The role of structural racism and geographical inequity in diabetes outcomes.

Diabetes is pervasive, exponentially growing in prevalence, and outpacing most diseases globally. In this Series paper, we use new theoretical frameworks and a narrative review of existing literature to show how structural inequity (structural racism and geographical inequity) has accelerated rates of diabetes disease, morbidity, and mortality globally. We discuss how structural inequity leads to large, fixed differences in key, upstream social determinants of health, which influence downstream social determinants of health and resultant diabetes outcomes in a cascade of widening inequity. We review categories of social determinants of health with known effects on diabetes outcomes, including public awareness and policy, economic development, access to high-quality care, innovations in diabetes management, and sociocultural norms. We also provide regional perspectives, grounded in our theoretical framework, to highlight prominent, real-world challenges.

Interventions to address global inequity in diabetes: international progress.

Diabetes is a serious chronic disease with high associated burden and disproportionate costs to communities based on socioeconomic, gender, racial, and ethnic status. Addressing the complex challenges of global inequity in diabetes will require intentional efforts to focus on broader social contexts and systems that supersede individual-level interventions. We codify and highlight best practice approaches to achieve equity in diabetes care and outcomes on a global scale. We outline action plans to target diabetes equity on the basis of the recommendations established by The Lancet Commission on Diabetes, organising interventions by their effect on changing the ecosystem, building capacity, or improving the clinical practice environment. We present international examples of how to address diabetes inequity in the real world to show that approaches addressing the individual within a larger social context, in addition to addressing structural inequity, hold the greatest promise for creating sustainable and equitable change that curbs the global diabetes crisis.

Neonatal adiposity is associated with microRNAs in adipocyte-derived extracellular vesicles in maternal and cord blood, a discovery analysis.

BACKGROUND: Maternal body size, nutrition, and hyperglycemia contribute to neonatal body size and composition. There is little information on maternal-fetal transmission of messages which influence fetal growth. We analyzed adipocyte-derived small extracellular vesicular (ADsEV) microRNAs in maternal and cord blood to explore their adipogenic potential. METHODS: There were 279 mother-neonate pairs with all phenotypic data (normal glucose tolerant NGT = 148, gestational diabetes mellitus GDM = 131). Neonates with adiposity were those in the highest tertile (T3) of sex-specific sum of skinfolds and those without adiposity (lean) in the lowest tertile T1 of NGT pregnancies. We studied ADsEV miRNAs in 76 and 51 neonates with and without adiposity respectively and their mothers based on power calculations (68 NGT and 59 GDM pregnancies). ADsEV miRNAs from maternal and cord blood plasma samples were profiled on Agilent 8*60 K microarray. Differential expression (DE) of ADsEV miRNAs in adipose vs. lean groups was studied before and after adjustment for maternal GDM, adiposity, and vitamin B12-folate status. RESULTS: Multiple miRNAs were common in maternal and cord blood and positively correlated. We identified 24 maternal and 5 cord blood miRNAs differentially expressed (discovery p ≤ 0.1) in the adipose group in unadjusted, and 19 and 26, respectively, in the adjusted analyses. Even though DE miRNAs were different in maternal and cord blood, they targeted similar adipogenic pathways (e.g., the forkhead box O (FOXO) family of transcription factors, mitogen­activated protein kinase (MAPK) pathway, transforming growth factor beta (TGF-ß) pathway). Maternal GDM and adiposity were associated with many DE ADsEV miRNAs. CONCLUSION: Our results suggest that the ADsEV miRNAs in mothers are potential regulators of fetal adiposity. The expression and functionality of miRNAs appear to be influenced by maternal adiposity, hyperglycemia, and micronutrient status during pregnancy.

