Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

Epidemiology and management of gestational diabetes.

Gestational diabetes is defined as hyperglycaemia first detected during pregnancy at glucose concentrations that are less than those of overt diabetes. Around 14% of pregnancies globally are affected by gestational diabetes; its prevalence varies with differences in risk factors and approaches to screening and diagnosis; and it is increasing in parallel with obesity and type 2 diabetes. Gestational diabetes direct costs are US$1·6 billion in the USA alone, largely due to complications including hypertensive disorders, preterm delivery, and neonatal metabolic and respiratory consequences. Between 30% and 70% of gestational diabetes is diagnosed in early pregnancy (ie, early gestational diabetes defined by hyperglycaemia before 20 weeks of gestation). Early gestational diabetes is associated with worse pregnancy outcomes compared with women diagnosed with late gestational diabetes (hyperglycaemia from 24 weeks to 28 weeks of gestation). Randomised controlled trials show benefits of treating gestational diabetes from 24 weeks to 28 weeks of gestation. The WHO 2013 recommendations for diagnosing gestational diabetes (one-step 75 gm 2-h oral glucose tolerance test at 24-28 weeks of gestation) are largely based on the Hyperglycemia and Adverse Pregnancy Outcomes Study, which confirmed the linear association between pregnancy complications and late-pregnancy maternal glycaemia: a phenomenon that has now also been shown in early pregnancy. Recently, the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) trial showed benefit in diagnosis and treatment of early gestational diabetes for women with risk factors. Given the diabesity epidemic, evidence for gestational diabetes heterogeneity by timing and subtype, and advances in technology, a life course precision medicine approach is urgently needed, using evidence-based prevention, diagnostic, and treatment strategies.

Metabolomic and genetic architecture of gestational diabetes subtypes.

AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. METHODS: This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). RESULTS: Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM. CONCLUSIONS/INTERPRETATION: This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

Prevalence and correlates of diagnosed and probable polycystic ovary syndrome (PCOS) in a cohort of parous women.

OBJECTIVES: To assess correlates of diagnosed and probable polycystic ovary syndrome (PCOS) among parous women. METHODS: This study includes 557 women recruited from multi-specialty clinics in eastern Massachusetts. We categorized women as "diagnosed PCOS" based on medical records and self-reported clinician-diagnoses. Next, we constructed a category of "probable PCOS" for women without a diagnosis but with ≥2 of the following: ovulatory dysfunction (cycle length<21 or ≥35 days), hyperandrogenism (free testosterone>75th percentile), or elevated anti-Müllerian hormone (>75th percentile). We classified the remaining as "no PCOS," and compared characteristics across groups. RESULTS: 9.7% had diagnosed and 9.2% had probable PCOS. The frequency of irregular cycles was similar for diagnosed and probable PCOS. Free testosterone and AMH were higher for probable than diagnosed PCOS. Frequency of irregular cycles and both hormones were higher for the two PCOS groups vs. the no PCOS group. Obesity prevalence for diagnosed PCOS was twice that of probable PCOS (43.9% vs. 19.6%), yet the two groups had similar HbA1c and adiponectin. CONCLUSIONS: Women with probable PCOS are leaner but have comparable glycemic traits to those with a formal diagnosis, highlighting the importance of assessing biochemical profiles among women with irregular cycles, even in the absence of overweight/obesity.

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Associations of Abnormal Maternal Glucose Regulation in Pregnancy with Offspring Adiposity, Insulin Resistance, and Adipokine Markers During Childhood and Adolescence.

