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Objective: The aim was to study the association between newborn anthropometrics and childhood cardiovascular risks and whether newborn anthropometrics mediate the effect of maternal gestational weight gain (GWG) on childhood risks., Methods: Data of 926 mother-child dyads from the Hyperglycemia and Adverse Pregnancy Outcomes study were analyzed. Newborn anthropometrics were treated as predictors and mediators by using a regression model and causal mediation model, respectively., Results: Newborn sum of skinfolds (SSF) was associated with childhood diastolic blood pressure (DBP) and pulse wave velocity (coefficients [95% CI]: 0.13 [0.06 to 0.20]; 0.08 [0.004 to 0.15]), whereas newborn ponderal index (PI) was inversely associated with childhood systolic blood pressure (SBP), DBP, and pulse wave velocity (-0.08 [-0.15 to -0.01]; -0.08 [-0.14 to -0.008]; -0.09 [-0.16 to -0.03]). Newborn SSF mediated the effects of maternal excessive GWG on childhood SSF and DBP (proportion of total effect 9% and 8%, respectively). In contrast, a significant negative mediation through newborn PI was found for the effect of maternal excessive GWG on childhood DBP (-8%) and its effect on childhood SBP through birth weight (-27%)., Conclusions: Childhood cardiovascular risks are positively associated with newborn SSF but inversely associated with newborn PI. Newborn SSF mediates the impact of excessive maternal GWG on childhood BP, but birth weight and newborn PI negatively mediate it., (© 2022 The Obesity Society.)

Objective: To compare the performance of diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) with those endorsed by the National Institute for Health and Care Excellence (NICE) in predicting adverse pregnancy outcomes., Research Design and Methods: We performed a secondary data analysis of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study participants in five study centers. Logistic regression analyses were performed, and Akaike information criterion were applied for the comparison of different statistical prediction models. We further analyzed the performance by four racial/ethnic subgroups, namely, Whites, Hispanics, Asians, and Blacks., Results: Among all, IADPSG criteria diagnosed 267 (4.1%) more women with GDM, but predicted primary caesarean section (CS) and large for gestational age (LGA) and neonatal adiposity better than did NICE criteria after adjustment for potential confounders. Among Whites, IADPSG criteria diagnosed 65 (2.5%) more subjects with GDM and predicted LGA and neonatal adiposity better, but predicted hypertensive disorders, primary CS and clinical neonatal hypoglycemia worse. Among Hispanics, the IADPSG criteria diagnosed 203 (12.1%) more with GDM but performed better in predicting hypertensive disorders, LGA, neonatal adiposity, and hyperinsulinemia. Among Asians, the IADPSG criteria diagnosed 34 (2.0%) fewer subjects with GDM but predicted hypertensive disorders better in the unadjusted model. In Blacks, IADPSG criteria diagnosed 34 (10.5%) more women with GDM., Conclusions: IADPSG criteria appear to be more favorable than NICE for identification of adverse pregnancy outcomes among Hispanic and Asian women, while they are comparable to NICE among White women., (© 2022 by the American Diabetes Association.)

Context: Pregnancy is characterized by progressive decreases in glucose insulin sensitivity. Low insulin sensitivity resulting in hyperglycemia is associated with higher neonatal adiposity. However, less is known regarding lipid metabolism, particularly lipid insulin sensitivity in pregnancy and neonatal adiposity., Objective: Because higher maternal prepregnancy body mass index is strongly associated with both hyperlipidemia and neonatal adiposity, we aimed to examine the longitudinal changes in basal and clamp maternal lipid metabolism as contributors to neonatal adiposity., Methods: Twelve women planning a pregnancy were evaluated before pregnancy, in early (12-14 weeks), and late (34-36 weeks) gestation. Body composition was estimated using hydrodensitometry. Basal and hyperinsulinemic-euglycemic clamp glucose and glycerol turnover (GLYTO) were measured using 2H2-glucose and 2H5-glycerol and substrate oxidative/nonoxidative metabolism with indirect calorimetry. Total body electrical conductivity was used to estimate neonatal body composition., Results: Basal free-fatty acids decreased with advancing gestation (P = 0.0210); however, basal GLYTO and nonoxidative lipid metabolism increased over time (P = 0.0046 and P = 0.0052, respectively). Further, clamp GLYTO and lipid oxidation increased longitudinally over time (P = 0.0004 and P = 0.0238, respectively). There was a median 50% increase and significant positive correlation during both basal and clamp GLYTO from prepregnancy through late gestation. Neonatal adiposity correlated with late pregnancy basal and clamp GLYTO (r = 0.6515, P = 0.0217; and r = 0.6051, P = 0.0371)., Conclusions: Maternal prepregnancy and late pregnancy measures of basal and clamp lipid metabolism are highly correlated. Late pregnancy basal and clamp GLYTO are significantly associated with neonatal adiposity and account for ~40% of the variance in neonatal adiposity. These data emphasize the importance of maternal lipid metabolism relating to fetal fat accrual., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy., Methods: In a secondary analysis of a longitudinal study, participants were studied prepregnancy (n = 40), in early pregnancy (n = 36; 12-14 weeks' gestation), and in late pregnancy (n = 36; 34-36 weeks' gestation). Participants underwent an OGTT, an intravenous glucose tolerance test (IVGTT), and a hyperinsulinemic-euglycemic clamp at each timepoint. We calculated homeostatic model assessment of beta-cell function (HOMA-2B), insulinogenic index (IGI), corrected insulin response (CIR), ratio of the area under the insulin curve and the area under the glucose curve (AUCins/AUCglu), and Stumvoll first-phase estimate (Stumvoll) from OGTT insulin and glucose levels. We used Pearson correlation to compare measures from OGTT and IVGTT. We used mixed effects models to examine longitudinal changes in insulin secretory response., Results: Stumvoll was the only OGTT-based measure that was significantly correlated with first-phase insulin response prior to and across gestation (prepregnancy: r = 0.44, P = 0.01; early pregnancy: r = 0.67, P = 0.0001; late pregnancy: r = 0.67, P = 0.0001). In early and late pregnancy, AUCins/AUCglu had the strongest correlation with first-phase insulin response (early pregnancy: r = 0.79, P < 0.0001; late pregnancy: r = 0.69, P < 0.0001) but was not significantly correlated prepregnancy. IGI and CIR were significantly correlated with first-phase insulin response prepregnancy (IGI: r = 0.50, P = 0.005; CIR r = 0.47, P = 0.008) and in late pregnancy (IGI: r = 0.68, P = 0.0001; CIR r = 0.57, P = 0.002) but not in early pregnancy. HOMA-2B was the weakest correlate of first-phase insulin response. Stumvoll and AUCins/AUCglu recapitulated the longitudinal changes in insulin secretory response observed by IVGTT., Conclusions: Stumvoll and AUCins/AUCglu are valid OGTT-based insulin secretory response measures for pregnancy studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest.

