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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 Conclusions Stumvoll and AUCins/AUCglu are valid OGTT-based insulin secretory response measures for pregnancy studies.

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.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.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%).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.

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.

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.

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

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. [Figure not available: see fulltext.]

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. 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

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

Significance These human data are consistent with reproductive control of liver size and function in women and concur with recent observations in rodents, suggesting a conserved liver biology. The question of whether this described liver biology has implications for maternal health during pregnancy or sex-specific risk for liver disease remains to be determined. However, our evidence suggestive of weaning-induced liver involution in women may lead to improved understanding of the high rates of liver metastasis observed in young postpartum breast cancer patients., During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women’s livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.

Context An increase in maternal insulin resistance (IR) during pregnancy is essential for normal fetal growth. The mechanisms underlying this adaptation are poorly understood. Placental factors are believed to instigate and maintain these changes, as IR decreases shortly after delivery. Methylation of placental gene loci that are common targets for miRNAs are associated with maternal IR. Objective We hypothesized that placental miRNAs targeting methylated loci are associated with maternal IR during late pregnancy. Methods We collected placentas from 132 elective cesarean sections and fasting blood samples at delivery to estimate maternal homeostasis model assessment of insulin resistance (HOMA-IR). Placental miRNA expression was measured via whole genome small-RNA sequencing in a subset of 40 placentas selected by maternal pre-gravid body mass index (BMI) and neonatal adiposity. Five miRNAs correlated with maternal HOMA-IR and previously identified as targeting methylated genes were selected for validation in all 132 placenta samples via RT-qPCR. Multiple regression adjusted for relevant clinical variables. Results Median maternal age was 27.5 years, with median pre-pregnancy BMI of 24.7 kg/m2, and median HOMA-IR of 2.9. Among the 5 selected miRNA, maternal HOMA-IR correlated with the placental expression of miRNA-371b-3p (r = 0.25; P = 0.008) and miRNA-3940-3p (r = 0.32; P = 0.0004) across the 132 individuals. After adjustment for confounding variables, placental miRNA-3940-3p expression remained significantly associated with HOMA-IR (β = 0.16; P = 0.03). Conclusion Placental miRNA-3940-3p was associated with maternal IR at delivery. This placental miRNA may have an autocrine or paracrine effect—regulating placental genes involved in modulating maternal IR.

Background: Decrease in insulin sensitivity in late gestation is thought to promote fetal growth in humans. Methods: Cohorts with serial glucose and insulin measurements during pregnancy were included in this study. These include two Indian (n=248), a Mexican (n=115), two European (n=326) and an American (n=32) cohort. HOMA-S was correlated with neonatal weight. Results: Indian mothers were short & thin (153.7 cm, 48.8 kg and 20.2 kg/m2) and gained 5.9 kg between first and third trimesters, babies were 2720g. Mexican mothers were short (156cm, 63 kg and BMI 25.1kg/m2) and gained 7.5 kg, babies were 2955g. European mothers were tall and obese (168.0 cm, 95.5 kg and 33.7 kg/m2), gained 7.4 kg and babies were 3640g. In Indian mothers, FPG progressively decreased with increasing gestation with a small (15%) increase in insulin concentrations, HOMA-S remained stable. In Mexican and European mothers FPG remained stable, insulin increased (>50%) and HOMA-S decreased (>30%). American mothers showed the classic increase in HOMA-S in early pregnancy and a fall in late gestation (Figure 1). In Indian and Mexican mothers HOMA-S was not associated with offspring birth weight while in European cohorts, it was inversely associated. Conclusion: Chronic maternal undernutrition (stunting) and failure to reduce insulin sensitivity in late gestation may contribute to poor fetal growth in India and Mexico. Mechanistic studies are warranted. Disclosure S. Deshpande-joshi: None. O. Perichart-perera: Other Relationship; Self; IFA CELTICS, Nestle. M. Van poppel: None. C. A. Vinter: None. D. M. Jensen: None. G. Desoye: None. P. Catalano: None. C. S. Yajnik: None. H. Damle: None. M. K. Deshmukh: None. D. Bhat: None. N. S. Memane: None. A. A. Bhalerao: None. R. Ladkat: None. P. Tiwari: None. S. R. Otiv: None.