OBJECTIVE: To examine the associations of abnormal maternal glucose regulation in pregnancy with offspring adiposity, insulin resistance, adipokine, and inflammatory markers during childhood and adolescence. STUDY DESIGN: Project Viva is a prospective prebirth cohort (n = 2128 live births) initiated from 1999 through 2002 in Eastern Massachusetts, US. During the second trimester of pregnancy, clinicians used 2-step oral glucose challenge testing to screen for gestational diabetes mellitus. In the offspring, we measured anthropometry, insulin resistance, adipokines, lipids, and inflammatory markers in mid-childhood (n = 1107), early adolescence (n = 1027), and mid-adolescence (n = 693). We used multivariable linear regression models and generalized estimating equations adjusted for child age and sex, and for maternal age, race/ethnicity, education, parity, and smoking during pregnancy; we further adjusted for prepregnancy body mass index (BMI). RESULTS: In mid-adolescence (17.1 [0.8] years of age), offspring of mothers with gestational diabetes mellitus (n = 27) had a higher BMI z-score (ß; 95% Cl; 0.41 SD; 0.00, 0.82), sum of skinfolds (8.15 mm; 2.48, 13.82), homeostatic model assessment for insulin resistance (0.81 units; 0.13, 1.50), leptin z-score (0.40 SD; 0.01, 0.78), and leptin/adiponectin ratio z-score (0.51 SD; CI 0.09, 0.93) compared with offspring of mothers with normoglycemia (multivariable-adjusted models). The associations with BMI, homeostatic model assessment for insulin resistance, and adiponectin seemed stronger in mid-adolescence compared with earlier time points. The associations were attenuated toward the null after adjustment for maternal prepregnancy BMI. CONCLUSION: Exposure to gestational diabetes mellitus is associated with higher adiposity, insulin resistance, and altered adipokines in mid-adolescence. Our findings suggest that the peripubertal period could be a key time for the emergence of prenatally programmed metabolic abnormalities.

Metabolomic signatures for blood pressure from early to late adolescence: findings from a U.S. cohort.

INTRODUCTION: Metabolite signatures for blood pressure (BP) may reveal biomarkers, elucidate pathogenesis, and provide prevention targets for high BP. Knowledge regarding metabolites associated with BP in adolescence remains limited. OBJECTIVES: Investigate the associations between metabolites and adolescent BP, both cross-sectionally (in early and late adolescence) and prospectively (from early to late adolescence). METHODS: Participants are from the Project Viva prospective cohort. During the early (median: 12.8 years; N = 556) and late (median: 17.4 years; N = 501) adolescence visits, we conducted untargeted plasma metabolomic profiling and measured systolic (SBP) and diastolic BP (DBP). We used linear regression to identify metabolites cross-sectionally associated with BP at each time point, and to assess prospective associations of changes in metabolite levels from early to late adolescence with late adolescence BP. We used Weighted Gene Correlation Network Analysis and Spearman's partial correlation to identify metabolite clusters associated with BP at each time point. RESULTS: In the linear models, higher androgenic steroid levels were consistently associated with higher SBP and DBP in early and late adolescence. A cluster of 59 metabolites, mainly composed of androgenic steroids, correlated with higher SBP and DBP in early adolescence. A cluster primarily composed of fatty acid lipids was marginally associated with higher SBP in females in late adolescence. Multiple metabolites, including those in the creatine and purine metabolism sub-pathways, were associated with higher SBP and DBP both cross-sectionally and prospectively. CONCLUSION: Our results shed light on the potential metabolic processes and pathophysiology underlying high BP in adolescents.

Genetic predisposition to macronutrient preference and workplace food choices.

Prior research identified genetic variants influencing macronutrient preference, but whether genetic differences underlying nutrient preference affect long-term food choices is unknown. Here we examined the associations of polygenic scores for carbohydrate, fat, and protein preference with 12 months' workplace food purchases among 397 hospital employees from the ChooseWell 365 study. Food purchases were obtained retrospectively from the hospital's cafeteria sales data for the 12 months before participants were enrolled in the ChooseWell 365 study. Traffic light labels, visible to employees when making purchases, measured the quality of workplace purchases. During the 12-month study period, there were 215,692 cafeteria purchases. Each SD increase in the polygenic score for carbohydrate preference was associated with 2.3 additional purchases/month (95%CI, 0.2 to 4.3; p = 0.03) and a higher number of green-labeled purchases (ß = 1.9, 95%CI, 0.5-3.3; p = 0.01). These associations were consistent in subgroup and sensitivity analyses accounting for additional sources of bias. There was no evidence of associations between fat and protein polygenic scores and cafeteria purchases. Findings from this study suggest that genetic differences in carbohydrate preference could influence long-term workplace food purchases and may inform follow-up experiments to enhance our understanding of the molecular mechanisms underlying food choice behavior.