Test the hypothesis that women with obesity have greater gestation weight gain (GWG) with a moderately higher, vs lower, carbohydrate (CHO) diet, independent of energy intake, whereas GWG for women of normal weight would not differ by CHO group. This was a secondary analysis of data collected from glucose tolerant women with normal weight (NW) or obesity in pregnancy. Women completed a three-day food diary 16 to 20 weeks. A median split for percent kilocalories from CHO (median = 49.6%) categorized women into moderately highCHO vs lowCHO groups (n = 13-15/group). GWG was calculated between consent and the last prenatal care visit. A two-way ANOVA was used to examine whether there was an interaction between weight status and CHO group on GWG, independent of energy intake, time between consent and last prenatal visit, and age. Women in both highCHO groups consumed more sugars and starches compared to women in the lowCHO groups (P < .05). A significant interaction between weight status and CHO content of the diet was found (P < .05), such that, for women with obesity, those consuming a lowCHO diet had less GWG than those consuming a highCHO diet, whereas the pattern was opposite for women with NW. Results suggest that intake of a moderately lower CHO diet may help limit GWG among glucose tolerant women with obesity. Given that women in this study were eligible only if they had normal fasting glucose concentrations in early pregnancy, it is not clear if these results would generalize to all women with obesity during pregnancy., (© 2021 World Obesity Federation.)

Aims: Using data from a large multi-centre cohort, we aimed to create a risk prediction model for large-for-gestational age (LGA) infants, using both logistic regression and naïve Bayes approaches, and compare the utility of these two approaches., Methods: We have compared the two techniques underpinning machine learning: logistic regression (LR) and naïve Bayes (NB) in terms of their ability to predict large-for-gestational age (LGA) infants. Using data from five centres involved in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, we developed LR and NB models and compared the predictive ability and stability between the models. Models were developed combining the risks of hyperglycaemia (assessed in three forms: IADPSG GDM yes/no, GDM subtype, OGTT z-score quintiles), demographic and clinical variables as potential predictors., Results: The two approaches resulted in similar estimates of LGA risk (intraclass correlation coefficient 0.955, 95% CI 0.952, 0.958) however the AUROC for the LR model was significantly higher (0.698 vs 0.682; p < 0.001). When comparing the three LR models, use of individual OGTT z-score quintiles resulted in statistically higher AUROCs than the other two models., Conclusions: Logistic regression can be used with confidence to assess the relationship between clinical and biochemical variables and outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Background: Maternal gestational weight gain (GWG) influences not only on pregnancy outcome but also impacts on mothers' and children's long-term health. However, there is no consensus on recommendations of optimal GWG in Asians or the Chinese population., Methods: We performed a secondary analysis of the birth outcome of Chinese women who had joined the "Hyperglycemia and Adverse Pregnancy Outcome" study in Hong Kong and their children's cardiometabolic risk at 7-year of age. Optimal ranges of GWG were derived from models based on the probabilities of small for gestational age and large for gestational age (model 1), lean and fat infants (model 2) and the integration of model 1 and 2 (model 3), and were compared with that recommended by the Institute of Medicine (IOM) on children's cardiometabolic risk., Findings: GWG range derived from model 2 is associated with 8 cardiometabolic risk factors, while that from models 1 and 3 are associated with 1 and 7 of them respectively. Mothers whose GWG lie within the recommended range increases from 40.8% according to the IOM recommendation to 50.2% according to that derived from model 2., Interpretation: Optimal GWG derived from model 2 (i.e. 14.0-18.5 kg, 9.0-16.5 kg and 5.0-11.0 kg for underweight, normal weight and overweight Chinese women, respectively) appeared to be associated with the lowest cardiometabolic risk in the offspring., Funding: General Research Fund of the Research Grants Council of the Hong Kong SAR, China (grants CUHK 473408 and, in part, CUHK 471713)., Competing Interests: All the authors declared no conflict of interest., (© 2021 The Authors.)

Background: Inflammation is a common factor in adverse pregnancy outcomes (APOs). Behavioral factors influence inflammatory markers and APOs but rarely have been investigated simultaneously in pregnancy. Our purpose was to determine how diet, physical activity, and obesity are associated with interleukin (IL)-6 in early and late pregnancy., Methods: We conducted a secondary analysis of 49 overweight/obese pregnant women. Health behavior data, including diet quality using the Dietary Inflammatory Index (DII®); physical activity (Leisure Time Physical Activity scale); body mass index (BMI); and plasma IL-6 concentrations were collected at 13-16 weeks (early pregnancy) and 34-36 weeks (late pregnancy) gestation. Multiple linear regression analyses were used to determine the amount of variance explained in early and late pregnancy IL-6 concentrations by early and late pregnancy diet, physical activity, and BMI., Results: Early diet and early BMI were the strongest predictors of early IL-6 concentrations (R 2 = 0.43; p < .001) and late IL-6 concentrations (R 2 = 0.30; p < .001). Late BMI predicted late IL-6 (R 2 = .11; p = .02). Change in diet over pregnancy predicted late IL-6 (R 2 = 0.17; p = .03)., Conclusion: These findings suggest that maternal diet and BMI in early pregnancy, which likely reflects prepregnancy status, may have a greater impact on inflammatory processes than factors later in pregnancy. Future work should assess if behavioral factors before pregnancy produce similar relationships to those reported here, which may clarify the timing and type of lifestyle interventions to effectively reduce APOs.

Objective: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity., Research Design and Methods: Data on mother/offspring pairs ( N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes., Results: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z -score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%)., Conclusions: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity., (© 2021 by the American Diabetes Association.)

