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Abstract Background Maternal psychological distress during pregnancy is associated with infant temperament. Whether associations persist into late childhood, whether maternal distress is associated with temperament change from infancy to late childhood, whether associations are independent of maternal concurrent distress, and whether maternal distress has sensitive exposure periods on child temperament remain unclear. Methods Our study includes mother‐child dyads from Finnish, prospective Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. The mothers completed the Center for Epidemiologic Studies Depression Scale, State Anxiety Inventory and Perceived Stress Scale: biweekly up to 14 times during pregnancy; once in infancy (at child age 4–12 months); and once in late childhood (at child age 7–11 years). They also completed the Infant Behavior Questionnaire Revised at the infancy (n = 2538) and Temperament in Middle Childhood Questionnaire at the late childhood (n = 2004; 1693 children had data at both follow‐ups) follow‐up on child negative affectivity, extraversion and effortful control. We examined the associations of maternal distress with child temperament with linear regression, linear mixed and Bayesian relevant lifecourse exposure models. Results Maternal distress during pregnancy was associated with higher negative affectivity and lower effortful control in children in infancy and late childhood. Maternal distress during pregnancy was also associated with increases in negative affectivity, decreases in effortful Control, and smaller decreases in extraversion from infancy to late childhood. The associations with late childhood temperament and temperament change were independent of maternal concurrent distress. Late childhood was a sensitive period for lifetime‐to‐date effects of maternal distress on late childhood negative affectivity and effortful control. Distress during pregnancy and infancy had smaller contributions. Conclusions Maternal psychological distress during pregnancy is associated with individual differences and change in child temperament from infancy to late childhood. However, distress during pregnancy has a smaller effect on late childhood temperament than maternal concurrent distress.

Glucocorticoids are understood to represent useful biomarkers of stress and can be measured in saliva, hair, and breastmilk. The collection of such biosamples is increasingly included in biobank and cohort studies. While collection is considered “non-invasive” by biomedical researchers (compared to sampling blood), community perspectives may differ. This cross-sectional, qualitative study utilising eight focus groups aimed to determine the feasibility and acceptability of collecting ostensibly “non-invasive” biological samples in Malawi. Breastfeeding women, couples, field workers, and healthcare providers were purposively sampled. Data about prior understandings of, barriers to, and feasibility of “non-invasive” biosampling were analysed. Participants described biomaterials intended for “non-invasive” collection as sometimes highly sensitive, with sampling procedures raising community concerns. Sampling methods framed as physically “non-invasive” within biomedicine can consequently be considered socially “invasive” by prospective sample donors. Biomedical and community framings of “invasiveness’ can therefore diverge, and the former must respond to and be informed by the perspectives of the latter. Further, considerations of collection procedures are shaped by therapeutic misconceptions about the immediate health-related utility of biomedical and public health research. When researchers engage with communities about biosampling, they must ensure they are not furthering therapeutic misconceptions and actively seek to dispel these.

Abstract Gestational diabetes and the maternal mental disorders of anxiety and depression have been implicated in adverse offspring neuro-behavioural outcomes but these exposures have only been studied in isolation. 1051 children whose mothers were diagnosed with gestational diabetes in UK’s Born in Bradford cohort had linkage to maternal primary care records, providing diagnostic and treatment codes for depression and anxiety. Education record linkage provided results of the Early Years Foundation Stage Profile from the first year of school, aged five. Risk of not attaining a ‘Good level of development’ was analysed using multivariable Poisson regression within a generalised estimating equation framework. Multiple imputation was implemented for missing data. There was limited evidence of increased risk of failure to attain a ‘good level of development’ in those additionally exposed to maternal mental disorders (adjusted RR 1.21; 95% CI 0.94, 1.55). However, there was more evidence in children of Pakistani maternal ethnicity (adjusted RR 1.36; 95% CI 1.04, 1.77) than White British; this may have been driven by English not being the primary language spoken in the home. Therefore there may be groups with GDM in whom it is particularly important to optimise both maternal physical and mental health to improve child outcomes.