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.

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 pre-gestational and gestational diabetes; in each case, effectiveness appears limited by co-morbid obesity due to overlapping maternal and offspring risks associated with obesity and diabetes in pregnancy. Despite changes in patient characteristics and increasing evidence of heterogeneous pathophysiology contributing to diabetes in pregnancy, current practice still presupposes a single common treatment strategy, including pharmacologic agents and glycemic targets, with little distinction by diabetes type or pathophysiologic mechanism. Furthermore, while diabetes in pregnancy is associated with long-term offspring risks, few studies have assessed long-term outcomes following exposure to different diabetes treatments in utero. 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, we will summarize recent clinical studies to highlight established pharmacologic treatments for diabetes in pregnancy and provide suggestions for further research.

Objectives Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature. Design Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide. Results Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = −0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001]. Conclusions Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.

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.

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.

Newborn adiposity, a nutritional measure of the maternal–fetal intra-uterine environment, is representative of future metabolic health. An anthropometric model using weight, length and flank skinfold to estimate neonatal fat mass has been used in numerous epidemiological studies. Air displacement plethysmography (ADP), a non-invasive technology to measure body composition, is impractical for large epidemiological studies. The study objective was to determine the consistency of the original anthropometric fat mass estimation equation with ADP. Full-term neonates were studied at 12–72 h of life with weight, length, head circumference, flank skinfold thickness and ADP measurements. Statistical analyses evaluated three models to predict neonatal fat mass. Lin’s concordance correlation coefficient, mean prediction error and root mean squared error between the predicted and observed ADP fat mass values were used to evaluate the models, where ADP was considered the gold standard. A multi-ethnic cohort of 468 neonates were studied. Models (M) for predicting fat mass were developed using 349 neonates from site 1, then independently evaluated in 119 neonates from site 2. M0 was the original anthropometric model, M1 used the same variables as M0 but with updated parameters and M2 additionally included head circumference. In the independent validation cohort, Lin’s concordance correlation estimates demonstrated reasonable accuracy (model 0: 0·843, 1: 0·732, 2: 0·747). Mean prediction error and root mean squared error in the independent validation was much smaller for M0 compared with M1 and M2. The original anthropometric model to estimate neonatal fat mass is reasonable for predicting ADP, thus we advocate its continued use in epidemiological studies.

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 mid-pregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS Data on mother/offspring pairs (N=4832) 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 sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, p-value) BMI(0.26,0.12-0.39, 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.

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/m2 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/m2. 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.

Exposure to maternal diabetes in utero increases the risk in the offspring for a range of metabolic disturbances. However, the timing and variability of in utero hyperglycemic exposure necessary to cause impairment have not been elucidated. The TEAM Study was initiated to evaluate young adult offspring of mothers with pregestational diabetes mellitus. This paper outlines the unique enrollment challenges of the TEAM Study and preliminary analysis of the association between exposure to diabetes in pregnancy and adverse metabolic outcomes. The TEAM Study enrolls offspring of women who participated in a Diabetes in Pregnancy (DiP) Program Project Grant between 1978 and 1995. The DiP Study collected medical and obstetric data across pregnancy. The first 96 eligible offspring of women with pregestational diabetes were age-, sex-, and race-matched to adults from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 with an OGTT. Descriptive and regression analyses were employed to compare TEAM participants to NHANES participants. Among a subset of TEAM participants, we compared the metabolic outcomes across maternal glucose profiles using a longitudinal data clustering technique that characterizes level and variability, in maternal glucose across pregnancy. By comparing categories of BMI, TEAM Study participants had over 2.0 times the odds of being obese compared to matched NHANES participants (for class III obesity, OR = 2.81 ; 95% confidence interval (CI): 1.15, 6.87). Increasing levels of two-hour glucose were also associated with in utero exposure to pregestational diabetes in matched analyses. Exposure to pregestational diabetes in utero may be associated with an increased risk of metabolic impairment in the offspring with clinical implications.

