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Abstract Background It is not clear if conventional liver fat cutoff of 5.56% weight which has been used for identifying fatty liver in western populations is also applicable for Asians. In Asian women of reproductive age, we evaluate the optimum metabolic syndrome (MetS)-linked liver fat cutoff, the specific metabolomic alterations apparent at this cutoff, as well as prospective associations of preconception liver fat levels with gestational dysglycemia. Methods Liver fat (measured by magnetic resonance spectroscopy), MetS, and nuclear magnetic resonance (NMR)-based plasma metabolomic profiles were assessed in 382 Asian women, who were planning to conceive. Ninety-eight women went on to become pregnant and received an oral glucose tolerance test at week 26 of gestation. Results The optimum liver fat cutoff for diagnosing MetS was 2.07%weight. Preconception liver fat was categorized into Low (liver fat

Abstract Background Phenotypic age (PhenoAge), a widely used marker of biological aging, has been shown to be a robust predictor of all-cause mortality and morbidity in different populations. Existing studies on biological aging have primarily focused on individual domains, resulting in a lack of a comprehensive understanding of the multi-systemic dysregulation that occurs in aging. Methods PhenoAge was evaluated based on a linear combination of chronological age (CA) and 9 clinical biomarkers in 952 multi-ethnic Asian women of reproductive age. Phenotypic age acceleration (PhenoAgeAccel), an aging biomarker, represents PhenoAge after adjusting for CA. This study conducts an in-depth association analysis of PhenoAgeAccel with clinical, nutritional, lipidomic, gut microbiome, and genetic factors. Results Higher adiposity, glycaemia, plasma saturated fatty acids, kynurenine pathway metabolites, GlycA, riboflavin, nicotinamide, and insulin-like growth factor binding proteins were positively associated with PhenoAgeAccel. Conversely, a healthier diet and higher levels of pyridoxal phosphate, all-trans retinol, betaine, tryptophan, glutamine, histidine, apolipoprotein B, and insulin-like growth factors were inversely associated with PhenoAgeAccel. Lipidomic analysis found 132 lipid species linked to PhenoAgeAccel, with PC(O-36:0) showing the strongest positive association and CE(24:5) demonstrating the strongest inverse association. A genome-wide association study identified rs9864994 as the top genetic variant (P = 5.69E-07) from the ZDHHC19 gene. Gut microbiome analysis revealed that Erysipelotrichaceae UCG-003 and Bacteroides vulgatus were inversely associated with PhenoAgeAccel. Integrative network analysis of aging-related factors underscored the intricate links among clinical, nutritional and lipidomic variables, such as positive associations between kynurenine pathway metabolites, amino acids, adiposity, and insulin resistance. Furthermore, potential mediation effects of blood biomarkers related to inflammation, immune response, and nutritional and energy metabolism were observed in the associations of diet, adiposity, genetic variants, and gut microbial species with PhenoAgeAccel. Conclusions Our findings provide a comprehensive analysis of aging-related factors across multiple platforms, delineating their complex interconnections. This study is the first to report novel signatures in lipidomics, gut microbiome and blood biomarkers specifically associated with PhenoAgeAccel. These insights are invaluable in understanding the molecular and metabolic mechanisms underlying biological aging and shed light on potential interventions to mitigate accelerated biological aging by targeting modifiable factors.

BackgroundMaternal and child health outcomes are positively influenced by early intervention, and digital health (DH) tools provide the potential for a low-cost and scalable solution such as informational platforms or digital tracking tools. Despite the wide availability of DH tools out there for women from before to after pregnancy, user engagement remains low. ObjectiveThis study aims to explore the factors that shape women’s DH adoption and sustained use across the maternal journey from preconception to postbirth, to improve user engagement with DH tools. MethodsOne-hour semistructured qualitative interviews were conducted with 44 women from before to after pregnancy (age range 21-40 years) about their experiences with DH. This study is part of a larger study on women’s maternal experiences with health care and DH and focuses on the factors that affected women’s DH adoption and sustained use. Interviews were audio recorded, transcribed verbatim, and analyzed using inductive thematic analysis. ResultsFive main themes and 10 subthemes were identified that affected women’s adoption and sustained use of DH tools. These included themes on their preexisting attitudes to DH, perceived ease of use, perceived usefulness, perceived credibility, and perceived value of the tool. ConclusionsThe themes that emerged were fully or partially mapped according to the Unified Theory of Acceptance and Use of Technology 2 model. The applicability of the model and the need to consider specific cultural nuances in the Asian context (such as the importance of trust and social influence) are discussed. The interaction of the 5 themes with DH adoption and sustained use are explored with different themes being relevant at various points of the DH adoption journey. The insights gained serve to inform future DH design and implementation of tools for women to optimize their DH engagement and the benefits they derive from it. Trial RegistrationClinicalTrials.gov NCT05099900; https://clinicaltrials.gov/study/NCT05099900

