Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Associations of maternal and cord blood adipokines with offspring adiposity in Project Viva: is there an interaction with child age?

OBJECTIVES: Higher leptin and lower adiponectin correlate with adult and childhood adiposity, but it is unclear how exposure to these adipokines during gestation relates to offspring growth. We aimed to investigate the relationships of maternal and cord adipokines with offspring adiposity across childhood to early adolescence, as well as interactions with child age. METHODS: In mother-child pairs in the Project Viva cohort, we measured adipokines in mothers at second trimester (n=1106) and in cord blood at birth (n=657). We measured offspring adiposity indices at early childhood (mean 3.3±s.d. 0.3 years), mid-childhood (7.9±0.8 years) and early adolescence (13.2±0.9 years). We analyzed associations of maternal and cord adipokines with offspring longitudinal adiposity using a linear mixed model adjusting for pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and other confounders. RESULTS: Mothers with higher BMI and GWG had higher leptin. Offspring born to mothers with the highest vs lowest quartile of leptin had lower BMI z-score (-0.49 units, 95% confidence interval (CI):-0.72,-0.26), waist circumference (-2.6 cm, 95% CI: -3.7,-1.5) and sum of subscapular and triceps skinfolds (-2.8 mm, 95% CI: -4.1,-1.4) in early life. An interaction term between maternal leptin and child age was positive, suggesting that the associations between maternal leptin and child adiposity were not constant over time. Offspring born to mothers with lowest vs highest quartile of maternal adiponectin had lower early life adiposity (BMI z-score -0.27 units, 95% CI: -0.48,-0.05). Results were similar for cord leptin but not cord adiponectin. CONCLUSIONS: Our findings showed higher maternal and cord leptin, and lower maternal adiponectin are associated with lower offspring adiposity from childhood to early adolescence, independent of maternal BMI and GWG. However, the strength of these associations was not constant over time.

Plasma metabolite profiles in children with current asthma.

BACKGROUND: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. OBJECTIVE: To identify differences in plasma metabolites between children with and without current asthma at mid-childhood. METHODS: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid-childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case-control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. RESULTS: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1-Methyl-2-pyridone-5-carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1-8.0)), a pyrimidine metabolite (5,6-dihydrothymine (OR = 0.4 (95% CI 0.2-0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1-0.9), taurocholate (OR = 2.0 (95% CI 1.2-3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p-cresol sulphate OR = 0.5 (95% CI 0.2-0.9)). The associations for N1-Methyl-2-pyridone-5-carboxamide and p-cresol sulphate replicated in the independent VDAART population (one-sided P values = .03-.04). CONCLUSIONS AND CLINICAL RELEVANCE: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome.

Differential impact of changes in adiposity distribution on insulin resistance and adiponectin variations over 4 years in normal weight young adults.

The aim of the study was to evaluate the influence of weight gain and changes in adiposity distribution on insulin resistance and circulating adiponectin variations over 4 years in free-living normal weight young adults. In this prospective observational cohort (n=42 women, 18 men), anthropometric measurements and blood samples were collected in the fasting state at baseline and at 4 years. Insulin resistance was estimated using the homeostatic model assessment (HOMA-IR). Circulating adiponectin levels were determined by radioimmunoassay. To investigate increase in adiposity more specifically, subsidiary analyses were performed in a subgroup of individuals (n=31) who gained adiposity over the course of the 4-year follow-up (defined as gain >1% in percent body fat). Regression analyses were performed to adjust for sex, age, parental education, lifestyle, and fitness levels. At baseline, the participants were young adults (age=20.0 years old) in the normal weight range [body mass index (BMI)=22.7 kg/m2 (IQR=21.1-24.4)]. Median change in body fat percentage was +1.4% (IQR=-0.3-3.4; p=0.01) and in waist circumference was +1.2 cm (IQR=-2.6-5.3; p=0.05). In the subgroup of individuals who gained more than 1% body fat, increase in HOMA-IR was associated with an increase in BMI (r=0.44; p=0.01; p<0.01 in fully adjusted model), while decrease in adiponectin levels was associated with an increase in waist circumference (r=-0.38; p=0.03) but this was no longer significant after adjustment for sex and other potential confounders (p=0.14). In a population of young adults, small variations in adiposity within the normal weight range were associated with increase in insulin resistance.

Construct validity and reliability of a French-Canadian translation of the eating in the absence of hunger questionnaire for children and adolescents.