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).

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, 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.

Highlights • Guidelines for GDM diagnosis during COVID have changed. • Current guidelines are empirical and do not consider pregnancy outcomes. • Current guidelines all result in reduced detection of GDM cases. • Proposed Canadian guidelines reduce GDM by around 80%, but miss many complications. • Guidelines should consider both GDM frequency and complications detected or missed., 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 75g 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.

Background: We previously showed that insulin response to an IV glucose load increases in early pregnancy, independent of changes in insulin sensitivity. It is unknown whether oral glucose tolerance test (OGTT)-based measures of insulin secretory response (ISR) capture the same phenomenon. Methods: This is a secondary analysis of a longitudinal study. Participants (N=31) were studied pre-pregnancy and in early (12-14 wks) and late (34-36 wks) gestation. On separate days, after overnight fasts, an OGTT (75g pre-pregnancy/100g in pregnancy) and an hyperinsulinemic-euglycemic clamp were performed. We calculated Insulinogenic index (IGI), Corrected insulin response (CIR), insulin/glucose area under the curve (AUCins/AUCglu), and Stumvoll 1st Phase Estimate (Stumvoll) from OGTT insulin and glucose levels. Linear mixed effects models examined ISR in early as compared to pre- and late pregnancy; we adjusted p-values for 2 comparisons. Adjusted models included insulin sensitivity, measured with the clamp, as a time-dependent covariate. Results: IGI (adjusted mean ± SEM) increased between pre- and early pregnancy (1.25 ± 0.13 vs. 1.52 ± 0.15, P0.99). The results for Stumvoll were similar. Conclusion: OGTT-based ISR indices capture an insulin sensitivity-independent augmentation of insulin secretion in early pregnancy. Disclosure C.E. Powe: None. J.J. Locascio: None. P. Catalano: None. Funding National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award

Background: Maternal obesity is a growing health burden associated with adverse cardiometabolic health outcomes in the offspring. Higher omega-3 polyunsaturated fatty acids (n3 PUFA) status in pregnancy is associated with higher birthweight. However, the effect of n3 supplementation, specifically in pregnant women with overweight and obesity, on fetal growth and adiposity has not been explored. Objective: To examine the effect of n-3 supplementation in overweight and obese pregnancy on offspring anthropometry and body composition. Methods: A secondary analysis of a double-blind randomized controlled trial of pregnant women with pre-pregnancy BMI≥ 25 randomized to daily DHA plus EPA (2 g/d) or placebo (wheat germ oil) from 10-16 weeks gestation to delivery. We compared the following newborn outcomes i) birthweight z-score derived from anthropometrics, ii) % adiposity, fat-mass and fat-free mass using PeaPodTM and skin fold thickness measurement, by randomization group using Student T-test and Wilcoxon rank-sum for bivariate analyses, and linear regression adjusting for gestational age (GA) and sex. Results: For the 46 mother-child dyads with complete exposure and outcome data, median (IQR) maternal BMI was 30.2 (27.9, 35.5) kg/m2. Gestation was longer in the treatment vs. placebo group (40 (38.6,40.1) vs. 38.9 (38.0,39.4) weeks, p=0.009). Sex- and GA- specific birthweight z-score (-0.2 ± 0.7 vs. -0.6 ± 0.6-unit, p =0.035), but not birth length z-score (-0.3 ± 0.7 vs. -0.6 ± 0.6-unit, p =0.21), was higher in the treatment vs. placebo group. N-3 treatment was associated with higher fat-free mass (β 131.4g higher for treatment vs. control, 95% CI 3.1, 259.7) by skinfolds but not %bodyfat or fat mass at birth. Conclusion: n-3 supplementation early in pregnancy in women with obesity increased birthweight, but this results from increased fetal lean mass accrual. Future investigations should explore the long-term impact of this intervention on offspring cardiometabolic health. Disclosure C. Monthe-Dreze: None. S. Enstad: None. S. Sen: None. S. Hauguel de Mouzon: None. P. Catalano: None. Funding National Institutes of Health (RHD057236); Case Western Reserve University/Cleveland Clinic Clinical and Translational Science Award (UL1RR024989)