Introduction: Preconception is a critical period to optimise gamete function and early placental development, essential for successful conception and long-term maternal-child health. However, there is a lack of preconception services and consequently, global fertility rates continue to fall and mothers embark on their pregnancy journey in poor health. There is an urgent need to implement a holistic community-level preconception care programme to optimise risk factors for poor fecundability and improve long-term maternal-child health. Method: We reviewed current evidence on fecundability lifestyle risk factors, the efficacy of existing preconception interventions and the use of digital platforms for health optimisation, to create a new digital-based preconception intervention model that will be implemented via an app. We present the theory, content and mode of delivery of this holistic model targeting couples planning for pregnancy. Results: We propose a new model featuring a user-friendly mobile app, which enables couples to self-assess fecundability risks through a personalised risk score that drives a tailored management plan. This tiered management provides anticipatory guidance supported by evidence-based recommendations, and promotes ongoing engagement for behavioural optimisation and specialist referrals as required. Based on the health belief model, this new model delivered with a mobile app seeks to shift couples’ perceptions about their susceptibility and severity of subfertility, benefits of making a change and barriers to change. Conclusion: Our proposed digital-based intervention model via a mobile app stands to enhance preconception care by providing personalised risk assessments, real-time feedback and tiered management to optimise preconception reproductive health of couples. This model forms a reference content framework for future preconception care intervention delivery.

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

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

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

Abstract Background Nutritional intervention preconception and throughout pregnancy has been proposed as an approach to promoting healthy postnatal weight gain in the offspring but few randomised trials have examined this. Methods Measurements of weight and length were obtained at multiple time points from birth to 2 years among 576 offspring of women randomised to receive preconception and antenatally either a supplement containing myo-inositol, probiotics, and additional micronutrients (intervention) or a standard micronutrient supplement (control). We examined the influence on age- and sex-standardised BMI at 2 years (WHO standards, adjusting for study site, sex, maternal parity, smoking and pre-pregnancy BMI, and gestational age), together with the change in weight, length, BMI from birth, and weight gain trajectories using latent class growth analysis. Results At 2 years, there was a trend towards lower mean BMI among intervention offspring (adjusted mean difference [aMD] − 0.14 SD [95% CI 0.30, 0.02], p = 0.09), and fewer had a BMI > 95th percentile (i.e. > 1.65 SD, 9.2% vs 18.0%, adjusted risk ratio [aRR] 0.51 [95% CI 0.31, 0.82], p = 0.006). Longitudinal data revealed that intervention offspring had a 24% reduced risk of experiencing rapid weight gain > 0.67 SD in the first year of life (21.9% vs 31.1%, aRR 0.76 [95% CI 0.58, 1.00], p = 0.047). The risk was likewise decreased for sustained weight gain > 1.34 SD in the first 2 years of life (7.7% vs 17.1%, aRR 0.55 [95% CI 0.34, 0.88], p = 0.014). From five weight gain trajectories identified, there were more intervention offspring in the “normal” weight gain trajectory characterised by stable weight SDS around 0 SD from birth to 2 years (38.8% vs 30.1%, RR 1.29 [95% CI 1.03, 1.62], p = 0.029). Conclusions Supplementation with myo-inositol, probiotics, and additional micronutrients preconception and in pregnancy reduced the incidence of rapid weight gain and obesity at 2 years among offspring. Previous reports suggest these effects will likely translate to health benefits, but longer-term follow-up is needed to evaluate this. Trial registration ClinicalTrials.gov, NCT02509988 (Universal Trial Number U1111-1171–8056). Registered on 16 July 2015.