Background: Birth weight percentiles provide limited information on qualitative infant growth. Body composition provides estimates of fat mass, fat-free mass, and body fat percentage (adiposity). We sought to implement assessment of body composition at birth into clinical practice using a validated anthropometric equation and to evaluate measurement reliability., Methods: Body composition was incorporated into newborn nursery admission procedure. Body fat percentage derived from skinfold measurements performed by clinical nurses were compared to a historical database of similar measurements performed on newborns by experienced research staff. Body Mass Index (BMI) and Ponderal Index (PI) were used as surrogates for adiposity. Comparison of correlations between groups assessed measurement reliability. P < 0.05 was considered significant., Results: Nine hundred and ninety-one infants had body composition evaluated. Correlations were similar between BMI and %BF for measurements performed by research and clinical nurses (r 2  = 0.82 versus r 2  = 0.80; P = 0.142 for the difference between correlation coefficients) demonstrating good reliability. Similar results were found using PI (r 2  = 0.58 versus r 2 0.53; P = 0.105)., Conclusions: Body composition can be assessed at birth using a validated anthropometric equation. Measurements performed by clinical RNs were found to be reliable, allowing for a qualitative measure of growth beyond birth weight., Impact: Assessment of neonatal body composition at birth can be implemented into routine clinical practice using an anthropometric equation to estimate fat free-mass, fat mass, and percentage body fat. It provides a detailed, reproducible protocol to incorporate into routine practice. Assessment of fat mass, fat-free mass, and adiposity at birth allows for a qualitative measure of intrauterine growth beyond birth weight. Routine assessment of body composition provides a foundation for longitudinal follow-up of metabolic health in infancy and childhood.

Aims/hypothesis: We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity., Methods: Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study., Results: In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (β = 1.388; 95% CI 0.870, 1.906; p < 0.001; β = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (β = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (β = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model., Conclusions/interpretation: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

Maternal obesity, a state of chronic low-grade metabolic inflammation, is a growing health burden associated with offspring adiposity, abnormal fetal growth and prematurity, which are all linked to adverse offspring cardiometabolic health. Higher intake of anti-inflammatory omega-3 (n-3) polyunsaturated fatty acids (PUFA) in pregnancy has been associated with lower adiposity, higher birthweight and longer gestation. However, the effects of n-3 supplementation specifically in pregnant women with overweight and obesity (OWOB) have not been explored. We conducted a pilot double-blind randomized controlled trial of 72 pregnant women with first trimester body mass index (BMI) ≥ 25 kg/m 2 to explore preliminary efficacy of n-3 supplementation. Participants were randomized to daily DHA plus EPA (2 g/d) or placebo (wheat germ oil) from 10-16 weeks gestation to delivery. Neonatal body composition, fetal growth and length of gestation were assessed. For the 48 dyads with outcome data, median (IQR) maternal BMI was 30.2 (28.2, 35.4) kg/m 2 . In sex-adjusted analyses, n-3 supplementation was associated with higher neonatal fat-free mass (β: 218 g; 95% CI 49, 387) but not with % body fat or fat mass. Birthweight for gestational age z-score (-0.17 ± 0.67 vs. -0.61 ± 0.61 SD unit, p = 0.02) was higher, and gestation longer (40 (38.5, 40.1) vs. 39 (38, 39.4) weeks, p = 0.02), in the treatment vs. placebo group. Supplementation with n-3 PUFA in women with OWOB led to higher lean mass accrual at birth as well as improved fetal growth and longer gestation. Larger well-powered trials of n-3 PUFA supplementation specifically in pregnant women with OWOB should be conducted to confirm these findings and explore the long-term impact on offspring obesity and cardiometabolic health., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Aims/hypothesis: Gestational diabetes mellitus (GDM) is generally defined based on glycaemia during an OGTT, but aetiologically includes women with defects in insulin secretion, insulin sensitivity or a combination of both. In this observational study, we aimed to determine if underlying pathophysiological defects evaluated as continuous variables predict the risk of important obstetric and neonatal outcomes better than the previously used dichotomised or categorical approaches., Methods: Using data from blinded OGTTs at mean gestational week 28 from five Hyperglycemia and Adverse Pregnancy Outcome study centres, we estimated insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral disposition index [DI]) in 6337 untreated women (1090 [17.2%] with GDM as defined by the International Association of Diabetes and Pregnancy Study Groups). Rather than dichotomising these variables (i.e. GDM yes/no) or subtyping by insulin impairment, we related insulin secretion and sensitivity as continuous variables, along with other maternal characteristics, to obstetric and neonatal outcomes using multiple regression and receiver operating characteristic curve analysis., Results: Stratifying by GDM subtype offered superior prediction to GDM yes/no only for neonatal hyperinsulinaemia and pregnancy-related hypertension. Including the DI and the Matsuda score significantly increased the area under the receiver operating characteristic curve (AUROC) and improved prediction for multiple outcomes (large for gestational age [AUROC 0.632], neonatal adiposity [AUROC 0.630], pregnancy-related hypertension [AUROC 0.669] and neonatal hyperinsulinaemia [AUROC 0.688]). Neonatal hypoglycaemia was poorly predicted by all models. Combining the DI and the Matsuda score with maternal characteristics substantially improved the predictive power of the model for large for gestational age, neonatal adiposity and pregnancy-related hypertension., Conclusion/interpretation: Continuous measurement of insulin secretion and insulin sensitivity combined with basic clinical variables appeared to be superior to GDM (yes/no) or subtyping by insulin secretion and/or sensitivity impairment in predicting obstetric and neonatal outcomes in a multi-ethnic cohort. Graphical abstract.