No clinical consensus regarding the optimal diagnostic approach for gestational diabetes mellitus (GDM) exists. Participants were randomized to two GDM testing criteria following a blinded non-fasting 50g glucose challenge test (GCT): Carpenter Coustan (CC) or IADPSG. GDM was diagnosed in the CC arm if the 50g GCT was > 135 mg/dL and the fasting 100g OGTT had 2 or more abnormal values. GDM was diagnosed in the IADPSG arm if the fasting 75g OGTT had one or more abnormal values; the 50g GCT was ignored for diagnosis. Participants and providers were informed whether GDM was present but blinded to all test results and which criteria were used for diagnosis. Treatment for GDM occurred per routine clinical care. We hypothesized lower rates of LGA favoring the IADPSG arm, both overall and after restricting to women without GDM. From 2015-2019, 921 women were enrolled and randomized (CC=460; IADPSG-461); however, delivery records were available for only 878 women. Baseline characteristics were similar between groups. While GDM diagnosis (14.4% vs. 4.5%, p Disclosure C.M. Scifres: None. K. Abebe: None. H. Simhan: None. P. Catalano: None. T. Costacou: None. D.M. Comer: None. S.R. Orris: None. K. Ly: None. A. Decker: None. D. Mendez: None. E. Davis: None. Funding National Institutes of Health (1R01HD079647)

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.

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.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.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 (rBody 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.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.

Background: We previously showed that 1st phase insulin response increases dramatically in pregnancy, independent of changes in insulin sensitivity. Measurement of 1st phase insulin response requires the use of hyperglycemic clamps or intravenous glucose tolerance tests (IVGTTs) which are rarely performed in pregnant women. 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 of glucose metabolism in pregnancy, we examined Pearson correlations between OGTT-based insulin secretory response measures and 1st phase insulin response. Forty women were studied pre-pregnancy; 36 returned in early and late pregnancy (12–14 and 34–36 weeks gestation). At each time point, after overnight fasts, an IVGTT and an OGTT were performed on separate days. The 1st phase insulin response was calculated as the incremental area under the curve during the 1st 10 minutes after intravenous administration of a 0.5 g/kg glucose load (or 19g/m2 body surface area if weight >120% ideal body weight). Homeostatic Model Assessment (HOMAB), Insulinogenic index (IGI), Corrected insulin response (CIR), Insulin area under the curve/Glucose area under the curve (AUCins/AUCglu), and the Stumvoll 1st Phase Estimate (Stumvoll) were calculated from insulin and glucose levels measured fasting and 30, 60, 90, 120, and 180 minutes after an oral glucose load (75 grams pre-pregnancy, 100 grams in pregnancy). Results: The best OGTT-based measure for estimation of 1st phase insulin response differed across study timepoints. In early and late pregnancy, AUCins/AUCglu had the strongest correlation with 1st phase insulin response (early: R=0.79, P Conclusion: OGTT-based measures of insulin secretion do not have a consistent relationship with 1st phase insulin response across pre-, early, and late pregnancy. Our findings suggest that Stumvoll can be used in OGTT-based longitudinal studies of insulin secretory response that begin prior to pregnancy and span gestation. For cross-sectional studies in pregnancy, AUCins/AUCglu are the best estimates of 1st phase insulin response.