Eating in the absence of hunger (EAH) has been associated with overweight and obesity during childhood. The gold standard to assess this behavior is a laboratory-based protocol, but a questionnaire to assess EAH more efficiently in children and adolescents has been developed and validated in English. We assessed construct validity (structural and convergent validity) and reliability (internal consistency and temporal stability) of a French translation of the EAH Questionnaire for Children and Adolescents among French-Canadian youths. We recruited participants in Montreal (Canada) aged 7-15 years old, who completed the questionnaire and provided anthropometric data. We asked participants to complete the questionnaire a second time ∼4 weeks later. The questionnaire consists of 14 questions and 3 subscales that assess EAH due to negative affect, fatigue/boredom, and external cues. We performed an exploratory factor analysis to test the factor structure and we calculated Cronbach alpha coefficients and intra-class correlations to assess internal consistency and temporal stability, respectively. We assessed associations between EAH and BMI z-score using Pearson correlations. We included 196 participants (50% girls; mean (SD) 11.9 (2.3) years old) for the first completion and 153 for the second completion. The exploratory factor analysis generated the same three subscales as the original questionnaire: negative affect (α = 0.86; ICC = 0.78), fatigue/boredom (α = 0.75; ICC = 0.70), and external cues (α = 0.68; ICC = 0.54). Participant's BMI z-scores were positively associated with the average scores from the negative affect subscale (r = 0.19; ρ = 0.009). Our results suggest that this questionnaire has an adequate construct validity, internal consistency, and temporal stability.

Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study.

AIMS/HYPOTHESIS: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. METHODS: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR). RESULTS: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18). CONCLUSIONS/INTERPRETATION: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

Circulating IL-18 and the risk of type 2 diabetes in women.

AIMS/HYPOTHESIS: The pathophysiology of type 2 diabetes involves pro-inflammatory pathways. We tested the hypothesis that IL-18 predicts future diabetes cases. METHODS: We used a nested case-control design based in the Nurses' Health Study. Baseline blood samples were collected between 1989 and 1990. Questionnaires to assess body weight, lifestyle (physical activity, diet, smoking) and diabetes diagnosis were sent out and assessed biennially (follow-up until 2002). Cases (n = 1,012) were defined as women developing type 2 diabetes at least 1 year after blood sampling. Control women (n = 1,081) were matched to cases by age, date of blood draw, fasting status and race. We calculated the RR (95% CI) of type 2 diabetes in quintiles of IL-18 using conditional logistic regression with the first quintile as referent; adjustments included matching factors, diabetes risk factors, BMI, adipokine levels (adiponectin, resistin) and inflammatory proteins (C-reactive protein, tumour necrosis factor receptor 2 (TNFalpha-R2) and IL-6). RESULTS: Higher IL-18 levels were associated with increased risk of developing diabetes, even after adjustment for matching factors and multiple diabetes risk factors: being in the highest quintile of IL-18 was associated with a RR of 1.75 (1.41-2.18) for diabetes relative to the first quintile (p < 0.0001 for trend). Significant trends in association were still observed after adjustment for BMI (RR 1.44 [1.15-1.80], p < 0.0001 for trend) and adiponectin levels (RR 1.28 [1.02-1.60], p = 0.006 for trend). Further adjustment for inflammatory markers in a sub-sample did not significantly change the results. CONCLUSIONS/INTERPRETATION: Elevated IL-18 levels are associated with higher risk of diabetes. This association is independent of usual risk factors, including BMI and adipokine levels.

Association of prenatal antibiotics with foetal size and cord blood leptin and adiponectin.

BACKGROUND: Early postnatal antibiotic use has been shown to promote excess weight gain, but it is unclear whether intrauterine exposure to antibiotics is associated with foetal growth and adiposity. The objective of this study was to examine associations of antibiotic prescription in each trimester of pregnancy with foetal size and adipokine levels at birth. METHODS: In 2128 pregnant women from the pre-birth Project Viva cohort, from electronic medical records, we estimated antibiotic prescribing by timing during pregnancy. Outcomes were sex-specific birth weight-for-gestational-age z-score (BW/GA-z) and levels of umbilical cord leptin and adiponectin. We used linear regression models adjusted for maternal age, pre-pregnancy body mass index, parity, race/ethnicity, education, smoking during pregnancy, household income and child sex and additionally adjusted cord blood leptin and adiponectin models for gestation length. RESULTS: Of the 2128 women in our sample, 643 (30.2%) were prescribed with oral antibiotics during pregnancy. Mean (standard deviation) BW/GA-z was 0.17 (0.97), cord blood leptin was 9.0 ng mL-1 (6.6) and cord blood adiponectin was 28.8 ng mL-1 (6.8). Overall, antibiotic prescription in pregnancy was associated with lower BW/GA-z [multivariable adjusted ß -0.11; 95% confidence interval {CI} -0.20, -0.01]. In trimester-specific analyses, only second trimester antibiotic prescription was associated with lower BW/GA-z (ß -0.23; 95% CI -0.37, -0.08). Overall, antibiotic prescription in pregnancy was not associated with cord blood leptin or adiponectin levels. However, in trimester-specific analyses, third trimester antibiotic prescription was associated with higher cord blood leptin (ß 2.28 ng mL-1 ; 95% CI 0.38, 4.17). CONCLUSIONS: Antibiotics in mid-pregnancy were associated with lower birth weight for gestational age, whereas third trimester antibiotics were associated with higher cord blood leptin.

Metabolomics in the developmental origins of obesity and its cardiometabolic consequences.

In this review, we discuss the potential role of metabolomics to enhance understanding of obesity-related developmental origins of health and disease (DOHaD). We first provide an overview of common techniques and analytical approaches to help interested investigators dive into this relatively novel field. Next, we describe how metabolomics may capture exposures that are notoriously difficult to quantify, and help to further refine phenotypes associated with excess adiposity and related metabolic sequelae over the life course. Together, these data can ultimately help to elucidate mechanisms that underlie fetal metabolic programming. Finally, we review current gaps in knowledge and identify areas where the field of metabolomics is likely to provide insights into mechanisms linked to DOHaD in human populations.