Abstract Background Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus. Methods We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions. Results There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis. Conclusions Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.

Background: Earlier pubertal timing is associated with higher rates of depressive disorders in adolescence. Neuroimaging studies report brain structural associations with both pubertal timing and depression. However, whether brain structure mediates the relationship between pubertal timing and depression remains unclear. Methods: The current registered report examined associations between pubertal timing (indexed via perceived pubertal development), brain structure (cortical and subcortical metrics, and white matter microstructure) and depressive symptoms in a large sample (N = ∼5000) of adolescents (aged 9–13 years) from the Adolescent Brain Cognitive Development (ABCD) Study. We used three waves of follow-up data when the youth were aged 10–11 years, 11–12 years, and 12–13 years, respectively. We used generalised linear-mixed models (H1) and structural equation modelling (H2 & H3) to test our hypotheses. Hypotheses: We hypothesised that earlier pubertal timing at Year 1 would be associated with increased depressive symptoms at Year 3 (H1), and that this relationship would be mediated by global (H2a-b) and regional (H3a-g) brain structural measures at Year 2. Global measures included reduced cortical volume, thickness, surface area and sulcal depth. Regional measures included reduced cortical thickness and volume in temporal and fronto-parietal areas, increased cortical volume in the ventral diencephalon, increased sulcal depth in the pars orbitalis, and reduced fractional anisotropy in the cortico-striatal tract and corpus callosum. These regions of interest were informed by our pilot analyses using baseline ABCD data when the youth were aged 9–10 years. Results: Earlier pubertal timing was associated with increased depressive symptoms two years later. The magnitude of effect was stronger in female youth and the association remained significant when controlling for parental depression, family income, and BMI in females but not in male youth. Our hypothesised brain structural measures did not however mediate the association between earlier pubertal timing and later depressive symptoms. Conclusion: The present results demonstrate that youth, particularly females, who begin puberty ahead of their peers are at an increased risk for adolescent-onset depression. Future work should explore additional biological and socio-environmental factors that may affect this association so that we can identify targets for intervention to help these at-risk youth.

Abstract Background Pregnant women with type 1 diabetes strive for tight glucose targets (3.5-7.8 mmol/L) to minimise the risks of obstetric and neonatal complications. Despite using diabetes technologies including continuous glucose monitoring (CGM), insulin pumps and contemporary insulin analogues, most women struggle to achieve and maintain the recommended pregnancy glucose targets. This study aims to evaluate whether the use of automated closed-loop insulin delivery improves antenatal glucose levels in pregnant women with type 1 diabetes. Methods/design A multicentre, open label, randomized, controlled trial of pregnant women with type 1 diabetes and a HbA1c of ≥48 mmol/mol (6.5%) at pregnancy confirmation and ≤ 86 mmol/mol (10%) at randomization. Participants who provide written informed consent before 13 weeks 6 days gestation will be entered into a run-in phase to collect 96 h (24 h overnight) of CGM glucose values. Eligible participants will be randomized on a 1:1 basis to CGM (Dexcom G6) with usual insulin delivery (control) or closed-loop (intervention). The closed-loop system includes a model predictive control algorithm (CamAPS FX application), hosted on an android smartphone that communicates wirelessly with the insulin pump (Dana Diabecare RS) and CGM transmitter. Research visits and device training will be provided virtually or face-to-face in conjunction with 4-weekly antenatal clinic visits where possible. Randomization will stratify for clinic site. One hundred twenty-four participants will be recruited. This takes into account 10% attrition and 10% who experience miscarriage or pregnancy loss. Analyses will be performed according to intention to treat. The primary analysis will evaluate the change in the time spent in the target glucose range (3.5-7.8 mmol/l) between the intervention and control group from 16 weeks gestation until delivery. Secondary outcomes include overnight time in target, time above target (> 7.8 mmol/l), standard CGM metrics, HbA1c and psychosocial functioning and health economic measures. Safety outcomes include the number and severity of ketoacidosis, severe hypoglycaemia and adverse device events. Discussion This will be the largest randomized controlled trial to evaluate the impact of closed-loop insulin delivery during type 1 diabetes pregnancy. Trial registration ISRCTN 56898625 Registration Date: 10 April, 2018.