Long-Term Impact on Offspring (5 to 11 Years of Age) of Metformin Use in Pregnancy in Mothers With Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Data are scant on the impact of metformin use in gestational diabetes mellitus/diabetes in pregnancy on long-term outcomes in children and mothers beyond 5 years of childbirth. This systematic review and meta-analysis aimed to evaluate the long-term impact of metformin use in pregnancy on children and their mothers. METHODS: Electronic databases were searched for studies evaluating metformin compared with insulin for managing gestational diabetes mellitus/diabetes in pregnancy. The primary outcome was the change in body mass index (BMI) in children at the ages of 5 to 11 years. The secondary outcomes were alterations in other anthropometric measures, obesity, and changes in the levels of lipids and adipocytokines in children and mothers. RESULTS: Children at the age of 9 years born to mothers who were treated with metformin during pregnancy had similar BMI (mean difference [MD], 1.09 kg/m2 [95% confidence interval {CI}, -0.44 to 2.62]; P = .16; I2 = 16%), waist circumference-to-height ratio (MD, 0.13 [95% CI, -0.05 to 0.30]; P = .16; I2 = 94%), dual-energy X-ray absorptiometry (DXA) total fat mass (MD, 0.68 kg [95% CI, -2.39 to 3.79]; P = .66; I2 = 70%), DXA total fat percent (MD, 0.04% [95% CI, -3.44 to 3.51]; P = .98; I2 = 56%), DXA total fat-free mass (MD, 0.81 kg [95% CI, -0.96 to 2.58]; P = .37; I2 = 55%), magnetic resonance imaging visceral adipose tissue volume (MD, 80.97 cm3 [95% CI, -136.47 to 298.41]; P = .47; I2 = 78%), and magnetic resonance spectroscopy liver fat percentage (MD, 0.27% [95% CI, -1.26 to 1.79]; P = .73; I2 = 0%) to those born to mothers who were treated with insulin. Serum adiponectin, leptin, alanine aminotransferase, and ferritin were comparable among groups. In children between the ages of 9 and 11 years, the occurrence of obesity, diabetes, or challenges in motor and social development were comparable between the 2 groups. After 9 years of childbirth, BMI and the risk of developing diabetes were similar between the 2 groups of women. CONCLUSION: Metformin use in pregnancy did not show any adverse effects compared with insulin on long-term outcomes in children and their mothers.

Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6-7 Years: A Follow-Up of a Randomized Controlled Trial.

BACKGROUND: Deficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. OBJECTIVES: We investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6-7 y. METHODS: This is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6-30-mo-old children. The supplement contained 1.8 µg of vitamin B12, 150 µg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016-November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). RESULTS: At baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 µmol/L (95% CI: 0.09; 2.30 µmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin-adiponectin ratio in subgroups based on their nutritional status. CONCLUSIONS: Supplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations. The original trial was registered at www. CLINICALTRIALS: gov as NCT00717730, and the follow-up study at www.ctri.nic.in as CTRI/2016/11/007494.

Subgroups of patients with young-onset type 2 diabetes in India reveal insulin deficiency as a major driver.

AIM/HYPOTHESIS: Five subgroups were described in European diabetes patients using a data driven machine learning approach on commonly measured variables. We aimed to test the applicability of this phenotyping in Indian individuals with young-onset type 2 diabetes. METHODS: We applied the European-derived centroids to Indian individuals with type 2 diabetes diagnosed before 45 years of age from the WellGen cohort (n = 1612). We also applied de novo k-means clustering to the WellGen cohort to validate the subgroups. We then compared clinical and metabolic-endocrine characteristics and the complication rates between the subgroups. We also compared characteristics of the WellGen subgroups with those of two young European cohorts, ANDIS (n = 962) and DIREVA (n = 420). Subgroups were also assessed in two other Indian cohorts, Ahmedabad (n = 187) and PHENOEINDY-2 (n = 205). RESULTS: Both Indian and European young-onset type 2 diabetes patients were predominantly classified into severe insulin-deficient (SIDD) and mild obesity-related (MOD) subgroups, while the severe insulin-resistant (SIRD) and mild age-related (MARD) subgroups were rare. In WellGen, SIDD (53%) was more common than MOD (38%), contrary to findings in Europeans (Swedish 26% vs 68%, Finnish 24% vs 71%, respectively). A higher proportion of SIDD compared with MOD was also seen in Ahmedabad (57% vs 33%) and in PHENOEINDY-2 (67% vs 23%). Both in Indians and Europeans, the SIDD subgroup was characterised by insulin deficiency and hyperglycaemia, MOD by obesity, SIRD by severe insulin resistance and MARD by mild metabolic-endocrine disturbances. In WellGen, nephropathy and retinopathy were more prevalent in SIDD compared with MOD while the latter had higher prevalence of neuropathy. CONCLUSIONS /INTERPRETATION: Our data identified insulin deficiency as the major driver of type 2 diabetes in young Indians, unlike in young European individuals in whom obesity and insulin resistance predominate. Our results provide useful clues to pathophysiological mechanisms and susceptibility to complications in type 2 diabetes in the young Indian population and suggest a need to review management strategies.

Vitamin B12 and Folate Markers Are Associated with Insulin Resistance During the Third Trimester of Pregnancy in South Asian Women, Living in the United Kingdom, with Gestational Diabetes and Normal Glucose Tolerance.