Pre-pregnancy body mass index and gut microbiota of mothers and children 5 years postpartum.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) has been linked to altered gut microbiota in women shortly after delivery and in their offspring in the first few years of life. But little is known about how long these differences persist. METHODS: We followed 180 mothers and children from pregnancy until 5-year postpartum in the Gen3G cohort (Canada, enrolled 2010-2013). At 5 years postpartum we collected stool samples from mothers and children and estimated the gut microbiota by 16 S rRNA sequencing (V4 region) using Illumina MiSeq, and assigning amplicon sequence variants (ASV). We examined whether overall microbiota composition (as measured by microbiota ß diversity) was more similar between mother-child pairs compared to between mothers or between children. We also assessed whether mother-child pair sharing of overall microbiota composition differed by the weight status of mothers before pregnancy and of children at 5-year. Furthermore, in mothers, we examined whether pre-pregnancy BMI, BMI 5-year postpartum, and change in BMI between time points was associated with maternal gut microbiota 5-year postpartum. In children, we further examined associations of maternal pre-pregnancy BMI and child 5-year BMI z-score with child 5-year gut microbiota. RESULTS: Mother-child pairs had greater similarity in overall microbiome composition compared to between mothers and between children. In mothers, higher pre-pregnancy BMI and 5-year postpartum BMI were associated with lower microbiota observed ASV richness and Chao 1 index; in children's gut microbiota, higher maternal pre-pregnancy BMI was weakly associated with lower microbiota Shannon index, whereas child's 5-year BMI z-score was associated with higher observed ASV richness. Pre-pregnancy BMI was also linked to differential abundances of several microbial ASVs in the Ruminococcaceae and Lachnospiraceae families, but no specific ASV had overlapping associations with BMI measures in both mothers and children. CONCLUSIONS: Pre-pregnancy BMI was associated with gut microbiota diversity and composition of mothers and children 5 years after birth, however, the nature and direction of most associations differed for mothers and children. Future studies are encouraged to confirm our findings and look into potential mechanisms or factors that may drive these associations.

Growth Velocities Across Distinct Early Life Windows and Child Cognition: Insights from a Contemporary US Cohort.

OBJECTIVE: To evaluate the relative importance of overall and period-specific postnatal growth and their interaction with fetal growth on cognition in a generally well-nourished population. STUDY DESIGN: We included 1052 children from Project Viva, a prospective cohort in Boston, Massachusetts. Using linear spline mixed-effects models, we modeled length/height and body mass index (BMI) trajectories from birth to 7 years and estimated standardized overall (0-7 years) and period-specific growth velocities ie, early infancy (0-4 months), late infancy (4-15 months), toddlerhood (15-37 months), and early childhood (37-84 months). We investigated associations of growth velocities as well as their interactions with birthweight-for-gestational age on mid-childhood (mean age: 7.9 years) IQ, visual memory and learning, and visual motor ability. RESULTS: Greater overall height velocity was associated with modestly higher design memory score, (adjusted ß [95% CI] 0.19 [-0.01,0.38] P = .057])points per SD increase but lower verbal IQ (-0.88 [-1.76,0.00] P = .051). Greater early infancy height velocity was associated with higher visual motor score (1.92 [0.67,3.18]). Greater overall BMI velocity was associated with lower verbal IQ (-0.71 [-1.52,0.11] P = .090). Greater late infancy BMI velocity was associated with lower verbal IQ (-1.21 [-2.07,-0.34]), design memory score (-0.22 [-0.42,-0.03)], but higher picture memory score (0.22 [0.01,0.43]). Greater early infancy height velocity (-1.5 SD vs 1.5 SD) was associated with higher nonverbal IQ (margins [95% CI] 102.6 [98.9106.3] vs 108.2 [104.9111.6]) among small-for-gestational age infants (P-interaction = 0.04). CONCLUSIONS: Among generally well-nourished children, there might not be clear cognitive gains with faster linear growth except for those with lower birthweight-for-gestational age, revealing the potential importance of early infancy compensatory growth.

Associations of Prenatal First Trimester Essential and Nonessential Metal Mixtures with Body Size and Adiposity in Childhood.

BACKGROUND: Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity. METHODS: We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715-859), waist circumference (cm) (N = 717-882), and body mass index (BMI) (z-score) (N = 716-875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511-599). We estimated associations using adjusted quantile g-computation and linear regression. RESULTS: The nonessential metal mixture was associated with higher total (ß = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (ß = 0.12, CI = 0.02, 0.22), waist circumference (ß = 0.01, CI = 0.00, 0.01), and BMI (ß = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (ß = 0.07, CI = 0.01, 0.14), and BMI (ß = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(ß = -0.11, CI = -0.17, -0.04) and trunk- fat mass index (ß = -0.13, CI = -0.21, -0.05), subscapular+tricep skinfold thickness (ß = -0.02, CI = -0.03, -0.00), waist circumference (ß = -0.003, CI = -0.01, -0.00), and BMI (ß = -0.16, CI = -0.28, -0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints. CONCLUSIONS: Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence.