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

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

Abstract Background Volume assessment, dry weight titration, and blood pressure control in pregnant kidney failure patients are often challenging, with physiological fluid accumulation in the trunk and lower limbs and an increased risk of preeclampsia. We used segmental bioimpedance in the volume management of our kidney failure patient on haemodialysis. Case presentation We report a case of a female patient on maintenance haemodiafiltration with no residual kidney function for whom we used segmental bioimpedance to guide dry weight adjustment. At different gestational periods, we targeted a different extracellular to total body water ratio according to body segments. This allowed us to support her high-risk pregnancy, identify her as probably developing preeclampsia and trigger a plan for closer monitoring and delivery during the third trimester when she had rapid weight gain. Conclusion Segmental bioimpedance is a practical, simple, and non-invasive test that can be performed at the dialysis unit and is useful as an adjunct decision-making tool in the management of pregnant dialysis patients.

Abstract Health behaviors before, during and after pregnancy can have lasting effects on maternal and infant health outcomes. Although digital health interventions (DHIs) have potential as a pertinent avenue to deliver mechanisms for a healthy behavior change, its success is reliant on addressing the user needs. Accordingly, the current study aimed to understand DHI needs and expectations of women before, during and after pregnancy to inform and optimize future DHI developments. Forty-four women (13 pre-, 16 during and 15 postpregnancy; age range = 21–40 years) completed a 60-minute, semistructured, qualitative interview exploring participant’s experience in their current phase, experience with digital health tools, and their needs and expectations of DHIs. Interviews were audio-recorded, transcribed verbatim and thematically analyzed. From the interviews, two core concepts emerged—personalization and localization of DHI. Between both concepts, five themes and nine subthemes were identified. Themes and subthemes within personalization cover ideas of two-way interactivity, journey organization based on phases and circumstances, and privacy trade-off. Themes and subthemes within localization cover ideas of access to local health-related resources and information, and connecting to local communities through anecdotal stories. Here we report, through understanding user needs and expectations, the key elements for the development and optimization of a successful DHI for women before, during and after pregnancy. To potentially empower downstream DHI implementation and adoption, these insights can serve as a foundation in the initial innovation process for DHI developers and be further built upon through a continued co-design process.

IntroductionPharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort.MethodsBuffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models’ performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites.ResultsOverall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model.DiscussionThe development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.

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 (β range 1.22–1.41 mL/SD, all P

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

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

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

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

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

Abstract 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 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

Abstract This study aimed to cross-calibrate body composition measures from the GE Lunar Prodigy and GE Lunar iDXA in a cohort of young children. 28 children (mean age 3.4 years) were measured on the iDXA followed by the Prodigy. Prodigy scans were subsequently reanalysed using enCORE v17 enhanced analysis (“Prodigy enhanced”). Body composition parameters were compared across three evaluation methods (Prodigy, Prodigy enhanced, iDXA), and adjustment equations were developed. There were differences in the three evaluation methods for all body composition parameters. Body fat percentage (%BF) from the iDXA was approximately 1.5-fold greater than the Prodigy, whereas bone mineral density (BMD) was approximately 20% lower. Reanalysis of Prodigy scans with enhanced software attenuated these differences (%BF: − 5.2% [95% CI − 3.5, − 6.8]; and BMD: 1.0% [95% CI 0.0, 1.9]), although significant differences remained for all parameters except total body less head (TBLH) total mass and TBLH BMD, and some regional estimates. There were large differences between the Prodigy and iDXA, with these differences related both to scan resolution and software. Reanalysis of Prodigy scans with enhanced analysis resulted in body composition values much closer to those obtained on the iDXA, although differences remained. As manufacturers update models and software, researchers and clinicians need to be aware of the impact this may have on the longitudinal assessment of body composition, as results may not be comparable across devices and software versions.

Older pregnant women have increased risks of complications including gestational diabetes and stillbirth. Carnitine palmitoyl transferase (CPT) expression declines with age in several tissues and is linked with poorer metabolic health. Mitochondrial CPTs catalyze acylcarnitine synthesis, which facilitates fatty acid oxidization as fuel. We hypothesized that the placenta, containing maternally-inherited mitochondria, shows an age-related CPT decline that lowers placental acylcarnitine synthesis, increasing vulnerability to pregnancy complications. We assessed CPT1A, CPT1B, CPT1C and CPT2 mRNA expression by qPCR in 77 placentas and quantified 10 medium and long-chain acylcarnitines by LC-MS/MS in a subset of 50 placentas. Older maternal age associated with lower expression of placental CPT1B, but not CPT1A, CPT1C or CPT2. CPT1B expression positively associated with eight acylcarnitines and CPT1C with three acylcarnitines, CPT1A negatively associated with nine acylcarnitines, while CPT2 did not associate with any acylcarnitine. Older maternal age associated with reductions in five acylcarnitines, only in those with BMI≥ 25 kg/m2, and not after adjusting for CPT1B expression. Our findings suggest that CPT1B is the main transferase for placental long-chain acylcarnitine synthesis, and age-related CPT1B decline may underlie decreased placental metabolic flexibility, potentially contributing to pregnancy complications in older women, particularly if they are overweight.

