Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

BACKGROUND: Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4-17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults. RESULTS: Maternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes. CONCLUSIONS: Maternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism

Newborn and childhood differential DNA methylation and liver fat in school-age children

Background: Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. Results: The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. Conclusions: DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat

Associations Between Intake of Sugar-Containing Beverages in Infancy With Liver Fat Accumulation at School Age

Background and Aims: Sugar-containing beverage intake is a major risk factor for obesity in both children and adults and appears to be associated with NAFLD in adults. The purpose of this study was to examine the associations between sugar-containing beverage intake in infancy and liver fat accumulation and NAFLD among school-aged children. Approach and Results: In a population-based prospective cohort study of 1,940 infants, we assessed sugar-containing beverage intake at 1 year with a validated Food Frequency Questionnaire. Liver fat fraction and NAFLD (liver fat fraction ≥5.0%) were assessed with MR. Higher sugar-containing beverage intake in infancy was not associated with higher liver fat accumulation at 10 years of age when assessed continuously (SD, 0.03; 95% CI, (Formula presented.) 0.02, 0.07, per one-serving/day increase of sugar-containing beverage intake) or categorically (P = 0.38). However, compared to infants with 2.0 servings/day had the highest odds of NAFLD at 10 years of age (OR, 3.02; 95% CI, 1.34, 6.83). These associations remained borderline significant after additional adjustment for sugar-containing beverage intake and body mass index at school age (P = 0.13). Stratified analyses showed stronger associations between sugar-containing beverage intake in infancy and NAFLD at 10 years of age among children of mothers with lower educational attainment (OR, 1.48; 95% CI, 1.12, 1.97) and among children with overweight or obesity (OR, 1.47; 95% CI, 1.05, 2.07). Conclusions: Higher sugar-containing beverage intake in infancy was associated with NAFLD in school-aged children, independent of sugar-containing beverage intake and body mass index at school age. Limiting the intake of sugar-containing beverages in infancy may help prevent liver steatosis at school age

High maternal early-pregnancy blood glucose levels are associated with altered fetal growth and increased risk of adverse birth outcomes

Aims/hypothesis: The study aimed to assess the associations of maternal early-pregnancy blood glucose levels with fetal growth throughout pregnancy and the risks of adverse birth outcomes. Methods: In a population-based prospective cohort study among 6116 pregnant women, maternal non-fasting glucose levels were measured in blood plasma at a median 13.2 weeks of gestation (95% range 9.6–17.6). We measured fetal growth by ultrasound in each pregnancy period. We obtained information about birth outcomes from medical records and maternal sociodemographic and lifestyle factors from questionnaires. Results: Higher maternal early-pregnancy non-fasting glucose levels were associated with altered fetal growth patterns, characterised by decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, resulting in an increased length and weight at birth (p ≤0.05 for all). A weaker association of maternal early-pregnancy non-fasting glucose levels with fetal head circumference growth rates was present. Higher maternal early-pregnancy non-fasting glucose levels were also associated with an increased risk of delivering a large-for-gestational-age infant, but decreased risk of delivering a small-for-gestational-age infant (OR 1.28 [95% CI 1.16, 1.41], OR 0.88 [95% CI 0.79, 0.98] per mmol/l increase in maternal early-pregnancy non-fasting glucose levels, respectively). These associations were not explained by maternal sociodemographic factors, lifestyle factors or BMI. Maternal early-pregnancy non-fasting glucose levels were not associated with preterm birth or delivery complications. Conclusions/interpretation: Higher maternal early-pregnancy non-fasting glucose levels are associated with decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, and an increased risk of delivering a large-for-gestational-age infant. Future preventive strategies need to focus on screening for an impaired maternal glucose metabolism from preconception and early pregnancy onwards to improve birth outcomes

Associations of Maternal Early-Pregnancy Glucose Concentrations With Placental Hemodynamics, Blood Pressure, and Gestational Hypertensive Disorders

BACKGROUND: Gestational diabetes mellitus is associated with increased risks of gestational hypertension and preeclampsia. We hypothesized that high maternal glucose concentrations in early pregnancy are associated with adverse placental adaptations and subsequently altered uteroplacental hemodynamics during pregnancy, predisposing to an increased risk of gestational hypertensive disorders. METHODS: In a population-based prospective cohort study from early pregnancy onwards, among 6,078 pregnant women, maternal early-pregnancy non-fasting glucose concentrations were measured. Mid and late pregnancy uterine and umbilical artery resistance indices were assessed by Doppler ultrasound. Maternal blood pressure was measured in early, mid, and late pregnancy and the occurrence of gestational hypertensive disorders was assessed using hospital registries. RESULTS: Maternal early-pregnancy glucose concentrations were not associated with mid or late pregnancy placental hemodynamic markers. A 1 mmol/l increase in maternal early-pregnancy glucose concentrations was associated with 0.71 mm Hg (95% confidence interval 0.22-1.22) and 0.48 mm Hg (95% confidence interval 0.10-0.86) higher systolic and diastolic blood pressure in early pregnancy, respectively, but not with blood pressure in later pregnancy. Also, maternal glucose concentrations were not associated with the risks of gestational hypertension or preeclampsia. CONCLUSIONS: Maternal early-pregnancy non-fasting glucose concentrations within the normal range are associated with blood pressure in early pregnancy, but do not seem to affect placental hemodynamics and the risks of gestational hypertensive disorders

Glucose Metabolism and Liver Fat in Early Life

The first objective of this thesis was to examine the hypothesis that maternal early-pregnancy glucose concentrations are associated with adverse fetal, pregnancy, birth and child cardio-metabolic outcomes. Also, as second objective, we studied potential determinants of a specific outcome, childhood liver fat, as well as the cardio-metabolic consequences of childhood liver fat

Maternal First-Trimester Cow-Milk Intake Is Positively Associated with Childhood General and Abdominal Visceral Fat Mass and Lean Mass but Not with Other Cardiometabolic Risk Factors at the Age of 10 Years

Background: Higher maternal cow-milk intake during pregnancy is associated with higher fetal growth measures and higher birth weight. Objective: The aim of this study was to assess the associations of maternal milk intake during pregnancy with body fat measures and cardiometabolic risk factors at the age of 10 y. Methods: In a population-based cohort of Dutch mothers and their children (n = 2466) followed from early pregnancy onwards, we assessed maternal first-trimester milk intake (milk and milk drinks) by food-frequency questionnaire. Maternal milk intake was categorized into 0-0.9, 1-1.9, 2-2.9, 3-3.9, 4-4.9, and ≥5 g

Maternal Early-Pregnancy Glucose Concentrations and Liver Fat Among School-Age Children

Background and Aims: Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation. Approach and Results: In a multiethnic, population-based, prospective cohort study among 2,168 women and their offspring, maternal early-pregnancy glucose concentrations were measured at a median of 13.1 weeks’ gestation (95% CI, 9.6-17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early-pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9-4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early-pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early-pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1-mmol/L increase in maternal early-pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers. Conclusions: In this study, maternal early-pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early-pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.</p

Associations of Early Pregnancy and Neonatal Circulating Folate, Vitamin B-12, and Homocysteine Concentrations with Cardiometabolic Risk Factors in Children at 10 y of Age

Background: Higher circulating folate and vitamin B-12 concentrations and lower circulating homocysteine concentrations during pregnancy seem to be associated with fetal development. These micronutrients may also be associated with cardiometabolic health. Objective: We examined the associations of circulating folate, vitamin B-12