BACKGROUND: Gestational diabetes mellitus (GDM) can adversely affect the health of the developing fetus. Women of South Asian origin are particularly at risk of developing GDM. Insulin resistance (IR) contributes to the etiology of GDM, and although studies have shown associations of vitamin B12 (B12) and folate status with GDM and IR, only a limited number of B12 and folate markers have been used. OBJECTIVE: We used a comprehensive panel of B12 and folate markers to examine their association with IR in pregnant women with diet-controlled GDM and normal glucose tolerance (NGT). METHODS: In this cross-sectional study, 59 British-Bangladeshi women (24 GDM and 35 NGT) with a mean age of 29 y, BMI (in kg/m2) 26.7 and gestational age 33 wk were recruited. Serum total B12, holotranscobalamin, folate, methylmalonic acid, plasma homocysteine, 5-methyltetrahydrofolate, and red cell folate (RCF) were measured along with other parameters. The independent sample t-test and chi-squared test were used to assess differences in markers between GDM and NGT women. Spearman's test was used to look for correlations. A simple multiple regression analysis was used to investigate if markers of B12 and folate status predicted IR, using the HOMA-IR and adjusting for age, GDM status, and BMI. RESULTS: There were no differences in concentrations of B12 and folate markers between GDM and NGT women. In Spearman's analysis HOMA-IR correlated negatively with total serum B12 (P < 0.001) and holotranscobalamin (P < 0.05), and positively with BMI (P < 0.001), blood pressure (P < 0.05) and triglycerides (P < 0.05) in all women. MMA did not correlate with any of the B12 markers. In regression analysis, total B12 (ß = -0.622, P = 0.004), RCF (ß = 0.387, P = 0.018), and BMI (ß = 0.024, P < 0.001) were the significant predictors of HOMA-IR variance. CONCLUSIONS: Significant associations between markers of B12 and folate status with HOMA-IR were found during the third trimester in British-Bangladeshi women. B12 markers correlated poorly with each other.

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study).

AIMS/HYPOTHESIS: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26-28 weeks of gestation. METHODS: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. RESULTS: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26-28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: -0.06 mmol/l; 95% CI -0.04, -0.08; p < 0.0001) and 2 h plasma glucose levels (-0.07 mmol/l; 95% CI -0.02, -0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic ß: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12-high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). CONCLUSIONS/INTERPRETATION: B12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008824.

The double burden of malnutrition: aetiological pathways and consequences for health.

Malnutrition has historically been researched and addressed within two distinct silos, focusing either on undernutrition, food insecurity, and micronutrient deficiencies, or on overweight, obesity, and dietary excess. However, through rapid global nutrition transition, an increasing proportion of individuals are exposed to different forms of malnutrition during the life course and have the double burden of malnutrition (DBM) directly. Long-lasting effects of malnutrition in early life can be attributed to interconnected biological pathways, involving imbalance of the gut microbiome, inflammation, metabolic dysregulation, and impaired insulin signalling. Life-course exposure to early undernutrition followed by later overweight increases the risk of non-communicable disease, by imposing a high metabolic load on a depleted capacity for homoeostasis, and in women increases the risk of childbirth complications. These life-course trajectories are shaped both by societal driving factors-ie, rapidly changing diets, norms of eating, and physical activity patterns-and by broader ecological factors such as pathogen burden and extrinsic mortality risk. Mitigation of the DBM will require major societal shifts regarding nutrition and public health, to implement comprehensive change that is sustained over decades, and scaled up into the entire global food system.

Adolescent diet and physical activity in the context of economic, social and nutrition transition in rural Maharashtra, India: a qualitative study.

OBJECTIVE: To explore the perceptions of adolescents and their caregivers on drivers of diet and physical activity in rural India in the context of ongoing economic, social and nutrition transition. DESIGN: A qualitative study comprising eight focus group discussions (FGD) on factors affecting eating and physical activity patterns, perceptions of health and decision-making on food preparation. SETTING: Villages approximately 40-60 km from the city of Pune in the state of Maharashtra, India. PARTICIPANTS: Two FGD with adolescents aged 10-12 years (n 20), two with 15- to 17- year-olds (n 18) and four with their mothers (n 38). RESULTS: Dietary behaviour and physical activity of adolescents were perceived to be influenced by individual and interpersonal factors including adolescent autonomy, parental influence and negotiations between adolescents and caregivers. The home food environment, street food availability, household food security and exposure to television and digital media were described as influencing behaviour. The lack of facilities and infrastructure was regarded as barriers to physical activity as were insufficient resources for public transport, safe routes for walking and need for cycles, particularly for girls. It was suggested that schools take a lead role in providing healthy foods and that governments invest in facilities for physical activity. CONCLUSIONS: In this transitioning environment, that is representative of many parts of India and other Lower Middle Income Countries (LMIC), people perceive a need for interventions to improve adolescent diet and physical activity. Caregivers clearly felt that they had a stake in adolescent health, and so we would recommend the involvement of both adolescents and caregivers in intervention design.