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

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

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

BackgroundBioelectrical impedance analysis (BIA) is widely used to measure body composition but has not been adequately evaluated in infancy. Prior studies have largely been of poor quality, and few included healthy term-born offspring, so it is unclear if BIA can accurately predict body composition at this age.AimThis study evaluated impedance technology to predict fat-free mass (FFM) among a large multi-ethnic cohort of infants from the United Kingdom, Singapore, and New Zealand at ages 6 weeks and 6 months (n = 292 and 212, respectively).Materials and methodsUsing air displacement plethysmography (PEA POD) as the reference, two impedance approaches were evaluated: (1) empirical prediction equations; (2) Cole modeling and mixture theory prediction. Sex-specific equations were developed among ∼70% of the cohort. Equations were validated in the remaining ∼30% and in an independent University of Queensland cohort. Mixture theory estimates of FFM were validated using the entire cohort at both ages.ResultsSex-specific equations based on weight and length explained 75–81% of FFM variance at 6 weeks but only 48–57% at 6 months. At both ages, the margin of error for these equations was 5–6% of mean FFM, as assessed by the root mean squared errors (RMSE). The stepwise addition of clinically-relevant covariates (i.e., gestational age, birthweight SDS, subscapular skinfold thickness, abdominal circumference) improved model accuracy (i.e., lowered RMSE). However, improvements in model accuracy were not consistently observed when impedance parameters (as the impedance index) were incorporated instead of length. The bioimpedance equations had mean absolute percentage errors (MAPE) < 5% when validated. Limits of agreement analyses showed that biases were low (< 100 g) and limits of agreement were narrower for bioimpedance-based than anthropometry-based equations, with no clear benefit following the addition of clinically-relevant variables. Estimates of FFM from BIS mixture theory prediction were inaccurate (MAPE 11–12%).ConclusionThe addition of the impedance index improved the accuracy of empirical FFM predictions. However, improvements were modest, so the benefits of using bioimpedance in the field remain unclear and require further investigation. Mixture theory prediction of FFM from BIS is inaccurate in infancy and cannot be recommended.

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

Abstract Background 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.

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

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

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

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

Abstract 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 (

Abstract 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 (3.38 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.

Abstract 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.

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

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.

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

Abstract Background Gestational diabetes (GDM) is a known risk factor for type 2 diabetes mellitus (T2DM), and women with a history of GDM have a 7-fold increased risk of developing the disease. Achieving a healthy weight post-delivery is key in reducing the risk of future diabetes in these women. The aim of this trial is to investigate the use of an interactive smartphone application (APP) to restore women to optimal weight following delivery. Methods This will be an open-label randomized controlled trial. Two hundred women with gestational diabetes will be randomized to receive the intervention or standard care following delivery. Participants will be reviewed at 6 weeks and 4 months post-delivery. The intervention is an APP serving as a platform for weight, diet and physical activity tracking. The APP provides 3–5 min educational videos suggesting suitable lifestyle adjustments relevant to postnatal period such as breast feeding, diet and exercise. Lastly, the APP will allow real-time interaction between users and the team of dietitians, physiotherapists and occupational therapists to encourage restoration of optimal weight. Women in the control arm will be informed about the increased risk of developing T2DM and advised to maintain a healthy weight. Primary outcome measure is the restoration of participants’ booking weight if booking BMI ≤ 23, or weight loss of at least 5% from booking weight if booking BMI > 23 over the 4 month period. Secondary outcome measures will assess serum metabolic and inflammatory markers, quality of life via questionnaires and cost-effectiveness of the intervention at each follow-up visit. Discussion This will be the first randomised controlled trial investigating the use of a smartphone application for postpartum weight loss in women with gestational diabetes. The major ethnic groups in our study population represent the majority of ethnic groups in Asia, amongst which the prevalence of diabetes is high. If shown to be effective, this APP may be used in wider clinical settings to improve postpartum weight loss and reduce the risk of developing T2DM in these women. Trial registration This study was registered on clintrials.gov on the 30th of October 2017, under the trial registration number: NCT03324737.