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

Non-essential and essential trace element mixtures and kidney function in early pregnancy - A cross-sectional analysis in project viva.

Some trace elements are established nephrotoxicants, yet their associations with kidney function remain understudied in the context of pregnancy, a time of substantial change in kidney physiology and function. We aimed to estimate the individual and joint associations of trace element mixtures with maternal kidney function during the 1st trimester of pregnancy (mean 9.7 gestational weeks). 1040 women from Project Viva contributed blood samples which were assessed for erythrocyte non-essential [arsenic (As), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb)] and essential [barium (Ba), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)] trace elements, and plasma creatinine for kidney function. We estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI) equation without race-adjustment factors. We examined associations of eGFRCKD-EPI with individual trace elements using multivariable linear regression and their mixtures using quantile-based g-computation, adjusting for sociodemographics, pregnancy characteristics, and diet. Participants in our study were predominantly White (75%), college graduates (72%), and had household income >$70,000/year (63%). After adjusting for covariates, higher Pb (ß -3.51 ml/min/1.73 m2; 95% CI -5.83, -1.18) concentrations were associated with lower eGFRCKD-EPI, while higher Mg (ß 10.53 ml/min/1.73 m2; 95% CI 5.35, 15.71), Se (ß 5.56 ml/min/1.73 m2; 95% CI 0.82, 10.31), and Zn (ß 5.88 ml/min/1.73 m2; 95% CI 0.51, 11.26) concentrations were associated with higher eGFRCKD-EPI. In mixture analyses, higher non-essential trace elements mixture concentration was associated with reduced eGFRCKD-EPI (Ψ -1.03 ml/min/1.73 m2; 95% CI: 1.92, -0.14). Conversely, higher essential trace elements mixture concentration was associated with higher eGFR (Ψ 1.42; 95% CI: 0.48, 2.37). Exposure to trace elements in early pregnancy may influence women's kidney function although reverse causation cannot be eliminated in this cross-sectional analysis. These findings have important implications for long-term cardiovascular and postpartum kidney health that warrant additional studies.

Associations of prenatal maternal depressive symptoms with cord blood glucocorticoids and child hair cortisol levels in the project viva and the generation R cohorts: a prospective cohort study.

BACKGROUND: Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers. METHODS: In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts. RESULTS: 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort. CONCLUSIONS: The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels.

Maternal Hyperglycemia in Pregnancy and Offspring Internalizing and Externalizing Behaviors.

OBJECTIVE: To examine the associations between exposure to gestational diabetes mellitus (GDM) and maternal glycemic markers during pregnancy and offspring behaviors at 3 and 5 years. We hypothesized that exposure to maternal hyperglycemia would be associated with more behavioral problems in offspring. METHODS: We included 548 mother-child pairs from the prospective pre-birth Gen3G cohort (Canada). Glycemic markers were measured during a 75 g oral glucose tolerance test (OGTT) in the second trimester of pregnancy. Based on OGTT, we classified 59 women (10.8%) as having GDM according to international diagnostic criteria. Mothers reported offspring behavior using the Strengths and Difficulties Questionnaire (SDQ) at 3 and 5 years, and the Child Behavior Checklist (CBCL) at 5 years. We used linear mixed models and multivariate regression to assess the associations between GDM or glycemic markers and children's behavior, adjusted for child sex and age, and maternal demographic factors, body mass index and family history of diabetes. RESULTS: Exposure to GDM was associated with higher SDQ externalizing scores at 3 and 5 years [B = 1.12, 95% CI (0.14, 2.10)] in fully adjusted linear mixed models. These results were supported by the CBCL at 5 years. Higher levels of maternal glucose at 1 h and 2 h during OGTT were associated with greater SDQ externalizing scores. Fasting glucose levels were not associated with child behavior scores. We did not observe associations between glycemic markers and internalizing behaviors. CONCLUSIONS: Exposure to higher levels of maternal glycemia during pregnancy was associated with more externalizing behaviors in children at 3 and 5 years.

What is already known on this subject? Prenatal exposure to gestational diabetes mellitus (GDM) has been linked to a higher risk of long-term consequences in offspring including metabolic problems and cognitive difficulties. However, prior studies examining associations between GDM and behavior in children reported mixed results. What this study adds? We reported associations between exposure to maternal GDM and post-OGTT hyperglycemia during pregnancy and greater levels of externalizing behaviors in children at 3 and 5 years of age. Our results underscore the importance of early detection of behavioral problems in children.

