.67 (0.02, 1.32)] and relational binding tasks at 6 [0.41 (0.07, 0.74)], 41 [0.67 (0.04, 1.29)] and 54 [0.12 (0.01, 0.22)] months. Conclusions Our findings suggest that nutrients in breast milk may improve general child cognition, while nursing infants directly at the breast may influence memory. Electronic supplementary material The online version of this article (10.1007/s00394-019-01929-2) contains supplementary material, which is available to authorized users.

Background Modest associations have been reported between specific food groups or nutrients and fecundability [measured by time to pregnancy (TTP)]. Examining overall diets provides a more holistic approach towards understanding the relationships with fecundability. It is not known if plant-based diets indices or exploratory dietary patterns are associated with fecundability. Objective We examine the associations between adherence to 1) plant-based diet indices and 2) exploratory dietary patterns and fecundability among women planning pregnancy. Design Data were analysed from the Singapore S-PRESTO study. Pre-pregnancy diet was assessed using a semi-quantitative food frequency questionnaire from which the overall, healthful and unhealthful plant-based diet indices (oPDI, hPDI and uPDI) were calculated. Exploratory dietary patterns were derived using factor analysis based on forty-four pre-defined food groups. Participants were categorized into quintiles based on their dietary pattern scores. TTP (in menstrual cycles) was ascertained within a year of dietary assessment. Discrete-time proportional hazard models, adjusted for confounders, were used to estimate fecundability ratios (FRs) and 95% CIs, with FR > 1 indicating a shorter TTP. Results Among 805 women, 383 pregnancies confirmed by ultrasound scans occurred. Compared to women in the lowest quintile, those in the highest quintile of the uPDI had reduced fecundability [FR of Q5 vs Q1 (95% CI): 0.65 (0.46, 0.91), p trend: 0.009]. Conversely, greater adherence to the hPDI was associated with increased fecundability [1.46 (1.02, 2.07), p trend: 0.036]. The oPDI was not associated with fecundability. Among the three exploratory dietary patterns, only greater adherence to the “Fast Food and Sweetened Beverages” pattern (FFSB) was associated with reduced fecundability [0.61 (0.40, 0.91), p trend: 0.018]. Conclusions Greater adherence to the uPDI or the FFSB dietary pattern was associated with reduced fecundability among Asian women. Greater adherence to the hPDI may be beneficial for fecundability, though this requires confirmation by future studies. Clinical Trial Registry number: NCT 03531658 Secondary Abstract: Plant-based diets are increasingly popular as they are associated with reduced risks of chronic diseases and considered a sustainable diet for planetary health. Do these diets contribute to fecundability (as measured by time to pregnancy)?

Spontaneous miscarriage is one of the most common complications of pregnancy. Even though some risk factors are well documented, there is a paucity of risk scoring tools during preconception. In the S-PRESTO cohort study, Asian women attempting to conceive, aged 18-45 years, were recruited. Multivariable logistic regression model coefficients were used to determine risk estimates for age, ethnicity, history of pregnancy loss, body mass index, smoking status, alcohol intake and dietary supplement intake; from these we derived a risk score ranging from 0 to 17. Miscarriage before 16 weeks of gestation, determined clinically or via ultrasound. Among 465 included women, 59 had miscarriages and 406 had pregnancy ≥ 16 weeks of gestation. Higher rates of miscarriage were observed at higher risk scores (5.3% at score ≤ 3, 17.0% at score 4–6, 40.0% at score 7–8 and 46.2% at score ≥ 9). Women with scores ≤ 3 were defined as low-risk level (

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.