Aims: We assessed how altered diagnostic processes and criteria for gestational diabetes mellitus (GDM) recommended by the United Kingdom (UK), Canada and Australia for use during the COVID-19 pandemic would affect both GDM frequency and related adverse outcomes., Methods: Secondary analysis of 5974 HAPO study women with singleton pregnancies who underwent 75 g OGTTs and HbA1c assays between 24 and 32 weeks' gestation and who received no treatment for GDM., Results: All post COVID-19 modified pathways reduced GDM frequency - UK (81%), Canada (82%) and Australia (25%). Canadian women whose GDM would remain undetected post COVID-19 (missed GDMs) displayed similar rates of pregnancy complications to those with post COVID-19 GDM. Using UK modifications, the missed GDM group were at slightly lower risk whilst the women missed using the Australian modifications were at substantially lower risk., Conclusions: The modifications in GDM diagnosis proposed for the UK, Canada and Australia result in differing reductions of GDM frequency. Each has both potential benefits in terms of reduction in potential exposure to COVID-19 and costs in terms of missed opportunities to influence pregnancy and postpartum outcomes. These factors should be considered when deciding which protocol is most appropriate for a particular context., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest relevant to this work. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to account for potential confounders., Objective: Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring., Design and Setting: International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively., Participants and Main Outcome Measures: In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years., Results: Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR [95% confidence interval; CI], GDM OR [95% CI]; combined OR [95% CI]) of childhood overweight/obese BMI (3.00 [2.42-3.74], 1.39 [1.14-1.71], 3.55 [2.49-5.05]), obese BMI (3.54 [2.70-4.64], 1.73 [1.29-2.30], 6.10 [4.14-8.99]), percent body fat >85th percentile (2.15 [1.68-2.75], 1.33 [1.03-1.72], 3.88 [2.72-5.55]), sum of skinfolds >85th percentile (2.35 [1.83-3.00], 1.75 [1.37-2.24], 3.66 [2.55-5.27]), and waist circumference >85th percentile (2.52 [1.99-3.21], 1.39 [1.07-1.80], 4.18 [2.93-5.96])., Conclusions: Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Maternal obesity increases neonatal risk for obesity and metabolic syndrome later in life. Prior attempts to break this intergenerational obesity cycle by limiting excessive gestational weight gain have failed to reduce neonatal adiposity. Alternatively, pre-conception lifestyle interventions may improve the in utero metabolic milieu during early pregnancy leading to improved fetal outcomes. This randomized controlled trial (RCT) is evaluating whether a lifestyle intervention to reduce weight and improve maternal metabolism in preparation for pregnancy (LIPP) attenuates neonatal adiposity, compared to standard medical advice., Material and Methods: Overweight/class 1 obese women after a previous pregnancy, ~12 weeks postpartum, preparing for a subsequent pregnancy, will be block randomized (1:1) to either LIPP or standard of care in a parallel design. Randomization is stratified by lactation status and overweight vs. class 1 obesity. The LIPP program consists of intensive short-term weight loss followed by weight maintenance until conception using supervised exercise and a low glycemic Mediterranean diet., Primary Outcomes: Group differences in neonatal adiposity at birth assessed by PEA POD and placental mitochondrial lipid metabolism., Secondary Outcomes: Group differences in maternal pregravid and gestational body composition, insulin sensitivity, β-cell function, fasting metabolic and inflammatory biomarkers, and overall quality of life. Exploratory outcomes include umbilical cord blood insulin resistance, lipid profile and inflammation., Discussion: This RCT will determine the efficacy of maternal weight loss prior to pregnancy on reducing neonatal adiposity. Findings may change standard obstetrical care by providing Level 1 evidence on lifestyle interventions improving neonatal outcomes for women planning for pregnancy., Clinical Trial Registration: NCT03146156., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index ( P < 6.94 × 10 -8 ). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1 Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy., (© 2019 by the American Diabetes Association.)

Aims/hypothesis: This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; IS OGTT ), insulin response and disposition index (DI) from late pregnancy (34-37 weeks gestation, T1), to early postpartum (1-5 days, T2) and late postpartum (6-12 weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in IS OGTT , insulin response and DI., Methods: IS OGTT , insulin response and DI were calculated at the three time points (T1, T2 and T3) using the results of a 75 g OGTT. Adipokines, cytokines and lipids were measured prior to each OGTT. Linear mixed-effects models were used to compare changes across each time point. Changes in IS OGTT , insulin response and DI were correlated with changes in maternal adipokines, cytokines and lipids at each time point., Results: A total of 27 women completed all assessments. Compared with T1, IS OGTT was 11.20 (95% CI 8.09, 14.31) units higher at 1-5 days postpartum (p < 0.001) and was 5.49 (95% CI 2.38, 8.60) units higher at 6-12 weeks postpartum (p < 0.001). Compared with T1, insulin response values were 699.6 (95% CI 957.5, 441.6) units lower at T2 (p < 0.001) and were 356.3 (95% CI 614.3, 98.3) units lower at T3 (p = 0.004). Compared with T1, the DI was 6434.1 (95% CI 2486.2, 10,381.0) units higher at T2 (p = 0.001) and was 4262.0 (95% CI 314.6, 8209.3) units higher at T3 (p = 0.03). There was a decrease in mean cholesterol, triacylglycerol, LDL-cholesterol and VLDL-cholesterol from T1 to T2 (all p < 0.001), and an increase in mean C-reactive protein, IL-6 and IL-8 from T1 to T2 (all p < 0.001). Mean leptin decreased from T1 to T2 (p = 0.001). There was no significant change in mean adiponectin (p = 0.99) or TNF-α (p = 0.81) from T1 to T2. The mean maternal BMI decreased from T1 to T2 (p = 0.001) and T3 (p < 0.001). There were no significant correlations between any measure of change in IS OGTT , insulin response and DI and change in maternal cytokines, adipokines, lipids or weight from T1 to T2., Conclusions/interpretation: In women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12 weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight., Trial Registration: ClinicalTrials.gov NCT02082301.