Low total energy expenditure (TEE) has been a hypothesized risk factor for weight gain, but longitudinal repeatability of TEE is incompletely understood. Here the authors report that TEE is repeatable for adults, but not for children, and increases in TEE (adjusted for fat-free mass, fat mass, age and sex) are not associated with body composition changes in short-term longitudinal analyses.

Background Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the “therapeutic window” and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. Methods The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. Results and discussion The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks’ gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

Abstract Background Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non‐alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk‐stratification tools are suboptimal and perform worse in people with diabetes. Aims To determine whether the addition of complementary biomarker(s) to current NAFLD risk‐stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC. Methods The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60–75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow‐up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression. Results Of existing risk‐stratification scores tested, the Fibrosis‐4 (FIB‐4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut‐point ≥ 50 μ g/L) to FIB‐4 (cut‐point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as “high risk” for incident disease by ∼50%. Conclusions The addition of hyaluronic acid to FIB‐4 reduced the proportion of people inappropriately identified as “high risk” for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

Abstract Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (β range = −0.057 to −0.104, all P FDR

Abstract Maternal obesity in pregnancy predicts offspring psychopathology risk in childhood but it remains unclear whether maternal obesity or underweight associate with adult offspring mental disorders. We examined longitudinally whether maternal body mass index (BMI) in pregnancy predicted mental disorders in her offspring and whether the associations differed by offspring birth year among 68,571 mother–child dyads of Aberdeen Maternity and Neonatal Databank, Scotland. The offspring were born 1950–1999. Maternal BMI was measured at a mean 15.7 gestational weeks and classified into underweight, normal weight, overweight, moderate obesity and severe obesity. Mental disorders were identified from nationwide registers carrying diagnoses of all hospitalizations and deaths in Scotland in 1996–2017. We found that maternal BMI in pregnancy was associated with offspring mental disorders in a time-dependent manner: In offspring born 1950–1974, maternal underweight predicted an increased hazard of mental disorders [Hazard Ratio (HR) = 1.74; 95% Confidence Interval (CI) = 1.01–3.00)]. In offspring born 1975–1999, maternal severe obesity predicted increased hazards of any mental (HR 1.60; 95% CI 1.08–2.38) substance use (HR 1.91; 95% CI 1.03–3.57) and schizophrenia spectrum (HR 2.80; 95% CI 1.40–5.63) disorders. Our findings of time-specific associations between maternal prenatal BMI and adult offspring mental disorders may carry important public health implications by underlining possible lifelong effects of maternal BMI on offspring psychopathology.

Summary: Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (−10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p

Metformin is increasingly prescribed in pregnancy, with beneficial maternal effects. However, it is not known how metformin-treatment impacts metabolism and energy production in the developing feto-placental unit. We assessed the human placental response to metformin using both in vivo and in vitro treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated in vitro with metformin (0.01 mM, 0.1 mM or vehicle). Metformin-concentrations were measured using liquid-chromatography mass-spectrometry. Oxygen consumption in cultured-trophoblasts was measured using a Seahorse-XF Mito Stress Test. Markers of oxidative-stress were assayed using qRT-PCR. Metformin-transporter mRNA and protein-levels were determined by quantitative RT-PCR and Western-blotting respectively. Metformin concentrations were also measured in sample trios (maternal plasma/fetal plasma/placental tissue) from pregnancies exposed to metformin on clinical-grounds. Maternal and fetal metformin concentrations in vivo were highly correlated over a range of concentrations (R2 = 0.76, p < 0.001; average fetal:maternal ratio 1.5; range 0.8–2.1). Basal respiration in trophoblasts was reduced by metformin treatment (0.01 mM metformin; p < 0.05, 0.1 mM metformin; p < 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (p < 0.001). Oxidative stress markers were significantly reduced in primary-trophoblast-cultures following treatment with metformin. There is a close linear relationship between placental, fetal, and maternal metformin concentrations. Primary-trophoblast cultures exposed to clinically-relevant metformin concentrations have reduced mitochondrial-respiration, mitochondrial-dependent ATP-production, and reduced markers of oxidative-stress. Given the crucial role of placental energy-production in supporting fetal growth and well-being during pregnancy, the implications of these findings are concerning for intrauterine fetal growth and longer-term metabolic programming in metformin-exposed pregnancies.