Abstract Purpose Integrated 24-Hour Movement Guidelines provide specific recommendations on screen viewing (SV), moderate-to-vigorous physical activity (MVPA) and sleep to improve health of children and youth. However, few studies have examined whether these guidelines are met in young children, particularly in Asia. We evaluated adherence to integrated and individual guidelines and its predictors in 5.5-year-old Singaporean children. Methods Growing Up in Singapore towards Healthy Outcomes (GUSTO) is a mother-offspring birth cohort study. At age 5.5 years, child SV was reported by parents. Movement behaviours (MBs) were measured continuously using wrist-worn accelerometers over 7 consecutive days and nights. For accelerometer data including ≥3 days with ≥16 h/day we estimated mean (±SD) daily MVPA, SV and nighttime sleep duration across the week. Adherence to integrated (Canadian/Australian) guidelines was defined as meeting all individual guidelines: ≥60 min of MVPA/day, ≤2 h of screen time/day, and 9–11 h of sleep/night. Socio-demographic and maternal predictors collected at pregnancy enrolment and at 26–28 weeks’ gestation were examined by multivariable logistic regression. Results Of 864 children followed up age 5.5 years, 547 (63.3%) had both valid ActiGraph and questionnaire data (51.7% boys and 58.3% Chinese ethnicity). Children averaged 101.9 (± 88.7) min/day SV, 67.3 (± 23.7) min/day MVPA and 480.6 (± 57.2) min/night sleep. Few children met integrated guidelines. Specifically, the proportions of children who met none, SV, MVPA, sleep and integrated guidelines were 11.2, 70.2, 59.6, 13.7 and 5.5%, respectively. Multivariable analysis showed that maternal activity and television (TV) viewing were associated with meeting integrated guidelines (insufficiently vs. highly active (OR [95% CI]): 0.11 [0.01, 0.95]; 2–3 vs. ≥ 3 h TV: 3.52 [1.02, 12.22]). Examining higher adherence to individual guidelines, Chinese ethnicity, younger maternal age and lower maternal TV and sleep time were associated with greater SV; male sex, Malay ethnicity, higher birth order and higher maternal activity level were associated with greater MVPA; and older maternal age was associated with adherence to sleep guideline. Conclusions Beyond individual behaviours, consideration of the full spectrum of MBs may be important to improve children’s health. However, few Singaporean children adhere to integrated 24-h movement guidelines. Maternal behaviours as early as during pregnancy could be important targets for future interventions aiming to promote these MBs in children.

Abstract Background Although infant media exposure has received attention for its implications on child development, upstream risk factors contributing to media exposure have rarely been explored. The study aim was to examine the relationship between maternal risk factors, infant television (TV) viewing, and later child cognition. Methods We used a prospective population-based birth cohort study, Growing Up in Singapore Towards healthy Outcomes (GUSTO), with 1247 pregnant mothers recruited in their first trimester. We first explored the relationship of infant TV exposure at 12 months and the composite IQ score at 4.5 years, as measured by the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). Multivariable linear regressions were adjusted for maternal education, maternal mental health, child variables, birth parameters, and other relevant confounders. We then examined the associations of maternal risk factors with the amount of daily TV viewing of 12-month-old infants. Path analysis followed, to test a conceptual model designed a priori to test our hypotheses. Results The average amount of TV viewing at 12 months was 2.0 h/day (SD 1.9). TV viewing in hours per day was a significant exposure variable for composite IQ (ß = − 1.55; 95% CI: − 2.81 to − 0.28) and verbal IQ (ß = − 1.77; 95% CI: − 3.22 to − 0.32) at 4.5 years. Our path analysis demonstrated that lower maternal education and worse maternal mood (standardized ß = − 0.27 and 0.14, respectively, p 0.99, AIC 15249.82, RMSEA