We have previously described regulation of syncytial GLUT1 glucose transporters by IGF-I. Despite this, it is not clear what signal regulates transplacental glucose transport. In this report we asked whether changes in GLUT1 expression and glucose transport activity in diabetic pregnancies were associated with alterations in the fetal IGF axis. Cord blood samples and paired syncytial microvillous and basal membranes were isolated from normal term pregnancies and pregnancies characterized by gestational diabetes type A2 (GDM A2) and pre-existing insulin-dependent diabetes mellitus (IDDM). Circulating IGF-I, basal membrane GLUT1 expression and glucose transporter activity were correlated with birth weight, but only in control, not diabetic groups. Basal membrane GLUT1 and transporter activity were correlated with IGF-I concentrations in control, but not diabetic groups. IGF binding protein (IGFBP) binding capacity showed a ≥50% reduction in the diabetic groups compared to control; both showed a higher level of free IGF-I. The absence of a correlation between birth weight and factors such as fetal IGF-I or GLUT1 expression in the diabetic groups suggests that IGF-I-stimulated effects may have reached a limiting threshold, such that further increases in IGF-I (or GLUT1) are without effect. These data support that fetal IGF-I acts as a fetal nutritional signal, modulating placental GLUT1 expression and birth weight via altered levels of fetal circulating IGFBPs. Diabetes appears to exert its effects on fetal and placental factors prior to the third trimester and, despite good glycemic control immediately prior to, and in the third trimester, these effects persist to term., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims/hypothesis: This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity., Methods: This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones., Results: The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p < 0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p = 0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p = 0.001) and decreased in late pregnancy (to 0.06 [0.03], p < 0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p = 0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p = 0.13)., Conclusions/interpretation: The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Importance: Nutrition during pregnancy is a critical dimension not only for women's health but also for the lifelong health of the offspring. Very limited national data exist on the usual dietary intakes of pregnant women., Objective: To estimate total usual nutrient intakes (from foods and dietary supplements) and the population prevalence of meeting or exceeding the National Academies of Sciences, Engineering, and Medicine Dietary Reference Intake recommendations among pregnant US women., Design, Setting, and Participants: A cross-sectional analysis was performed of a nationally representative sample of 1003 pregnant US women aged 20 to 40 years from the 2001-2014 National Health and Nutrition Examination Survey., Exposure: Usual dietary intakes assessed by two 24-hour dietary recalls (including dietary supplements) adjusted for within-person variation using the National Cancer Institute method., Main Outcomes and Measures: The proportion of women at risk of inadequate dietary intake as determined by the Estimated Average Requirement, the proportion of women assumed to have adequate dietary intake as determined by the Adequate Intake, and the proportion of women at risk of excess dietary intake as determined by the Tolerable Upper Intake Level. Demographic differences between pregnant and nonpregnant women were compared with t tests., Results: As representative of the US population, this sample of 1003 pregnant women had a mean (SE) age of 28.0 (0.3) years, was predominantly non-Hispanic white (mean [SE], 54.5% [3.1%]), and was at above 185% of the income to poverty ratio (mean [SE], 56.8% [3.0%]). Most pregnant women used a dietary supplement (mean [SE], 69.8% [2.3%]). A total of 10% or more of pregnant women had a total usual intake that is less than the Estimated Average Requirement for magnesium (mean [SE], 47.5% [2.8%]), vitamin D (mean [SE], 46.4% [2.7%]), vitamin E (mean [SE], 43.3% [2.7%]), iron (mean [SE], 36.2% [2.8%]), vitamin A (mean [SE], 15.5% [2.1%]), folate (mean [SE], 16.4% [1.6%]), calcium (mean [SE], 12.9% [2.4%]), vitamin C (mean [SE], 11.5% [1.9%]), vitamin B6 (mean [SE], 11.5% [1.5%]), and zinc (mean [SE], 10.9% [1.9%]). Some pregnant women exceeded the Adequate Intake for potassium (mean [SE], 41.7% [2.9%]), choline (mean [SE], 7.9% [3.2%]), and vitamin K (mean [SE], 47.9% [4.3%]). Most women exceeded the Tolerable Upper Intake Level for sodium (mean [SE], 95.0% [2.2%]), and some women exceeded the Tolerable Upper Intake Level of folic acid (mean [SE], 33.4% [2.8%]), iron (mean [SE], 27.9% [2.8%]), calcium (mean [SE], 3.0% [0.8%]), and zinc (mean [SE], 7.1% [1.6%]). For iron, the prevalence of an at-risk intake from foods alone was lower among women who used supplements (mean [SE], 80.3% [4.3%]) than those who did not use supplements (mean [SE], 95.3% [7.3%]); however, supplement use increased the risk of excessive iron and folic acid intakes given the amounts that are being consumed from supplemental products., Conclusions and Relevance: This study suggests that a significant number of pregnant women are not meeting recommendations for vitamins D, C, A, B6, K, and E, as well as folate, choline, iron, calcium, potassium, magnesium, and zinc even with the use of dietary supplements. Almost all pregnant women in this study were at risk of excessive consumption of sodium, and many were at risk of excessive consumption of folic acid and iron. Improved dietary guidance to help pregnant women meet but not exceed dietary recommendations is warranted.

Diabetes is a common complication of pregnancy associated with both short- and long-term adverse maternal and offspring effects. All types of diabetes in pregnancy are increasing in prevalence. Treatment of diabetes in pregnancy, targeting glycemic control, improves both maternal and offspring outcomes, albeit imperfectly for many women. Pharmacologic treatment recommendations differ between pregestational and gestational diabetes. Improved treatment of diabetes in pregnancy will need to consider maternal disease heterogeneity and comorbidities as well as long-term offspring outcomes. In this review, the authors summarize recent clinical studies to highlight established pharmacologic treatments for diabetes in pregnancy and provide suggestions for further research., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort., Methods: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA 1c values during pregnancy., Results: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA 1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA 1c . Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls., Conclusions/interpretation: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

Objective: This study examined associations of maternal glycemia during pregnancy with childhood glucose outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort., Research Design and Methods: HAPO was an observational international investigation that established associations of maternal glucose with adverse perinatal outcomes. The HAPO Follow-up Study included 4,832 children ages 10-14 years whose mothers had a 75-g oral glucose tolerance test (OGTT) at ∼28 weeks of gestation. Of these, 4,160 children were evaluated for glucose outcomes. Primary outcomes were child impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Additional outcomes were glucose-related measures using plasma glucose (PG), A1C, and C-peptide from the child OGTT., Results: Maternal fasting plasma glucose (FPG) was positively associated with child FPG and A1C; maternal 1-h and 2-h PG were positively associated with child fasting, 30 min, 1-h, and 2-h PG, and A1C. Maternal FPG, 1-h, and 2-h PG were inversely associated with insulin sensitivity, whereas 1-h and 2-h PG were inversely associated with disposition index. Maternal FPG, but not 1-h or 2-h PG, was associated with child IFG, and maternal 1-h and 2-h PG, but not FPG, were associated with child IGT. All associations were independent of maternal and child BMI. Across increasing categories of maternal glucose, frequencies of child IFG and IGT, and timed PG measures and A1C were higher, whereas insulin sensitivity and disposition index decreased., Conclusions: Across the maternal glucose spectrum, exposure to higher levels in utero is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes., (© 2019 by the American Diabetes Association.)

Objective: Whether hyperglycemia in utero less than overt diabetes is associated with altered childhood glucose metabolism is unknown. We examined associations of gestational diabetes mellitus (GDM) not confounded by treatment with childhood glycemia in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort., Research Design and Methods: HAPO Follow-up Study (FUS) included 4,160 children ages 10-14 years who completed all or part of an oral glucose tolerance test (OGTT) and whose mothers had a 75-g OGTT at ∼28 weeks of gestation with blinded glucose values. The primary predictor was GDM by World Health Organization criteria. Child outcomes were impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes. Additional measures included insulin sensitivity and secretion and oral disposition index., Results: For mothers with GDM, 10.6% of children had IGT compared with 5.0% of children of mothers without GDM; IFG frequencies were 9.2% and 7.4%, respectively. Type 2 diabetes cases were too few for analysis. Odds ratios (95% CI) adjusted for family history of diabetes, maternal BMI, and child BMI z score were 1.09 (0.78-1.52) for IFG and 1.96 (1.41-2.73) for IGT. GDM was positively associated with child's 30-min, 1-h, and 2-h but not fasting glucose and inversely associated with insulin sensitivity and oral disposition index (adjusted mean difference -76.3 [95% CI -130.3 to -22.4] and -0.12 [-0.17 to -0.064]), respectively, but not insulinogenic index., Conclusions: Offspring exposed to untreated GDM in utero are insulin resistant with limited β-cell compensation compared with offspring of mothers without GDM. GDM is significantly and independently associated with childhood IGT., (© 2019 by the American Diabetes Association.)