Background Fetal docosahexaenoic acid (DHA) supply relies on preferential transplacental transfer, which is regulated by placental DHA lipid metabolism. Maternal hyperglycemia and obesity associate with higher birthweight and fetal DHA insufficiency but the role of placental DHA metabolism is unclear. Methods Explants from 17 term placenta were incubated with 13C-labeled DHA for 48 h, at 5 or 10 mmol/L glucose treatment, and the production of 17 individual newly synthesized 13C-DHA labeled lipids quantified by liquid chromatography mass spectrometry. Results Maternal BMI positively associated with 13C-DHA-labeled diacylglycerols, triacylglycerols, lysophospholipids, phosphatidylcholine and phosphatidylethanolamine plasmalogens, while maternal fasting glycemia positively associated with five 13C-DHA triacylglycerols. In turn, 13C-DHA-labeled phospholipids and triacylglycerols positively associated with birthweight centile. In-vitro glucose treatment increased most 13C-DHA-lipids, but decreased 13C-DHA phosphatidylethanolamine plasmalogens. However, with increasing maternal BMI, the magnitude of the glucose treatment induced increase in 13C-DHA phosphatidylcholine and 13C-DHA lysophospholipids was curtailed, with further decline in 13C-DHA phosphatidylethanolamine plasmalogens. Conversely, with increasing birthweight centile glucose treatment induced increases in 13C-DHA triacylglycerols were exaggerated, while glucose treatment induced decreases in 13C-DHA phosphatidylethanolamine plasmalogens were diminished. Conclusions Maternal BMI and glycemia increased the production of different placental DHA lipids implying impact on different metabolic pathways. Glucose-induced elevation in placental DHA metabolism is moderated with higher maternal BMI. In turn, findings of associations between many DHA lipids with birthweight suggest that BMI and glycemia promote fetal growth partly through changes in placental DHA metabolism. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00344-w.

International audience; 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 β [aβ, 95% CI] = -0.171 mmol/L [-0.208, -0.135]) and 1-h glycemia (aβ = -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 (aβ = 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.

Bioelectrical impedance techniques are easy to use and portable tools for assessing body composition. While measurements vary according to standing vs supine position in adults, and fasting and bladder voiding have been proposed as additional important influences, these have not been assessed in young children. Therefore, the influence of position, fasting, and voiding on bioimpedance measurements was examined in children. Bioimpedance measurements (ImpediMed SFB7) were made in 50 children (3.5 years). Measurements were made when supine and twice when standing (immediately on standing and after four minutes). Impedance and body composition were compared between positions, and the effect of fasting and voiding was assessed. Impedance varied between positions, but body composition parameters other than fat mass (total body water, intra- and extra-cellular water, fat-free mass) differed by less than 5%. There were no differences according to time of last meal or void. Equations were developed to allow standing measurements of fat mass to be combined with supine measurements. In early childhood, it can be difficult to meet requirements for fasting, voiding, and lying supine prior to measurement. This study provides evidence to enable standing and supine bioimpedance measurements to be combined in cohorts of young children.

Background Women with a history of gestational diabetes mellitus (GDM) are at an increased risk of developing type 2 diabetes mellitus (T2DM). Lifestyle interventions aimed at postpartum weight loss to reduce T2DM risk have been reported, but poor compliance remains a barrier. Smartphone-based interventions may improve compliance, but data on its use in women with recent GDM are limited. Objective This trial aimed to investigate the efficacy of a smartphone app in restoring optimal weight following delivery in women with GDM, in the setting of a population with high rates of GDM and type 2 diabetes. Methods In this unblinded randomized controlled trial, 200 women with GDM were randomized to receive the intervention or standard care following delivery. The intervention enabled logging of weight, meals, and activity, with web-based interaction with a team comprising dieticians, a physiotherapist, and an occupational therapist. The primary outcome was an achievement of optimal weight (defined as the restoration of first trimester weight if first trimester BMI≤23 kg/m2 or weight loss of at least 5% from first trimester weight if first trimester BMI>23 kg/m2) at 4 months post partum. Secondary outcome measures included absolute weight loss, serum metabolic markers, self-reported nutritional intake, health education, and quality of life via questionnaires and user engagement in the intervention group. Results In total, 40% (38/96) of women in the intervention group achieved optimal weight at 4 months post delivery compared with 32% (28/93) in the control group (P=.27). Compared with the control group, women in the intervention group reported significantly reduced caloric intake at 4 months after delivery (P Conclusions Although a statistically significant increase in women achieving healthy weight was not observed, this app remains promising, as women in the intervention group reported improved health behaviors and lower caloric intake. Importantly, the high retention rates suggest that a larger study with a longer follow-up period might confirm the effectiveness of this app for weight management. Trial Registration ClinicalTrials.gov NCT03324737; https://clinicaltrials.gov/ct2/show/NCT03324737 International Registered Report Identifier (IRRID) RR2-10.1186/s12889-019-7691-3