Characteristics of COVID-19 Patients Admitted to a Tertiary Care Hospital in Pune, India and Predictors of Requirement for Intensive Care Treatment.

OBJECTIVES: 1. To study associations of severity of COVID-19 disease with clinical features and laboratory markers. 2. To develop a model to predict the need for ICU treatment. METHODS: This is an analysis of clinical course in 800 consecutive patients from a dedicated COVID-19 tertiary care hospital in Pune, India (8th April to 15th June 2020). We obtained clinical and laboratory information, severity grading and progress from hospital records. We studied associations of these characteristics with need for ICU management. We developed a predictive model of need for ICU treatment among first 500 patients and tested its sensitivity and specificity in the following 300 patients. RESULTS: Average age was 41 years, 16% were 20 years of age, 55% were male, 50% were asymptomatic and 16% had at least one comorbidity. Using MoHFW India severity guidelines, 73% patients had mild, 6% moderate and 20% severe disease. Severity was associated with higher age, symptomatic presentation, elevated neutrophil and reduced lymphocyte counts and elevated inflammatory markers. Seventy-seven patients needed ICU treatment: they were older (56 years), more symptomatic and had lower SpO2 and abnormal chest X-ray and deranged hematology and biochemistry at admission. A model trained on the first 500 patients, using above variables predicted need for ICU treatment with sensitivity 80%, specificity 88% in subsequent 300 patients; exclusion of expensive laboratory tests (Ferritin, C- Reactive Protein) did not affect accuracy. CONCLUSION: In the early phase of COVID- 19 pendemic, a significant proportion of hospitalized patients were young and asymptomatic. Need for ICU treatment was predicted by simple measures including higher age, symptomatic onset, low SpO2 and abnormal chest X-ray. We propose a simple model for referring patients for treatment at specialized COVID-19 hospitals.

Developmental undernutrition, offspring obesity and type 2 diabetes.

The Developmental Origins of Health and Disease (DOHaD) paradigm posits that a mismatch between circumstances at or around conception and in later life leads to metabolic dysregulation and the development of obesity and diabetes. In this review we highlight three strands of evidence: prospective studies of patterns of growth from birth to adulthood, historical studies of exposure to famine at defined points during gestation and early life, and nutrition intervention studies. We conclude that, while much is still unknown, it is becoming clearer that the combination of early-life undernutrition and later development of obesity is associated with increased risk of diabetes. There is a need to support public health programmes aimed at intergenerational (primordial) prevention of diabetes and other non-communicable disease.

Racial/ethnic differences in the burden of type 2 diabetes over the life course: a focus on the USA and India.

Type 2 diabetes is a common disease worldwide, but its prevalence varies widely by geographical region and by race/ethnicity. This review summarises differences in the frequencies of type 2 diabetes according to race, ethnicity, socioeconomic position, area of residence and environmental toxins. Type 2 diabetes susceptibility often begins early in life, starting with genetic susceptibility at conception and continuing in later life, via in utero, childhood and adult exposures. Early-life factors may lead to overt type 2 diabetes in childhood or in later life, supporting the concept of developmental origins of health and disease. The causes of the racial/ethnic differences in incidence of type 2 diabetes are not well understood. Specifically, the relative contributions of genetic and environmental factors to such differences are largely unknown. With a few exceptions in isolated populations, there is little evidence that differences in frequencies of known type 2 diabetes susceptibility genetic alleles account for racial/ethnic differences, although the search for genetic susceptibility has not been uniform among the world's racial/ethnic groups. In the USA, race/ethnicity is associated with many other risk factors for type 2 diabetes, including being overweight/obese, diet and socioeconomic status. Some studies suggest that some of these factors may account for the race/ethnic differences in prevalence of type 2 diabetes, although there is inadequate research in this area. A better understanding of the impact of these factors on type 2 diabetes risk should lead to more effective prevention and treatment of this disease. This has not yet been achieved but should be a goal for future research.

GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians.