Use of oral agents to treat gestational diabetes mellitus remains controversial. Recent recommendations from the Society for Maternal-Fetal Medicine assert that metformin may be a safe first-line alternative to insulin for gestational diabetes mellitus treatment and preferable to glyburide. However, several issues should give pause to the widespread adoption of metformin use during pregnancy. Fetal concentrations of metformin are equal to maternal, and metformin can inhibit growth, suppress mitochondrial respiration, have epigenetic modifications on gene expression, mimic fetal nutrient restriction, and alter postnatal gluconeogenic responses. Because both the placenta and fetus express metformin transporters and exhibit high mitochondrial activity, these properties raise important questions about developmental programming of metabolic disease in offspring. Animal studies have demonstrated that prenatal metformin exposure results in adverse long-term outcomes on body weight and metabolism. Two recent clinical randomized controlled trials in women with gestational diabetes mellitus or polycystic ovary syndrome provide evidence that metformin exposure in utero may produce a metabolic phenotype that increases childhood weight or obesity. These developmental programming effects challenge the conclusion that metformin is equivalent to insulin. Although the Society for Maternal-Fetal Medicine statement endorsed metformin over glyburide if oral agents are used, there are few studies directly comparing the 2 agents and it is not clear that metformin alone is superior to glyburide. Moreover, it should be noted that prior clinical studies have dosed glyburide in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and high rates of maternal hypoglycemia. We concur with the American Diabetes Association and American Congress of Obstetricians and Gynecologists, which recommend insulin as the preferred agent, but we believe that it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Due to the uncertainty of the long-term metabolic risks of either metformin or glyburide, we call for carefully controlled studies that optimize oral medication dosing according to their pharmacodynamic and pharmacokinetic properties in pregnancy, appropriately target medications based on individual patterns of hyperglycemia, and follow the offspring long-term for metabolic risk., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear., Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum., Design, Setting, and Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016)., Exposures: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL)., Main Outcomes and Measures: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes)., Results: The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%)., Conclusions and Relevance: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.

Background: Cord blood adiponectin and leptin concentrations are associated with birth weight and adiposity. Birth size and rate of infant weight gain are associated with future obesity risk. However, it is unclear whether biomarkers reflecting the intrauterine environment are predictive of infant prospective body composition change., Objectives: To examine whether cord blood adiponectin and leptin are predictive of neonatal adiposity and fat mass (FM) accrual to 3 months of age., Methods: Participants (n = 36) were healthy African American infants. Leptin and adiponectin concentrations were measured in umbilical cord blood. At 2 weeks and 3 months, infant body composition was assessed via air displacement plethysmography. Weight-for-length z-scores (WLZ) were calculated using World Health Organization standards. Multiple linear regression was used to examine associations of cord blood adiponectin and leptin with birth WLZ; WLZ, FM and fat-free mass at 2 weeks, and the conditional change in these variables from 2 weeks to 3 months (body composition at 3 months adjusted for body composition at 2 weeks)., Results: Adiponectin was positively associated with FM at 2 weeks (r = 0.45, P < 0.01), but inversely associated with conditional FM change from 2 weeks to 3 months of age (r = -0.38, P < 0.05). Leptin was not significantly associated with infant body composition., Conclusions: Adiponectin may be a marker for FM accrual in African American infants, a relatively understudied population with a high long-term obesity risk. Mechanistic studies are needed to determine whether adiponectin directly influences infant growth or is simply a maker reflective of other ongoing biological changes after birth., (© 2018 World Obesity Federation.)

Background: There are significant variations in gestational weight gain, with many women gaining in excess of the Institute of Medicine guidelines. Unfortunately, efforts to improve appropriate gestational weight gain have had only limited success. To date, interventions have focused primarily on decreasing energy intake and/or increasing physical activity. Maternal resting energy expenditure, which comprises ∼60% of total energy expenditure compared with the ∼20% that comes from physical activity, may be an important consideration in understanding variations in gestational weight gain., Objective: Our objective was to quantify the changes in resting energy expenditure during pregnancy and their relationship to gestational weight gain and body composition changes among healthy women. We hypothesized that greater gestational weight gain, and fat mass accrual in particular, are inversely related to variations in resting energy expenditure., Study Design: We conducted a secondary analysis of a prospective cohort studied before conception and late pregnancy (34-36 weeks). Body composition (estimated using hydrodensitometry) and resting energy expenditure (estimated using indirect calorimetry) were measured. The relationship between the changes in resting energy expenditure and gestational weight gain and the change in fat mass and fat-free mass were quantified. Resting energy expenditure was expressed as kilocalories per kilogram of fat-free mass per day (kilocalories per kilogram of fat-free mass -1 /day -1 ) and kilocalories per day. Correlations are reported as r., Results: Among 51 women, preconception body mass index was 23.0 (4.7) kg/m 2 ; gestational weight gain was 12.8 (4.7) kg. Preconception and late pregnancy resting energy expenditure (kilocalories per day) correlated positively with the change in fat-free mass (r = 0.37, P = .008; r = 0.51, P = .001). Late-pregnancy resting energy expenditure (kilocalories per kilogram of fat-free mass -1 /day -1 ) was inversely associated with the change in fat mass (r = -0.34, P = .02) and gestational weight gain (r = -0.29, P = .04). From before pregnancy through late gestation, the increase in resting energy expenditure (kilocalories per day) correlated positively with the change in fat-free mass (r = 0.44, P = .002) and negatively with the change in fat mass (r = -0.27, P = .06)., Conclusion: The change in resting energy expenditure from before conception through late gestation correlated positively with changes in fat-free mass but negatively with fat mass accrual. Women with smaller increases in resting energy expenditure across pregnancy had greater gestational weight gain, specifically more adipose tissue. These data suggest that resting energy expenditure is an important factor in gestational weight gain, particularly excess fat mass accrual. Future lifestyle intervention studies need to consider clinically feasible means of estimating resting energy expenditure and, in response, tailor nutrient intake and composition recommendations. Implementing and testing such interventions would be a novel approach to improve compliance with gestational weight gain guidelines., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To assess the frequency of adverse outcomes for women who are diagnosed with gestational diabetes mellitus (GDM) by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria using data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study., Research Design and Methods: This is a secondary analysis from the North American HAPO study centers. Glucose measurements from a 75-g oral glucose tolerance test were used to group participants into three nonoverlapping categories: GDM based on Carpenter-Coustan (CC) criteria (also GDM based on IADPSG criteria), GDM diagnosed based on IADPSG criteria but not CC criteria, and no GDM. Newborn outcomes included birth weight, cord C-peptide, and newborn percentage fat above the 90th percentile; maternal outcomes included primary cesarean delivery and preeclampsia. Outcome frequencies were compared using multiple logistic regression, adjusting for predefined covariates., Results: Among 25,505 HAPO study participants, 6,159 blinded participants from North American centers were included. Of these, 81% had normal glucose testing, 4.2% had GDM based on CC criteria, and 14.3% had GDM based on IADPSG criteria but not CC criteria. Compared with women with no GDM, those diagnosed with GDM based on IADPSG criteria had adjusted odds ratios (95% CIs) for birth weight, cord C-peptide, and newborn percentage fat above the 90th percentile, as well as primary cesarean delivery and preeclampsia, of 1.87 (1.50-2.34), 2.00 (1.54-2.58), 1.73 (1.35-2.23), 1.31 (1.07-1.60), and 1.73 (1.32-2.27), respectively., Conclusions: Women diagnosed with GDM based on IADPSG criteria had higher adverse outcome frequencies compared with women with no GDM. These data underscore the need for research to assess the effect of treatment to improve outcomes in such women., (© 2016 by the American Diabetes Association.)