IntroductionAlthough ultrasound to determine gestational age is fundamental to the optimum management of pregnancy and is recommended for all women by the World Health Organisation, it remains unavailable to many women in low-income countries where trained practitioners are scarce. This study aimed to evaluate a novel, context-specific education package to teach midwives basic obstetric ultrasound, including the determination of gestational age by measurement of fetal femur length.MethodsThe study was conducted across six sites in Malawi in January 2021. Following a virtual “training of the trainers”, local teams delivered a 10-day programme encompassing both didactic and “hands on” components. Matched pre and post course tests assessed participants' knowledge of key concepts, with Objective Structured Clinical Examinations used to evaluate practical skills. To achieve a pass, trainees were required to establish the gestational age to within ±7 days of an experienced practitioner and achieve an overall score of >65% on five consecutive occasions. A matched pre and post course survey explored participants' attitudes and confidence in performing ultrasound examinations.ResultsOf the 29 midwives who participated, 28 finished the programme and met the criteria specified to pass. 22 midwives completed the matched knowledge tests, with the mean (SD) score increasing from 10.2 (3.3) to 18 (2.5) after training (P

IntroductionEstablishing an accurate gestational age is essential for the optimum management of pregnancy, delivery and neonatal care, with improved estimates of gestational age considered a public health priority by the World Health Organization (WHO). Although ultrasound is considered the most precise method to achieve this, it is unavailable to many women in low- and middle- income countries (LMICs), where the lack of trained practitioners is considered a major barrier. This systematic review explores what initiatives have previously been undertaken to train staff to date pregnancies using ultrasound, which were successful and what barriers and facilitators influenced training.MethodsThe systematic review was conducted according to PRISMA guidelines and the protocol registered (PROSPERO CRD42019154619). Searches were last performed in July 2021. Studies were screened independently by two assessors, with data extracted by one and verified by the other. Both reviewers graded the methodological quality using the Mixed Methods Assessment Tool. Results were collated within prespecified domains, generating a narrative synthesis.Results25/1,262 studies were eligible for inclusion, all of which were programme evaluations. Eighteen were undertaken in Africa, three in South-East Asia, one in South America, and three across multiple sites, including those in Africa, Asia, and South America. Five programs specified criteria to pass, and within these 96% of trainees did so. Trainee follow up was undertaken in 18 studies. Ten met recommendations for training outlined by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) but only 1 met the current standards set by the WHO.DiscussionThis systematic review is the first to evaluate this topic and has uncovered major inconsistencies in the delivery and reporting of basic obstetric ultrasound training in LMICs, with the majority of programs not meeting minimum recommendations. By identifying these issues, we have highlighted key areas for improvement and made recommendations for reporting according to the RE-AIM framework. With an increasing focus on the importance of improving estimates of gestational age in LMICs, we believe these findings will be of significance to those seeking to develop and expand the provision of sustainable obstetric ultrasound in LMICs.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019154619, PROSPERO CRD42019154619.

Background: Children born preterm (before 37 weeks of gestation) are at risk for several adverse childhood outcomes. Parent priorities for research into these outcomes, and preferences for receiving information about these risks, have not previously been established. Here we report the results of an online survey designed to understand parent priorities for research and their preferences for receiving information about childhood outcomes. Methods: An online survey was circulated through social media and was completed by 148 parents of preterm children between the ages of 0 and 12 years from around the United Kingdom (UK). Survey questions were in the form of rating scale, multiple choice, ranking or open-ended free text questions. Descriptive analysis was applied to the quantitative data. Illustrative quotes were extracted from the qualitative free text data and a subset of these questions were analysed using framework analysis. Results: Parent priorities for research centre around identification of factors which can protect against or improve adverse cognitive or developmental outcomes. The majority of parents would prefer for communication to begin within the first year of the child’s life. Parents reported a knowledge gap among health visitors, early years educators and schools. Conclusions: In order to align with parent preferences, research should prioritise identification of protective factors and the development of effective interventions to improve outcomes. Training for health visitors and educational professionals could improve the experiences of families and children.