Abstract Background Iron deficiency is the most prevalent nutrient deficiency and the most common cause of anaemia worldwide. Because of the increased iron requirements during pregnancy, iron deficiency can lead to maternal anaemia and reduced newborn iron stores. We examined the proportion and risk factors of iron deficiency among pregnant women in a developed Asian country. Methods Within a prospective cohort in Singapore, 985 Asian women were assessed for iron status at 26–28 weeks’ gestation, with plasma ferritin and soluble transferrin receptor (sTfR) measurements. Iron status was determined according to plasma ferritin concentrations at ≥30 μg/L (iron sufficiency), 15 to

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. Keywords: Metformin, Pregnancy, Gestational diabetes, GDM, Polycystic ovary syndrome, PCOS, Development

Abstract Background We assessed the impact of adopting the 2013 World Health Organization (WHO) diagnostic criteria on the rates of gestational diabetes (GDM), pregnancy outcomes and identification of women at future risk of type 2 diabetes. Methods During a period when the 1999 WHO GDM criteria were in effect, pregnant women were universally screened using a one-step 75 g 2-h oral glucose tolerance test at 26–28 weeks’ gestation. Women were retrospectively reclassified according to the 2013 criteria, but without the 1-h glycaemia measurement. Pregnancy outcomes and glucose tolerance at 4–5 years post-delivery were compared for women with GDM classified by the 1999 criteria alone, GDM by the 2013 criteria alone, GDM by both criteria and without GDM by both sets of criteria. Results Of 1092 women, 204 (18.7%) and 142 (13.0%) were diagnosed with GDM by the 1999 and 2013 WHO criteria, respectively, with 27 (2.5%) reclassified to GDM and 89 (8.2%) reclassified to non-GDM when shifting from the 1999 to 2013 criteria. Compared to women without GDM by both criteria, cases reclassified to GDM by the 2013 criteria had an increased risk of neonatal jaundice requiring phototherapy (relative risk (RR) = 2.78, 95% confidence interval (CI) 1.32, 5.86); despite receiving treatment for GDM, cases reclassified to non-GDM by the 2013 criteria had higher risks of prematurity (RR = 2.17, 95% CI 1.12, 4.24), neonatal hypoglycaemia (RR = 3.42, 95% CI 1.04, 11.29), jaundice requiring phototherapy (RR = 1.71, 95% CI 1.04, 2.82), and a higher rate of abnormal glucose tolerance at 4–5 years post-delivery (RR = 3.39, 95% CI 2.30, 5.00). Conclusions Adoption of the 2013 WHO criteria, without the 1-h glycaemia measurement, reduced the GDM rate. Lowering the fasting glucose threshold identified women who might benefit from treatment, but raising the 2-h threshold may fail to identify women at increased risk of adverse pregnancy and future metabolic outcomes. Trial registration NCT01174875. Registered 1 July 2010 (retrospectively registered).

Background: Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy. Objectives: The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses. Design: This was a randomised, double-blind, placebo-controlled, multicentre study. Setting: The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016. Participants: Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible. Intervention: Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation. Main outcome measures: The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time. Results: Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome. Conclusions: Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies. Limitations: Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored. Future work: Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism. Trial registration: Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

We previously reported that a combined myo-inositol, probiotics, and enriched micronutrient supplement (intervention) taken preconception and in pregnancy reduced postpartum blood loss (PBL) and major postpartum hemorrhage compared with a standard micronutrient supplement (control), as secondary outcomes of the NiPPeR trial. This study aimed to identify the intervention components that may contribute to this effect. Associations of plasma concentrations of myoinositol and vitamins B2, B6, B12, and D at preconception (before and after supplementation), early (~7-weeks), and late pregnancy (~28-weeks) with PBL were assessed by multiple linear regression, adjusting for site, ethnicity, preconception BMI, parity, and previous cesarean section. Amongst 583 women, a higher concentration of myo-inositol in early pregnancy was associated with a PBL reduction [βadj −1.26 (95%CI −2.23, −0.29) mL per µmol/L myo-inositol increase, p = 0.011]. Applying this co-efficient to the increase in mean 7-week-myo-inositol concentration of 23.4 µmol/L with the intervention equated to a PBL reduction of 29.5 mL (~8.4% of mean PBL of 350 mL among controls), accounting for 84.3% of the previously reported intervention effect of 35 mL. None of the examined vitamins were associated with PBL. Therefore, myo-inositol may be a key intervention component mediating the PBL reduction. Further work is required to determine the mechanisms involved [ABSTRACT FROM AUTHOR]