The global epidemic of obesity has led to an increasing number of obese women of reproductive age. Obesity is associated with reduced fertility, and pregnancies complicated by maternal obesity are associated with adverse outcomes, including increased risk of gestational diabetes, pre-eclampsia, preterm birth, instrumental and caesarean births, infections, and post-partum haemorrhage. The medical and obstetric management of obese women is focused on identifying, addressing, and preventing some of these associated complications, and is a daunting challenge given the high percentage of patients with obesity and few therapeutic options proven to improve outcomes in this population. The UK's National Institute for Health and Care Excellence guidelines and the American College of Obstetricians and Gynecologists recommend that all pregnant women follow a healthy diet, and consider at least half an hour of moderate physical activity per day during pregnancy. However, although obese women are often directed to seek the advice of a nutritionist and to limit gestational weight gain, guidelines for the management of pregnancy and delivery in this high-risk group are lacking. The post-partum period represents an important opportunity to optimise maternal health before the next pregnancy. As many of the physiological changes of pregnancy associated with maternal obesity are present from early pregnancy onward, reducing maternal obesity before conception is probably the best strategy to decrease the health burden associated with maternal obesity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

It is generally agreed that placental pathology accounts for the majority of perinatal morbidity and mortality. If a placental prodrome could be diagnosed in vivo, risk for maternal or fetal complications could be estimated and acted upon before clinical symptoms are apparent. This is especially relevant in early diagnoses of gestational diabetes mellitus, which can be controlled through carefully monitored diet and activity changes. To meet this important need, there have been increased efforts to identify early gestation biomarkers of placental dysfunction using innovative imaging technologies. Here we outline innovative quantitative markers of placental shape and their relationship to placental function, clinical implications of these quantifiers, and the most recent mathematical models that utilize placental images to delineate at risk from normal pregnancies. We propose that novel contexts of readily available placental measures and routine collection of in vivo placental images in all pregnancies may be all that are needed to advance the identification of early risk determination of complicated pregnancies from placental images., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Aims/hypothesis: Obesity triggers complex inflammatory networks within the innate immune system. During pregnancy, the placenta amplifies the low-grade inflammation through activation of Toll-like receptor 4 (TLR4) signalling pathways. The purpose of this study was to investigate the impact of obesity on placental TLR4 expression and inflammatory signals. The secondary aim was to analyse the placental cell type responsible for TLR4 activation., Methods: Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pre-gravid BMI (<25 kg/m(2) and >30 kg/m(2)). Placenta, venous maternal and cord blood were obtained at delivery for analysis. Data were analysed with linear regression and Spearman's rank correlation coefficient analysis., Results: TLR4, IL6 and IL8 expression was increased three- to ninefold (p < 0.001) in the placenta of obese vs lean women. There was a positive correlation between placental TLR4 and maternal systemic and placental IL6 and IL8 concentrations. Placental TLR4 expression was correlated with maternal pre-gravid BMI, insulin resistance index, plasma insulin and C-reactive protein (r = 0.57, 0.31, 0.35, 0.53, respectively; p < 0.001) but not with plasma glucose, maternal age, gestational age and gestational weight gain (r < 0.2; p > 0.1). TLR4 was located in both trophoblast and macrovascular endothelial cells lining fetal vasculature. Lipopolysaccharide-induced TLR4 activation was more robust in trophoblasts than in endothelial vascular cells (100-fold vs tenfold; p < 0.001)., Conclusions/interpretation: Trophoblastic TLR4 is strongly implicated in the propagation of placental inflammation. Placental inflammation is related to maternal metabolic conditions such as pre-gravid BMI, whilst gestational weight gain or gestational age are not. These results implicate the pre-gravid condition as a significant contributor to metabolic inflammation in late pregnancy.