(1) Background: Breastfeeding has been shown to support glucose homeostasis in women after a pregnancy complicated by gestational diabetes mellitus (GDM) and is potentially effective at reducing long-term diabetes risk. (2) Methods: Data from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study were analyzed to understand the influence of breastfeeding duration on long-term dysglycemia (prediabetes and diabetes) risk in women who had GDM in the index pregnancy. GDM and dysglycemia four to seven years postpartum were determined by the oral glucose tolerance test (OGTT). A Poisson regression model with a robust error variance was used to estimate incidence rate ratios (IRRs) for dysglycemia four to seven years post-delivery according to groupings of the duration of any breastfeeding (&lt, 1, &ge, 1 to &lt, 6, and &ge, 6 months). (3) Results: Women who had GDM during the index pregnancy and complete breastfeeding information and OGTT four to seven years postpartum were included in this study (n = 116). Fifty-one women (44%) had postpartum dysglycemia. Unadjusted IRRs showed an inverse association between dysglycemia risk and &ge, 1 month to &lt, 6 months (IRR 0.91, 95% confidence interval [CI] 0.57, 1.43, p = 0.68) and &ge, 6 months (IRR 0.50, 95% CI 0.27, 0.91, p = 0.02) breastfeeding compared to &lt, 1 month of any breastfeeding. After adjusting for key confounders, the IRR for the &ge, 6 months group remained significant (IRR 0.42, 95% CI 0.22, 0.80, p = 0.008). (4) Conclusions: Our results suggest that any breastfeeding of six months or longer may reduce long-term dysglycemia risk in women with a history of GDM in an Asian setting. Breastfeeding has benefits for mothers beyond weight loss, particularly for those with GDM.

Introduction: This study examined maternal, delivery and infant factors associated with cord thyroid-stimulating hormone (TSH) concentrations in an Asian population. Methods: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study is a mother–offspring birth cohort from 2 major hospitals in Singapore. Cord serum TSH was measured using the Abbott ARCHITECT TSH Chemiluminescent Microparticle Immunoassay and the ADVIA Centaur TSH-3 Immunoassay. After excluding infants with a maternal history of thyroid disease, screening cord TSH results from 604 infants were available for multivariable regression analysis in relation to the factors of interest. Results: Babies born by vaginal delivery had significantly higher cord serum TSH concentrations than babies born by caesarean section. Cord serum TSH concentrations differed significantly by measurement method. There was no association of cord TSH concentrations with ethnicity, sex, birth weight, gestational age, maternal body mass index, gestational weight gain, gestational diabetes mellitus status and other maternal, delivery and infant factors studied. Conclusion: Interpretation of cord serum TSH results may need to take into account mode of delivery and measurement method. Keywords: Cord blood, Growing Up in Singapore Towards healthy Outcomes, GUSTO, perinatal

International audience; Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

OBJECTIVE: To examine the association between plasma glycemia in women attempting to conceive and fecundability, as measured by time-to-pregnancy (TTP). DESIGN: Prospective preconception population-based study. SETTING: KK Women’s and Children’s Hospital, Singapore. PATIENT(S): Asian preconception women, aged 18-45 years, attempting conception for ≤12 cycles at study entry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We ascertained TTP within a year of glycemic assessment, in menstrual cycles. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) using discrete-time proportional hazards models, adjusting for age, ethnicity, education, body mass index and cycle regularity, and accounting for left-truncation and right censoring. RESULT(S): We studied a population sample of 766 women from the Singapore PREconception Study of long-Term maternal and child Outcomes prospective cohort. Compared to women with normoglycemia, women with dysglycemia (prediabetes and diabetes, defined by American Diabetes Association) had a lower FR (0.56, (95% confidence interval 0.38, 0.83)). Compared with the respective lowest quintiles, women in the highest quintile of fasting glucose (≥5.1 mmol/L) had a FR of 0.60 (0.42,0.86), while women in the highest 2-hour post-load glucose quintile (≥6.9 mmol/L) had a FR of 0.66 (0.45,0.97). Overall, the FRs decreased generally across the range of fasting and 2-hour plasma glucose. Glycated hemoglobin was not associated with fecundability. CONCLUSION(S): Increasing preconception plasma glucose is associated with reduced fecundability, even within the normal range of glucose concentrations.