Lifestyle interventions in pregnancy targeting GDM prevention: looking ahead to precision medicine.

Gestational diabetes mellitus (GDM) is the most prevalent pregnancy-related endocrinopathy, affecting up to 25% of pregnancies worldwide. Pregnant individuals who develop GDM have an increased risk of complications during pregnancy and birth, as well as future development of type 2 diabetes mellitus and CVD. This increased risk is subsequently passed along to the offspring, perpetuating a cycle of metabolic dysfunction across generations. GDM prevention strategies have had mixed results for many years, but more recent systematic reviews and meta-analyses have suggested potential new avenues of prevention. The objective of this review is to summarise the literature examining the efficacy of lifestyle interventions for the prevention of GDM and to uncover if specific individual-level characteristics influence this outcome. Based on the present literature, we determined that future trials should be designed to understand if initiation of lifestyle intervention in the preconception period is more effective to reduce GDM. Furthermore, trials initiated during pregnancy should be developed through the lens of precision prevention. That is, trials should tailor intervention approaches based on individual-level risk defined by the presence of modifiable and non-modifiable risk factors. Finally, future interventions might also benefit from just-in-time adaptive intervention designs, which allow for interventions to be modified in real-time based on objective assessments of an individual's response.

Longitudinal changes in glucose during pregnancy in women with gestational diabetes risk factors.

AIMS/HYPOTHESIS: Despite recommendations to screen women with diabetes risk factors for hyperglycaemia in the first trimester, criteria for normal glucose values in early pregnancy have not been firmly established. We aimed to compare glucose levels in early pregnancy with those later in gestation and outside of pregnancy in women with diabetes risk factors. METHODS: In pregnant women (N = 123) followed longitudinally through the postpartum period, and a separate cohort of non-pregnant women (N = 65), we performed 75 g oral glucose tolerance tests. All participants had one or more risk factors for diabetes. Using linear regression, we tested for differences in glucose levels between non-pregnant and pregnant women at early (7-15 weeks) and mid-late (24-32 weeks) gestation as well as postpartum, with adjustment for maternal age, parity, marital status and BMI. In a longitudinal analysis using mixed-effects models, we tested for differences in glucose levels across early and mid-late pregnancy compared with postpartum. Differences are expressed as ß (95% CI). RESULTS: Fasting glucose was lower in pregnant compared with non-pregnant women by 0.34 (0.18, 0.51) mmol/l (p < 0.0001) in early pregnancy and by 0.45 (0.29, 0.61) mmol/l (p < 0.0001) in mid-late pregnancy. In longitudinal models, fasting glucose was lower by 0.13 (0.04, 0.21) mmol/l (p = 0.003) in early pregnancy and by 0.16 (0.08, 0.25) mmol/l (p = 0.0003) in mid-late pregnancy compared with the same women postpartum. Early pregnancy post-load glucose levels did not differ from those in non-pregnant women or the same women postpartum. In mid-late pregnancy, compared with non-pregnant women, elevations in 1 h post-load glucose level (0.60 [-0.12, 1.33] mmol/l, p = 0.10) and 2 h post-load glucose (0.49 [-0.21, 1.19] mmol/l, p = 0.17) were not statistically significant. However, in longitudinal analyses, 1 h and 2 h post-load glucose levels were higher in mid-late pregnancy (by 0.78 [0.35, 1.21] mmol/l, p = 0.0004, and 0.67 [0.30, 1.04] mmol/l, p = 0.0005, respectively) when compared with postpartum. CONCLUSIONS/INTERPRETATION: In women with diabetes risk factors, fasting glucose declines in the first trimester. Post-load glucose increases later in pregnancy. These findings may inform criteria for diagnosing hyperglycaemia early in pregnancy.

Early-Life Exposure to Green Space and Mid-Childhood Cognition in the Project Viva Cohort, Massachusetts.

The association between early-life greenness and child cognition is not well understood. Using prospective data from Project Viva (n = 857) from 1999-2010, we examined associations of early-life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1 years), and mid-childhood (7.8 years) using 30-m resolution Landsat satellite imagery (normalized difference vegetation index). In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness <0.6), greenness exposure at early childhood was associated with a 0.48% increase in nonverbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early-childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with nonverbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.

Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy.

BACKGROUND: During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. METHODS: Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. RESULTS: A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. CONCLUSION: We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.