Background: Weight gain in pregnancy is an essential physiologic adaptation that supports growth and development of a fetus and is distributed among lean mass that includes total body water and fat mass gains. Although gestational weight gain provides a source of energy for the mother and fetus, excess gestational weight gain may underlie reported associations between parity and future metabolic disorders and is linked to postpartum weight retention and insulin resistance. Although weight gain often is proposed as a modifiable variable to mitigate adverse maternal and offspring health outcomes, our knowledge of specific maternal body composition changes with weight gain and the potential metabolic consequences is limited. Furthermore, although gestational weight gain alters maternal body composition, the impact of excess weight gain on fat and lean mass is not well-studied. Understanding the accrual of fat and lean body mass may improve our understanding of the role of excessive gestational weight gain and metabolic dysfunction., Objective: The purpose of our study was to quantify the relationship between gestational weight gain and maternal fat and lean body mass accrual and to compare fat and lean body mass accrual according to the 2009 Institute of Medicine Guidelines for Gestational Weight Gain in Pregnancy adherence. We hypothesized that exceeding current weight gain guidelines would be associated with greater fat, compared with lean body, mass accrual., Study Design: This is a secondary analysis of a randomized controlled trial of 49 overweight/obese women; all 49 are included in this secondary analysis. Maternal weight and body composition were collected in early (13 0/6 to 16 6/7 weeks gestation) and late (34 0/7 to 36 6/7 weeks gestation) pregnancy with the use of air densitometry. Correlations were drawn between gestational weight gain and change in fat and lean body mass. We compared change in fat and lean body mass by adherence to the 2009 Institute of Medicine Guidelines for Gestational Weight Gain in Pregnancy. Nonparametric tests and chi-square analyses were performed; a probability value of <.05 was significant., Results: Early pregnancy body mass index was 30.3 kg/m(2) (interquartile range [IQR], 28.5-35.2 kg/m(2)); women gained 9.0 kg (IQR, 5.3-13.2 kg). Overweight and obese women were equally likely to gain excess weight (48% vs 35%; P = .6). Weight gain correlated strongly with fat mass change (r = 0.87; P < .001); women with excess vs adequate vs inadequate weight gain had greater fat mass change overall (5.2 [IQR, 4.2-8.1] vs 0.2 [IQR, -0.4-2.2] vs -2.7 [IQR, -5.2- -0.7] kg, respectively; P < .001) and in all pairwise comparisons. Weight gain also correlated with lean body mass change (r = 0.52; P = .001), but women with excess vs adequate weight gain had similar lean body mass change (8.4 [IQR, 7.2-10.1] vs 7.8 [IQR, 6.0-8.7] kg; P = .1)., Conclusion: Excess gestational weight gain is associated primarily with maternal fat, but not with lean body mass accrual. Our results may help explain the reason that excess gestational weight gain or fat mass accrual is associated with long-term obesity, metabolic dysfunction, and cardiovascular disease risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To compare the accuracy of 2-dimensional (2D) and 3-dimensional (3D) fetal measurements for prediction of birth weight Z score and neonatal adiposity (percent body fat) in the setting of suspected fetal macrosomia., Methods: We conducted a prospective observational study of term singleton pregnancies with suspected macrosomia. Patients were enrolled on admission to labor and delivery and underwent sonographic examinations. Within 48 hours of delivery, neonatal anthropometric measurements were obtained., Results: Thirty-four neonates were included in the analysis. Mothers were very obese (mean body mass index ± SD, 39.1 ± 7.8 kg/m(2)); 56.5% were white; and 39.1% had diabetes. Neonates were 38% female and had a mean birth weight of 3940.0 ± 496.8 g, percent body fat of 18.5% ± 4.0%, and Ponderal index of 2.8 ± 0.3 g/cm(3). Mean 2D estimated fetal weight was 3973 ± 443 g; mean 3D estimated fetal weight was 3803 ± 528 g; and mean thigh volume was 102.5 ± 19.6 cm(3). Both 2D and 3D measurements accounted for about half the variance in predicted birth weight (R(2) for 2D = 0.53, 71% within 10% of birth weight; R(2) for 3D = 0.47, 65% within 10% of birth weight). Thigh volume Z score was the prenatal parameter most highly correlated with both birth weight Z score (R(2) = 0.52; r = 0.72; 95% confidence interval, 0.54-0.84; P < .001) and percent body fat (R(2) = 0.22; r = 0.47; 95% confidence interval, 0.17-0.69; P = .04)., Conclusions: In our population of fetuses with suspected macrosomia, fractional thigh volume was the best sonographic estimate of neonatal percent body fat and birth weight Z score. Future research on prediction of neonatal weight and adiposity in macrosomic fetuses should include an estimate of fetal soft tissue given the generalized increase in body fat of these fetuses., (© 2016 by the American Institute of Ultrasound in Medicine.)

Purpose: Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy., Methods: In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals., Results: Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3., Conclusion: The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.

Background: Excessive fat accumulation characterizes the over-nourished fetus in maternal diabetes and obesity with fetal insulin regarded as a primary driver. This study tested whether fetal insulin is related to subcutaneous adipose tissue (SAT) thickness at different body sites in neonates, and whether sites respond differentially to insulin. In addition, sex differences were assessed., Methods: Cord blood insulin was measured for 414 neonates. After birth, SAT thickness was measured at 15 body sites using a validated device, a lipometer, that measures back-scattered light intensities corresponding to SAT. Associations between fetal insulin and SAT were assessed in linear regression models, adjusted for gestational age and birth weight, for males and females separately., Results: No sex differences in insulin levels or total SAT thickness were found. In males, SAT thickness at most body sites was significantly correlated with insulin, with strongest associations between insulin and SAT on neck (beta 0.23, 95% CI 0.05; 0.41; P=0.01) and upper abdomen (beta 0.18, 95% CI 0.01; 0.36; P=0.04). In females, insulin was only associated with hip SAT thickness (beta 0.22, 95% CI 0.06; 0.39; P=0.01). Total SAT thickness was correlated with insulin in males (beta 0.03, 95% CI 0.01; 0.04; P=0.003), but not in females (beta 0.01, 95% CI -0.01; 0.02; P=0.38)., Conclusions: Fat deposition in female neonates seems less affected by insulin as compared to males. This may reflect lower insulin sensitivity in females, or may be accounted for by other metabolic/endocrine factors overriding the association.

Background: Recent reports have shown a decrease in birth weight, a change from prior steady increases. Therefore we sought to describe the demographic and anthropometric changes in singleton term fetal growth., Methods: This was a retrospective cohort analysis of term singleton deliveries (37-42 weeks) from January 1, 1995 to January 1, 2010 at a single tertiary obstetric unit. We included all 43,217 neonates from term, singleton, non-anomalous pregnancies. Data were grouped into five 3-year intervals. Mean and median birth weight (BW), birth length (BL), and Ponderal Index (PI) were estimated by year, race and gestational age. Our primary outcome was change in BW over time. The secondary outcomes were changes in BL and PI over time., Results: Mean and median BW decreased by 72 and 70 g respectively (p < 0.0001) over the 15 year period while BL also significantly decreased by 1.0 cm (P < 0.001). This contributed to an increase in the neonatal PI by 0.11 kg/m(3) (P < 0.001). Mean gestational age at delivery decreased while maternal BMI at delivery, hypertension, diabetes, and African American race increased. Adjusting for gestational age, race, infant sex, maternal BMI, smoking, diabetes, hypertension, and parity, year of birth contributed 0.1 % to the variance (-1.7 g/year; 26 g) of BW, 1.8% (-0.06 cm/year; 0.9 cm) of BL, and 0.7% (+0.008 kg/m(3)/year; 0.12 kg/m(3)) of PI. These findings were independent of the proportional change in race or gestational age., Conclusions: We observed a crude decrease in mean BW of 72 g and BL of 1 cm over 15 years. Furthermore, once controlling for gestational age, race, infant sex, maternal BMI, smoking, diabetes, hypertension, and parity, we identified that increasing year of birth was associated with a decrease in BW of 1.7 g/year. The significant increase in PI, despite the decrease in BW emphasizes the limitation of using birth weight alone to define changes in fetal growth.