Vitamin B12 is an important cofactor in one-carbon metabolism whose dysregulation is associated with various clinical conditions. Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12 concentrations in Indians. We performed a genome-wide association study in 1001 healthy participants in the Pune Maternal Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta-analysis identified new variants, rs3760775 (P = 1.2 × 10-23) and rs78060698 (P = 8.3 × 10-17) in FUT6 to be associated with circulating B12 concentrations. Although in-silico analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size and the linkage disequilibrium structure of credible set variants with the reported variants suggest population-specific characteristics in this region. We replicated previously reported variants rs602662, rs601338 in FUT2, rs3760776, rs708686 in FUT6, rs34324219 in TCN1 (all P < 5 × 10-8), rs1131603 in TCN2 (P = 3.4 × 10-5), rs12780845 in CUBN (P = 3.0 × 10-3) and rs2270655 in MMAA (P = 2.0 × 10-3). Circulating B12 concentrations in the PMNS and Parthenon study showed a significant decline with increasing age (P < 0.001), however, the genetic contribution to B12 concentrations remained constant. Luciferase reporter and electrophoretic-mobility shift assay for the FUT6 variant rs78060698 using HepG2 cell line demonstrated strong allele-specific promoter and enhancer activity and differential binding of HNF4α, a key regulator of expression of various fucosyltransferases. Hence, the rs78060698 variant, through regulation of fucosylation may control intestinal host-microbial interaction which could influence B12 concentrations. Our results suggest that in addition to established genetic variants, population-specific variants are important in determining plasma B12 concentrations.

Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health.

A woman who is healthy at the time of conception is more likely to have a successful pregnancy and a healthy child. We reviewed published evidence and present new data from low-income, middle-income, and high-income countries on the timing and importance of preconception health for subsequent maternal and child health. We describe the extent to which pregnancy is planned, and whether planning is linked to preconception health behaviours. Observational studies show strong links between health before pregnancy and maternal and child health outcomes, with consequences that can extend across generations, but awareness of these links is not widespread. Poor nutrition and obesity are rife among women of reproductive age, and differences between high-income and low-income countries have become less distinct, with typical diets falling far short of nutritional recommendations in both settings and especially among adolescents. Several studies show that micronutrient supplementation starting in pregnancy can correct important maternal nutrient deficiencies, but effects on child health outcomes are disappointing. Other interventions to improve diet during pregnancy have had little effect on maternal and newborn health outcomes. Comparatively few interventions have been made for preconception diet and lifestyle. Improvements in the measurement of pregnancy planning have quantified the degree of pregnancy planning and suggest that it is more common than previously recognised. Planning for pregnancy is associated with a mixed pattern of health behaviours before conception. We propose novel definitions of the preconception period relating to embryo development and actions at individual or population level. A sharper focus on intervention before conception is needed to improve maternal and child health and reduce the growing burden of non-communicable diseases. Alongside continued efforts to reduce smoking, alcohol consumption, and obesity in the population, we call for heightened awareness of preconception health, particularly regarding diet and nutrition. Importantly, health professionals should be alerted to ways of identifying women who are planning a pregnancy.

Origins of lifetime health around the time of conception: causes and consequences.

Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. OBJECTIVES: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. POPULATION: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. DESIGN: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. METHODS: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. PRELIMINARY RESULTS: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. CONCLUSIONS: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune Children's Study.

AIMS/HYPOTHESIS: The Pune Children's Study aimed to test whether glucose and insulin measurements in childhood predict cardiovascular risk factors in young adulthood. METHODS: We followed up 357 participants (75% follow-up) at 21 years of age who had undergone detailed measurements at 8 years of age (glucose, insulin, HOMA-IR and other indices). Oral glucose tolerance, anthropometry, plasma lipids, BP, carotid intima-media thickness (IMT) and arterial pulse wave velocity (PWV) were measured at 21 years. RESULTS: Higher fasting glucose, insulin and HOMA-IR at 8 years predicted higher glucose, insulin, HOMA-IR, BP, lipids and IMT at 21 years. A 1 SD change in 8 year variables was associated with a 0.10-0.27 SD change at 21 years independently of obesity/adiposity at 8 years of age. A greater rise in glucose-insulin variables between 8 and 21 years was associated with higher cardiovascular risk factors, including PWV. Participants whose HOMA-IR measurement remained in the highest quartile (n = 31) had a more adverse cardiovascular risk profile compared with those whose HOMA-IR measurement remained in the lowest quartile (n = 28). CONCLUSIONS/INTERPRETATION: Prepubertal glucose-insulin metabolism is associated with adult cardiovascular risk and markers of atherosclerosis. Our results support interventions to improve glucose-insulin metabolism in childhood to reduce cardiovascular risk in later life.