Gestational weight gain (GWG) is an important factor in the antenatal management of pregnancy. Most obstetrics professional societies [1–5] address the issue of appropriate weight gain during pregnancy. Recommendations for GWG, however, have varied over the years, often without the benefit of sound scientific evidence, ranging from encouraging pregnant women to ‘eat for two’, to recommending minimal weight gain to prevent complications of pregnancy. In 1990 the Institute of Medicine (IOM) of the National Academy of Science in the United States convened a committee to recommend dietary intake and specific GWG recommendations with the goal of delivery of a healthy full-term infant of appropriate size [6]. The 1990 IOM committee noted that there was a positive relationship of both pre-pregnancy maternal weight and GWG with birthweight. Their recommendations were in part a response to the increased risk of the perinatal morbidity and mortality of infants with low birthweight related to poor GWG. The committee report advised an average GWG of 9.1–11.4 kg and advised against the then-current practice of limiting GWG to 4.5–6.4 kg. In 2009, in part because of the increase in numbers of overweight and/or obese people in the population and the lack of specific GWG guidelines for obese women (the 1990 committee recommended target for women with a BMI >29.0 was at least 6.8 kg), the IOM convened a committee to reexamine the GWG guidelines [7]. The results of the report were published in 2009 based on the evidence available at that time (see Table 1). A further goal was to recommend support for researchers to conduct studies on the determinants and impact of GWG, and pattern of weight gain on maternal and child outcomes. This, in the context of the Developmental Origins of Health and Disease (DOHaD) hypothesis, has led to a substantial increase in the number of publications on GWG and impact on pregnancy outcomes over the last decade. Table 1 IOM 2009 gestational weight gain recommendations

Summary Background Excess gestational weight gain (GWG) among women with overweight or obesity synergistically increases their already elevated risk of having gestational diabetes, a caesarean delivery, a large for gestational age infant, and post-partum weight retention, and increases their child's risk of obesity. We investigated whether a primarily telehealth lifestyle intervention reduced excess GWG among women with overweight or obesity. Methods We did a randomised controlled trial in five antenatal clinics of Kaiser Permanente; Oakland, San Leandro, Walnut Creek, Fremont, and Santa Clara, CA, USA. Women at 8–15 weeks' gestation with singletons, pre-pregnancy BMI 25·0–40·0 kg/m2, and aged 18 years or older were randomly assigned (1:1) to receive the telehealth lifestyle intervention or usual antenatal care. Randomisation was adaptively balanced for age, BMI, and race and ethnicity. Data collectors and investigators were masked to group assignments. The core lifestyle intervention consisted of two in-person and 11 telephone sessions on behavioural strategies to improve weight, diet, and physical activity, and stress management to help women meet a trial goal of gaining at the lower limit of the Institute of Medicine (IOM) guidelines range for total GWG: 7 kg for women with overweight and 5 kg for women with obesity. Usual antenatal care included an antenatal visit at 7–10 weeks' gestation, an additional seven antenatal visits, on average, and periodic health education newsletters, including the IOM GWG guidelines and information on healthy eating and physical activity in pregnancy. The primary outcome was weekly rate of GWG expressed as excess GWG, per Institute of Medicine guidelines and mean assessed in the intention-to-treat population. The trial is registered at ClinicalTrials.gov , NCT02130232 . Findings Between March 24, 2014, and Sept 26, 2017, 5329 women were assessed for eligibility and 200 were randomly assigned to the lifestyle intervention group and 198 to the usual care group. Analyses included 199 women in the lifestyle intervention group (one lost to follow-up) and 195 in the usual care group (three lost to follow-up). 96 (48%) women in the lifestyle intervention group and 134 (69%) women in the usual care group exceeded Institute of Medicine guidelines for rate of GWG per week (relative risk 0·70, 95% CI 0·59 to 0·83). Compared with usual care, women in the lifestyle intervention had reduced weekly rate of GWG (mean 0·26 kg per week [SD 0·15] vs 0·32 kg per week [0·13]; mean between-group difference −0·07 kg per week, 95% CI −0·09 to −0·04). No between-group differences in perinatal complications were observed. Interpretation Our evidence-based programme showed that health-care delivery systems could further adapt to meet the needs of their clinical settings to prevent excess GWG and improve healthy behaviours and markers of insulin resistance among women with overweight or obesity by using telehealth lifestyle interventions. Funding US National Institutes of Health.