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Background: Maternal depression and anxiety during pregnancy may enhance fetal exposure to glucocorticoids (GCs) and harm neurodevelopment. We tested whether a novel cross-tissue polyepigenetic biomarker indicative of in utero exposure to GC is associated with mental and behavioral disorders and their severity in children, possibly mediating the associations between maternal prenatal depressive and anxiety symptoms and these child outcomes. Methods: Children (n = 814) from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study were followed-up from birth to age 7.1–10.7 years. A weighted polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs from umbilical cord blood. Child diagnosis of mental and behavioral disorder (n = 99) and its severity, defined as the number of days the child had received treatment (all 99 had received outpatient treatment and 8 had been additionally in inpatient treatment) for mental or behavioral disorder as the primary diagnosis, came from the Care Register for Health Care. Mothers (n = 408) reported on child total behavior problems at child's age of 2.3–5.8 years and their own depressive and anxiety symptoms during pregnancy (n = 583). Results: The fetal polyepigenetic GC exposure score at birth was not associated with child hazard of mental and behavioral disorder (HR = 0.82, 95% CI 0.54; 1.24, p = 0.35) or total behavior problems (unstandardized beta = −0.10, 95% CI -0.31; 0.10, p = 0.33). However, for one standard deviation decrease in the polyepigenetic score, the child had spent 2.94 (95%CI 1.59; 5.45, p

Abstract Background Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0–13.2 years-old. Results Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist (p values

Abstract Background Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. Methods We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks’ gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes. Results Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6–90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings

Abstract Background A recent study has shown that it is possible to accurately estimate gestational age (GA) at birth from the DNA methylation (DNAm) of fetal umbilical cord blood/newborn blood spots. This DNAm GA predictor may provide additional information relevant to developmental stage. In 814 mother-neonate pairs, we evaluated the associations between DNAm GA and a number of maternal and offspring characteristics. These characteristics reflect prenatal environmental adversity and are expected to influence newborn developmental stage. Results DNAm GA acceleration (GAA; i.e., older DNAm GA than chronological GA) of the offspring at birth was associated with maternal age of over 40 years at delivery, pre-eclampsia and fetal demise in a previous pregnancy, maternal pre-eclampsia and treatment with antenatal betamethasone in the index pregnancy, lower neonatal birth size, lower 1-min Apgar score, and female sex. DNAm GA deceleration (GAD; i.e., younger DNAm GA than chronological GA) of the offspring at birth was associated with insulin-treated gestational diabetes mellitus (GDM) in a previous pregnancy and Sjögren’s syndrome. These findings were more accentuated when the DNAm GA calculation was based on the raw difference between DNAm GA and GA than on the residual from the linear regression of DNAm GA on GA. Conclusions Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity.