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns.

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (ß = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10(-11); N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (ß = -0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (ß = -0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Placental lipoprotein lipase DNA methylation levels are associated with gestational diabetes mellitus and maternal and cord blood lipid profiles.

Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. Impaired LPL gene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placental LPL DNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placental LPL DNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. Placental LPL DNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels within LPL proximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels at LPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT; r=-0.22; P=0.02) and HDL-cholesterol levels (third trimester of pregnancy; r=-0.20; p=0.03), respectively. Moreover, we report correlation between LPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r⩽-0.51; P<0.001) of placental LPL mRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placental LPL DNA methylation dysregulation. Our results suggest that site-specific LPL epipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.

A cost-effective moderate-intensity interdisciplinary weight-management programme for individuals with prediabetes.

AIM: To compare the effectiveness and cost of two lifestyle-modification programmes in individuals at high risk of developing type 2 diabetes. METHODS: Forty-eight men and women with a body mass index ≥27 kg/m(2) and prediabetes were randomly assigned to either a 1-year interdisciplinary intervention including individual counseling every 6 weeks and 25 group seminars (group I; n=22) or a group intervention comprising seminars only (group G; n=26). These interventions were compared in terms of weight loss and improvement of anthropometric measures, metabolic variables and costs. RESULTS: Participants in group I lost an average of 4.9 kg (95% CI: -7.3, -2.4; P<0.01) and 5 cm in waist circumference (95% CI: -7.0, -3.0; P<0.01), whereas no significant change was noted in those assigned to group G. Among the participants in group I, 50 and 27% lost at least 5 and 10% of their initial weight, respectively, compared with only 12 and 4%, respectively, in group G. Fasting glucose, 2-hour glucose and lipid profiles improved significantly in group I, and no participant (zero on 22) developed diabetes compared with 11.5% (3/26) in group G. Most participants (nine on 11) with impaired fasting glucose in group I returned to normal. The direct cost of the individual intervention was estimated to be $733.06/year per subject compared with $81.36/year per subject for the group intervention. CONCLUSION: This study demonstrates that a low-cost, moderate-intensity, individual interdisciplinary approach combined with group seminars leads to clinically significant weight loss and metabolic improvement in people with prediabetes. Group seminars alone were not effective in this population (www.ClinicalTrial.gov, Identifier: NCT00991549).

The entero-insular axis and adipose tissue-related factors in the prediction of weight gain in humans.

Obesity has now reached epidemic proportions. Epidemiological studies in the past decades have shown that adults gain weight and adiposity from the early twenties until their sixties. In the paediatric population, growing numbers of children and adolescents put on unhealthy weight. Many environmental, socio-economical and biological determinants that predispose to weight gain have been identified thus far. The aim of the present review is to summarize the current knowledge on the role of the circulating levels of adipokines and other entero-insular hormones and biological markers of obesity to predict weight gain in humans. The review focuses on relationship between hormonal and biochemical markers (insulin, insulin-like growth factors, gastrointestinal hormones, leptin, adiponectin, resistin, inflammatory proteins and cytokines) and weight gain in prospective studies. The complex relationships displayed by these hormonal factors with future weight gain in humans are critically reviewed and integrative models are proposed. Overall, most of the studies reported to date made adjustments for baseline body mass index but failed to consider dietary intake and physical activity as confounding factors. Outstanding questions are raised and new directions for future prospective studies are proposed in order to improve our understanding of the role of biological determinants of energy balance and development of obesity in humans.

Prevention of weight gain in young adults through a seminar-based intervention program.

OBJECTIVE: Prevention would be the ideal public health strategy to face the current obesity epidemic. Adoption of healthy lifestyles during the first years of college or university could prevent the onset of weight gain associated with this period of acquired independence and eventually decrease the incidence of obesity. DESIGN: Randomized-controlled trial over a period of 2 years. The subjects received an educational/behavioral intervention (small group seminars) designed to help maintain a healthy lifestyle or no specific intervention (control group). SUBJECTS: One-hundred and fifteen non-obese freshmen in a Faculty of Medicine. MEASUREMENTS: Anthropometric measurements, physical activity level, fitness level, food intake and lipid profile were recorded at predetermined intervals. RESULTS: The control group gained weight, whereas the intervention group lost a slight amount of weight over 2 years. The difference between the two groups was 1.3 kg at the end of the follow-up, the trend of weight gain differing between the two groups during the 2-year intervention period (P=0.04). There was no detectable difference in fitness, physical activity level or total caloric intake between the two groups during follow-up. However, plasma triglyceride levels increased in the control group and decreased in the intervention group (P=0.04). CONCLUSION: In this randomized-controlled trial, a small-group seminar educational/behavioral intervention successfully prevents weight gain in normal weight young healthy university students. Such small absolute changes in body composition and lipid profile, if maintained over a prolonged period, could result in significant long-term health benefits for the general population.