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

Objective The objective was to estimate the optimal screen-positive 1-hour 50 g glucose challenge test (GCT) threshold for gestational diabetes (GDM) and predictive characteristics of increasing screen-positive GCT threshold values (135–199 mg/dL) for GDM. Study Design It is a secondary analysis of a multicenter mild GDM study. At 24 to 30 weeks' gestation, women with elevated GCT (135–199 mg/dL) completed a diagnostic 3-hour oral glucose tolerance test (OGTT). A novel change-point analysis method was used to compare the GDM rates for the adjacent GCT values, delineating categories of changing risk such that values within categories have equal risk for GDM. Positive (PPV) and negative (NPV) predictive values for GDM were computed for increasing GCT cut-offs. Results In 7,280 women with both GCT (135–199 mg/dL) and OGTT results, 4 GDM risk-equivalent GCT categories were identified with escalations at 144, 158, and 174 mg/dL (all p-values Conclusion Elevated GCT cut-off values between 135 and 143 mg/dL may carry equivalent GDM risk. No threshold GCT value

Obese women, on average, give birth to babies with high fat mass. Placental lipid metabolism alters fetal lipid delivery, potentially moderating neonatal adiposity, yet how it is affected by maternal obesity is poorly understood. We hypothesized that fatty acid (FA) accumulation (esterification) is higher and FA β-oxidation (FAO) is lower in placentas from obese, compared with lean women. We assessed acylcarnitine profiles (lipid oxidation intermediates) in mother-baby-placenta triads, in addition to lipid content, and messenger RNA (mRNA)/protein expression of key regulators of FA metabolism pathways in placentas of lean and obese women with normal glucose tolerance recruited at scheduled term Cesarean delivery. In isolated trophoblasts, we measured [3H]-palmitate metabolism. Placentas of obese women had 17.5% (95% confidence interval: 6.1, 28.7%) more lipid than placentas of lean women, and higher mRNA and protein expression of FA esterification regulators (e.g., peroxisome proliferator-activated receptor γ, acetyl-CoA carboxylase, steroyl-CoA desaturase 1, and diacylglycerol O-acyltransferase-1). [3H]-palmitate esterification rates were increased in trophoblasts from obese compared with lean women. Placentas of obese women had fewer mitochondria and a lower concentration of acylcarnitines, suggesting a decrease in mitochondrial FAO capacity. Conversely, peroxisomal FAO was greater in placentas of obese women. Altogether, these changes in placental lipid metabolism may serve to limit the amount of maternal lipid transferred to the fetus, restraining excess fetal adiposity in this population of glucose-tolerant women.

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.

Background: Augmentation of insulin secretory response (ISR) in pregnancy has been attributed to a pregnancy-associated reduction in insulin sensitivity. We hypothesized that ISR in pregnancy increases prior to and independent of decrements in insulin sensitivity. Methods: In 34 women, ISR (by intravenous glucose tolerance test) and insulin sensitivity (by euglycemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation), and in late pregnancy (34-36 weeks gestation). In a secondary analysis of data from a prior study, we used mixed effects models to compare ISR and insulin sensitivity in early pregnancy to the same parameters prior to pregnancy and in late pregnancy, with adjustment for age, obesity, and GDM status. We next explored the relationship between ISR and circulating hormones. Results: ISR increased from prior to pregnancy to early pregnancy (unadjusted mean [standard deviation] 1st phase insulin response 465.1 [268.5] to 720 [358.2], P Conclusion: ISR increases markedly in early pregnancy, prior to and independent of the late pregnancy decrement in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Disclosure C.E. Powe: None. L. Presley: None. J.J. Locascio: None. P. Catalano: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD22965); National Center for Research Resources (UL1RR024989); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218); Robert Wood Johnson Foundation; National Center for Advancing Translational Sciences (UL1TR002541)