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

Background: While socioeconomic position (SEP) is consistently related to pregnancy and birth outcome disparities, relevant biological mechanisms are manifold, thus necessitating more comprehensive characterization of SEP-exposome associations during pregnancy. Objectives: We implemented an exposomic approach to systematically characterize the socioeconomic landscape of prenatal exposures in a setting where social segregation was less distinct in a hypotheses-generating manner. Methods: We described the correlation structure of 134 prenatal exogenous and endogenous sources (e.g., micronutrients, hormones, immunomodulatory metabolites, environmental pollutants) collected in a diverse, population-representative, urban, high-income longitudinal mother-offspring cohort (N = 1341; 2009–2011). We examined the associations between maternal, paternal, household, and areal level SEP indicators and 134 exposures using multiple regressions adjusted for precision variables, as well as potential effect measure modification by ethnicity and nativity. Finally, we generated summary SEP indices using Multiple Correspondence Analysis to further explore possible curved relationships. Results: Individual and household SEP were associated with anthropometric/adiposity measures, folate, omega-3 fatty acids, insulin-like growth factor-II, fasting glucose, and neopterin, an inflammatory marker. We observed paternal education was more strongly and consistently related to maternal exposures than maternal education. This was most apparent amongst couples discordant on education. Analyses revealed additional non-linear associations between areal composite SEP and particulate matter. Environmental contaminants (e.g., per- and polyfluoroalkyl substances) and micronutrients (e.g., folate and copper) showed opposing associations by ethnicity and nativity, respectively. Discussion: SEP-exposome relationships are complex, non-linear, and context specific. Our findings reinforce the potential role of paternal contributions and context-specific modifiers of associations, such as between ethnicity and maternal diet-related exposures. Despite weak presumed areal clustering of individual exposures in our context, our approach reinforces subtle non-linearities in areal-level exposures. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This research is supported by the Singapore National Research Foundation under the Translational and Clinical Research (TCR) Flagship, and Open Fund Large Collaborative Grant (OFLCG) Programmes and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore - NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014; OFLCG/MOH-000504. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore.

Background Cord blood leptin and adiponectin are adipokines known to be associated with birth weight and overall infant adiposity. However, few studies have investigated their associations with abdominal adiposity in neonates. We examined maternal factors associated with cord blood leptin and adiponectin, and the association of these adipokines with neonatal adiposity and abdominal fat distribution measured by magnetic resonance imaging (MRI) in an Asian mother–offspring cohort. Methods Growing Up in Singapore Towards healthy Outcomes (GUSTO), is a prospective mother–offspring birth cohort study in Singapore. Cord blood plasma leptin and adiponectin concentrations were measured using Luminex and Enzyme-Linked Immunosorbent Assay respectively in 816 infants. A total of 271 neonates underwent MRI within the first 2-weeks after delivery. Abdominal superficial (sSAT), deep subcutaneous (dSAT), and intra-abdominal (IAT) adipose tissue compartment volumes were quantified from MRI images. Multivariable regression analyses were performed. Results Indian or Malay ethnicity, female sex, and gestational age were positively associated with cord blood leptin and adiponectin concentrations. Maternal gestational diabetes (GDM) positively associated with cord blood leptin concentrations but inversely associated with cord blood adiponectin concentrations. Maternal pre-pregnancy body mass index (BMI) showed a positive relationship with cord blood leptin but not with adiponectin concentrations. Each SD increase in cord blood leptin was associated with higher neonatal sSAT, dSAT and IAT; differences in SD (95% CI): 0.258 (0.142, 0.374), 0.386 (0.254, 0.517) and 0.250 (0.118, 0.383), respectively. Similarly, each SD increase in cord blood adiponectin was associated with higher neonatal sSAT and dSAT; differences in SD (95% CI): 0.185 (0.096, 0.274) and 0.173 (0.067, 0.278), respectively. The association between cord blood adiponectin and neonatal adiposity was observed in neonates of obese mothers only. Conclusions Cord blood leptin and adiponectin concentrations were associated with ethnicity, maternal BMI and GDM, sex and gestational age. Both adipokines showed positive association with neonatal abdominal adiposity.

Inositols, a group of 6-carbon polyols, are highly bioactive molecules derived from diet and endogenous synthesis. Inositols and their derivatives are involved in glucose and lipid metabolism and participate in insulin-signaling, with perturbations in inositol processing being associated with conditions involving insulin resistance, dysglycemia and dyslipidemia such as polycystic ovary syndrome and diabetes. Pregnancy is similarly characterized by substantial and complex changes in glycemic and lipidomic regulation as part of maternal adaptation and is also associated with physiological alterations in inositol processing. Disruptions in maternal adaptation are postulated to have a critical pathophysiological role in pregnancy complications such as gestational diabetes and pre-eclampsia. Inositol supplementation has shown promise as an intervention for the alleviation of symptoms in conditions of insulin resistance and for gestational diabetes prevention. However, the mechanisms behind these affects are not fully understood. In this review, we explore the role of inositols in conditions of insulin dysregulation and in pregnancy, and identify priority areas for research. We particularly examine the role and function of inositols within the maternal-placental-fetal axis in both uncomplicated and pathological pregnancies. We also discuss how inositols may mediate maternal-placental-fetal cross-talk, and regulate fetal growth and development, and suggest that inositols play a vital role in promoting healthy pregnancy.