BackgroundPreterm birth associates with a substantially increased risk of later cardiovascular disease and neurodevelopmental disorders. Understanding underlying mechanisms will facilitate the development of screening and intervention strategies to reduce disease risk. Changes in DNA methylation have been proposed as one mechanism linking the early environment with later disease risk. We tested the hypothesis that preterm birth associates with altered DNA methylation in genes encoding insulin-like growth factor 2 (IGF2) and FK506-binding protein 5 (FKBP5), which appear particularly vulnerable to early life adversity.MethodsFifty preterm infants were seen and assessed at birth, term equivalent age, 3 months and 1-year corrected ages; 40 term infants were seen at birth, 3 months and 1 year. Saliva was collected for DNA extraction at birth, term, and 1 year. Pyrosequencing of bisulfite-converted DNA was performed to measure DNA methylation at specific CpG sites within the IGF2 and FKBP5 loci.ResultsWeight and head circumference was reduced in preterm infants at all time points. Preterm infants had a higher percentage body fat at term-corrected age, but this difference was not persistent. DNA methylation at the differentially methylated region (DMR) of IGF2 (IGF2DMR2) and FKBP5 was lower in preterm infants at birth- and term-corrected age compared to term infants at birth. IGF2DMR2 and FKBP5 methylation was related to birthweight SD score in preterm infants. Among preterm infants, social deprivation was an independent contributor toward reducing DNA methylation at IGF2DMR2 at birth- and term-corrected age and maternal smoking was associated with reduced DNA methylation at FKBP5 at birth. There were no persistent differences in DNA methylation at 1 year of age.ConclusionChanges in DNA methylation were identified at key regions of IGF2/H19 and FKBP5 in preterm infants in early life. Potential contributing factors include maternal smoking and social deprivation. However, these changes did not persist at 1 year of age and further longitudinal studies are required to determine any associations between altered DNA methylation in the perinatal period of individuals born preterm and their long-term health.

Rationale/statement of the problem : Obesity is associated with increased symptoms of anxiety and depression. We hypothesised that severe obesity in pregnancy would be associated with adverse psychological health, with effects on gestational weight gain (GWG) and baby birthweight (BWT). We aimed to study mood and birth outcomes among participants in a longitudinal study of severe obesity in pregnancy. Methods : In this study, 140 severely obese (body mass index [BMI] (mean (SD)) 44.1 (4.1) kg/m2) and 96 lean (BMI 22.6 (1.6) kg/m2) pregnant women were recruited. Ethical approval and written, informed consent were obtained. Obese women were advised about healthy eating and weight maintenance. Serial weights were recorded and GWG calculated between 16 and 36 weeks’ gestation. Women were asked to complete validated questionnaires to assess mood, including ‘satisfaction with life’, Hospital Anxiety and Depression Scale (HADS) and Spielberger State and Trait Anxiety in early (12–20 weeks’ gestation) and late pregnancy (28–32 weeks’ gestation). Term BWT (>37 weeks’ gestation) was recorded (n=234). Results : Obese women were significantly less satisfied with life than lean women and had higher HADS depression and anxiety scores, and state and trait anxiety scores at both time points (all p

Rationale/statement of the problem : One in five UK women is obese at antenatal booking. Maternal obesity increases risk of offspring obesity, behavioural and metabolic disorders. Animal studies suggest male offspring are more vulnerable to these effects than females. We hypothesised that this is mediated by altered action of maternal glucocorticoids, key regulators of development and stimulators of appetite and weight gain. Methods : Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n=156 class III obese (BMI > 40 kg/m2) and n=87 lean (BMI 4000 g) offspring (p

Statement of the problem : Stressful life events have been shown to have great influence on the onset or recurrence of psychotic symptoms [1]. Increased stressful life events [2], perceived stress [3], and higher cortisol levels [4,5] have been described in subjects with a first psychotic episode. The main aim of our study was to explore the relationship between stress measures and cortisol levels in subjects with early psychoses. Methods : We included 85 subjects, aged between 18 and 35 years, who attended the Early Psychosis Program from Reus (Tarragona, Spain). All subjects were assessed at baseline using a structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry) to obtain a clinical diagnosis. We stratified the sample into three groups: Group 1, first episode of psychosis (FEP, N = 36); Group 2, critical period (CP, defined as a psychotic disorder >1 year of duration of illness, N=35); and Group 3, ultra high risk (UHR, subjects with prodromal psychotic symptoms, N=14). Perceived stress was assessed with perceived stress scale (PSS). Stressful life events during the previous 6 months were assessed with the Holmes Rahe Social Readjustment Scale. A fasting morning blood sample (9 h) was obtained to determine total cortisol in plasma. SPSS v.17.0 was used for the statistical analyses. Spearman correlations were used to explore the association between continuous variables. Wilcoxon test was used to compare continuous variables between diagnostic groups. A p-value