Key Points Question How do the usual dietary intakes of pregnant US women compare with the National Academies of Science, Engineering, and Medicine Dietary Reference Intakes for nutritional adequacy and excess? Findings This cross-sectional analysis of 1003 pregnant US women found that many pregnant women did not consume enough key nutrients during pregnancy, specifically, vitamins A, C, D, E, K, and B6, as well as folate, choline, and minerals including iron, potassium, calcium, magnesium, and zinc. Almost all pregnant women consumed excessive sodium, and many were at risk of excessive consumption of folic acid and iron. Meaning Improved dietary guidance appears to be warranted to help pregnant women to meet but not exceed dietary recommendations., 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., This cross-sectional study uses data from the 2001-2014 National Health and Nutrition Examination Survey (NHANES) to estimate total usual nutrient intakes from foods and dietary supplements of pregnant women.

An underlying principle of the IADPSG GDM classification is that women at similar risk of adverse pregnancy outcomes related to hyperglycemia should be classified similarly. Powe et al have described heterogeneous GDM phenotypes related to impaired insulin secretion and/or insulin sensitivity and reported that pregnancy complications relate primarily to impaired insulin sensitivity. However, their Gen3G cohort was largely Caucasian and GDM women received treatment. Our study was designed to further examine this hypothesis in a diverse population of 6128 untreated women from 5 centers in the blinded epidemiologic HAPO study. Following similar methodology (Impairment = parameter value Disclosure D. McIntyre: None. L.R. Madsen: None. K.S. Gibbons: None. D.A. Sacks: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. W.H. Tam: None. P. Catalano: None.

Powe et al described variable “defects” (defined as parameter values Disclosure D. McIntyre: None. K.S. Gibbons: None. L.R. Madsen: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. D.A. Sacks: None. W.H. Tam: None. P. Catalano: None. Funding National Institutes of Health

Clinical experience suggests that diverse clinical phenotypes exist within the broader diagnosis of GDM. Recent published analysis from a single center outlined heterogeneity in GDM with respect to insulin secretion and sensitivity, defining four GDM phenotypes: 1) GDMsecr ( Disclosure K.S. Gibbons: None. D. McIntyre: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. W. Tam: None. L.R. Madsen: None. D.A. Sacks: None. P. Catalano: None.

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 intravenous glucose tolerance test) 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

Women with pre-gestational diabetes have a high rate of large for gestational age (LGA) babies compared to women without diabetes. In particular, there is a high rate of asymmetric LGA defined as ponderal index (PI) &gt, 90th percentile for gestational age. We examined the association of birth weight and PI, with body mass index (BMI) and obesity status in adulthood, in a cohort of offspring of women with pre-gestational diabetes. The women participated in the Diabetes in Pregnancy (DiP) study at the University of Cincinnati from 1978 to 1995. The offspring of these women are the cohort participating in an observational study being conducted at Cincinnati Children&rsquo, s Hospital Medical Center. Once located, the offspring were invited to come in for a one-day clinic visit to assess anthropometrics, and their metabolic, renal and cardiovascular status. Linear and logistic regression was used to assess the association between birth weight and PI with current BMI. We report on 107 offspring. A statistically significant association was found between offspring current BMI with birth PI (&beta, = 1.89, 95%CI 0.40&ndash, 3.38), and between offspring current obesity status and birth asymmetric LGA (aOR = 2.44, 95%CI 1.01&ndash, 5.82). This is consistent with in utero &ldquo, metabolic programming&rdquo

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.

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.Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pre-gravid BMI (25 kg/m(2) and30 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.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).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.