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.

Overt hypothyroidism is a common endocrine disorder affecting 1–2% of women of reproductive age. Optimizing treatment in pregnant women with overt hypothyroidism can reduce adverse fetal and maternal outcomes. Ideally, women who are known to have a history of hypothyroidism or those with risk factors for becoming hypothyroid, should have adequate preconception care to ensure euthyroidism from the onset of pregnancy, with a TSH target of below 2.5mIU/L. On women who are already on levothyroxine, an empirical dose increase of 30–50% as soon as pregnancy is confirmed may be considered. During pregnancy, levothyroxine doses should be titrated against TSH, which have trimester-specific ranges. In women who are known to be hypothyroid but are inadequately treated, we recommend a doubling of levothyroxine dose on at least three days a week to rapidly achieve euthyroidism. In newly diagnosed overt hypothyroidism in pregnancy, starting doses of either 100 or 150 mg daily may be considered safe.

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. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version The S-PRESTO study group includes Anne Eng Neo Goh, Anne Rifkin-Graboi, Anqi Qiu, Bee Wah Lee, Bobby Cheon, Christiani Jeyakumar Henry, Ciaran Gerard Forde, Claudia Chi, Doris Fok, Elaine Quah, Elizabeth Tham, Evelyn Chung Ning Law, Evelyn Xiu Ling Loo, Faidon Magkos, Falk Mueller-Riemenschneider, George Seow Heong Yeo, Helen Yu Chen, Hugo P S van Bever, Joanne Yoong, Joao N. Ferreira., Jonathan Tze Liang Choo, Kenneth Kwek, Kuan Jin Lee, Lieng Hsi Ling, Ling Wei Chen, Lourdes Mary Daniel, Marielle V. Fortier, Mary Foong-Fong Chong, Mei Chien Chua, Michael Meaney, Neerja Karnani, Oon Hoe Teoh, Queenie Ling Jun Li, Sendhil Velan, Shephali Tagore, Shirong Cai, Shu E Soh, Sok Bee Lim, Stella Tsotsi, Stephen Chin-Ying Hsu, Sue Anne Toh, Teng Hong Tan, Tong Wei Yew, Victor Samuel Rajadurai, Wee Meng Han, Wei Wei Pang, Yin Bun Cheung, and Yiong Huak Chan. We also acknowledge the efforts of the research coordinators, admin staff, study managers and participants. This work was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore - NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore.

OBJECTIVE SMART-GDM examined whether Habits-GDM, a smartphone application (app) coaching program, can prevent excessive gestational weight gain (EGWG) and improve glycemic control and maternal and neonatal outcomes in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS In this randomized controlled trial, women diagnosed with GDM between 12 and 30 weeks were randomly assigned to usual care (control) or to additional support from Habits-GDM that integrated dietary, physical activity, weight, and glucose monitoring (intervention). The primary outcome was the proportion of participants with EGWG. Secondary outcomes included absolute gestational weight gain (GWG), glycemic control, and maternal, delivery, and neonatal outcomes. RESULTS In total, 340 women were randomized (170 intervention, 170 control; mean ± SD age 32.0 ± 4.2 years; mean BMI 25.6 ± 5.6 kg/m2). There were no statistically significant differences in the proportions of women with EGWG, absolute GWG, or maternal and delivery outcomes between experimental groups. Average glucose readings were lower in the intervention group (mean difference −0.15 mmol/L [95% CI −0.26; −0.03], P = 0.011) as were the proportions of glucose above targets (premeal: 17.9% vs. 23.3%, odds ratio 0.68 [95% CI 0.53; 0.87], P = 0.003; 2-h postmeal: 19.9% vs. 50%, 0.54 [0.42; 0.70], P < 0.001). When regarded as a composite (although not prespecified), the overall neonatal complications (including birth trauma, neonatal hypoglycemia, hyperbilirubinemia, respiratory distress, neonatal intensive care unit admission, and perinatal death) were significantly lower in the intervention group (38.1% vs. 53.7%, 0.53 [0.34; 0.84], P = 0.006). CONCLUSIONS When added to usual care, Habits-GDM resulted in better maternal glycemic control and composite neonatal outcomes (nonprespecified) but did not reduce EGWG among women with GDM.

Background: Screen viewing is a sedentary behaviour reported to interfere with sleep and physical activity. However, few longitudinal studies have assessed such associations in children of preschool age (0–6 years) and none have accounted for the compositional nature of these behaviours. We aimed to investigate the associations between total and device-specific screen viewing time at age 2–3 years and accelerometer-measured 24 h movement behaviours, including sleep, sedentary behaviour, light physical activity, and moderate-to-vigorous physical activity (MVPA) at age 5·5 years. Methods: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study is an ongoing longitudinal birth cohort study in Singapore, which began in June 2009. We recruited pregnant women during their first ultrasound scan visit at two major public maternity units in Singapore. At clinic visits done at age 2–3 years, we collected parent-reported information about children's daily total and device-specific screen viewing time (television, handheld devices, and computers). At 5·5 years, children's movement behaviours for 7 consecutive days were measured using wrist-worn accelerometers. We assessed the associations between screen viewing time and movement behaviours (sedentary behaviour, light physical activity, MVPA, and sleep) using Dirichlet regression, which accounts for the compositional nature of such behaviours. This study is active but not recruiting and is registered with ClinicalTrials.gov, NCT01174875. Findings: Between June 1, 2009, and Oct 12, 2010, 1247 pregnant women enrolled and 1171 singleton births were enrolled. 987 children had parent-reported screen data at either 2 or 3 years, of whom 840 attended the clinic visit at age 5·5 years, and 577 wore an accelerometer. 552 children had at least 3 days of accelerometer data and were included in the analysis. Total screen viewing time at age 2–3 years had a significant negative association with sleep (p=0·008), light physical activity (p

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., 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.

Individual differences in children's eating behaviours emerge early. We examined the relationship between breastfeeding exposure and subsequent eating behaviours among children from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Children (n = 970) were grouped according to their breastfeeding exposure: high (full breastfeeding ≥ 4 months with continued breastfeeding ≥ 6 months), low (any breastfeeding < 3 months or no breastfeeding) and intermediate (between low and high breastfeeding categories). Aspects of eating behaviour from ages 15 months to 6 years were captured using a combination of maternal reports (Child Eating Behaviour Questionnaire; Infant Feeding Questionnaire; Preschooler Feeding Questionnaire) and laboratory-based measures of meal size, oral processing behaviours (e.g. average eating speed and bite size) and tendency to eat in the absence of hunger. Most children had low (44%) or intermediate (44%) breastfeeding exposure; only 12% had high exposure. After adjusting for confounders, multivariable linear regression analyses indicated the high (but not intermediate) breastfeeding group was associated with significantly lower reported food fussiness at 3 years compared to low breastfeeding group (−0.38 [-0.70, −0.06]), with similar but non-significant trends observed at 6 years (−0.27 [-0.66, 0.11]). At 3 years, mothers in the high breastfeeding group also reported the least difficulty in child feeding compared to low breastfeeding group (−0.22 [-0.43, −0.01]). However, high breastfeeding was not associated with any other maternal-reports of child feeding or eating behaviours, and no significant associations were observed between breastfeeding exposure and any of the laboratory measures of eating behaviour at any of the time points. These results do not strongly support the view that increased breastfeeding exposure alone has lasting and consistent associations with eating behaviours in early childhood.

For more than 40 years, metformin has been used before and during pregnancy. However, it is important to note that metformin can cross the placenta and circulate in the developing foetus. Recent studies reported that the concentration of metformin in foetal cord blood ranges from half to nearly the same concentration as in the maternal plasma. Since metformin has anti-cell growth and pro-apoptotic effects, there are persistent concerns over the use of metformin in early pregnancy. Current human studies are limited by sample size, lack of controls or, short follow-up durations. In this review, we examine the settings in which metformin can be passed on from mother to child during pregnancy and address the current controversies relating to the cellular and molecular mechanisms of metformin. Our efforts highlight the need for more data on the effects of metformin on general offspring health as well as further scrutiny into foetal development upon exposure to metformin. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version