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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

One potential mechanism by which maternal obesity impacts fetal growth is through hyperglycemia below the threshold for gestational diabetes. Data regarding which measures of maternal glucose metabolism mediate this association is sparse. The objectives of this study were to (i) quantify the associations of maternal pre-pregnancy body mass index (BMI) with neonatal size and adiposity and (ii) examine the role of markers of maternal glucose metabolism as mediators in these associations. This is a secondary analysis of 6,379 mother-infant dyads from the Hyperglycemia and Adverse Pregnancy Outcome cohort. Markers of glucose metabolism, including plasma glucose and c-peptide values, Stumvoll first-phase estimate, modified Matsuda index, and oral disposition index were measured and calculated from an oral glucose tolerance test (OGTT) between 24- and 32-weeks’ gestation. We calculated the direct effect of maternal BMI category, measured at the time of the OGTT and regressed to estimate pre-pregnancy BMI, on neonatal (1) birth weight (BW), (2) fat mass (FM), (3) % body fat (BF%), and (4) sum of skinfold thickness (sSFT). We then calculated the indirect effect of BMI category on these measures through markers of glucose metabolism. Maternal BMI category was positively associated with neonatal BW, FM, BF%, and sSFT. Additionally, mothers who were overweight or obese had higher odds of delivering an infant with BW, FM, BF%, or sSFT >90th percentile. Fasting glucose and c-peptide values were the strongest mediators in the linear associations between maternal BMI category and neonatal size and adiposity. Maternal overweight and obesity were associated with higher odds of neonatal BW and adiposity >90th percentile. Fasting measures of glucose metabolism were the strongest mediators of these associations, suggesting that future studies should investigate whether incorporation of these markers in pregnant women with obesity may improve prediction of neonatal size and adiposity.

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.]

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

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.

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.

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).

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.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.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.Logistic regression can be used with confidence to assess the relationship between clinical and biochemical variables and outcome.

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.

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.

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.

Background: Australian Indigenous women experience high rates of social disadvantage and type 2 diabetes (T2D) in pregnancy, but it is not known how social factors and maternal behaviours impact neonatal adiposity in offspring of women with hyperglycaemia in pregnancy.Methods: Participants were Indigenous (n = 404) and Europid (n = 240) women with gestational diabetes mellitus (GDM) or T2D in pregnancy and their offspring in the Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) study. Social, economic factors, and maternal behaviours were measured in pregnancy and six neonatal anthropometric outcomes were examined after birth.Results: On univariate analysis, maternal education < 12 years (p = 0.03), unemployment(p = 0.001), welfare income vs no welfare income (p = 0.001), lower area based socioeconomic score (p < 0.001), and fast food intake > 2 times/week (p = 0.002) were associated with increased sum of skinfolds (SSF) in offspring. Smoking was significantly associated witha reduction in anthropometric measures, except SSF. In multivariable models adjusted for ethnicity, BMI and hyperglycaemia, social and economic factors were no longer significant predictors of neonatal outcomes. Smoking was independently associated with a reduction inlength, head circumference and fat free mass. Frequent fast food intake remained independently associated with SSF (b-coefficient 1.08 mm, p = 0.02).Conclusion: In women with hyperglycaemia in pregnancy, social factors were associated with neonatal adiposity, particularly skinfold measures. Promoting smoking cessation and limited intake of energy-dense, nutrient-poor foods in pregnancy are important to improve neonatal adiposity and lean mass outcomes. Addressing inequities in social and economic factors are likely to be important, particularly for Indigenous women or women experiencing social disadvantage. Refereed/Peer-reviewed

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)

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

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.

BACKGROUND The placentas of obese women accumulate lipids that may alter fetal lipid exposure. The long-chain omega-3 fatty acids (n–3 FAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alter FA metabolism in hepatocytes, although their effect on the placenta is poorly understood. OBJECTIVE We aimed to investigate whether n–3 supplementation during pregnancy affects lipid metabolism in the placentas of overweight and obese women at term. DESIGN A secondary analysis of a double-blind randomized controlled trial was conducted in healthy overweight and obese pregnant women who were randomly assigned to DHA plus EPA (2 g/d) or placebo twice a day from early pregnancy to term. Placental FA uptake, esterification, and oxidation pathways were studied by measuring the expression of key genes in the placental tissue of women supplemented with placebo and n–3 and in vitro in isolated trophoblast cells in response to DHA and EPA treatment. RESULTS Total lipid content was significantly lower in the placentas of overweight and obese women supplemented with n–3 FAs than in those supplemented with placebo (14.14 ± 1.03 compared with 19.63 ± 1.45 mg lipid/g tissue; P < 0.05). The messenger RNA expression of placental FA synthase (FAS) and diacylglycerol O-acyltransferase 1 (DGAT1) was negatively correlated with maternal plasma enrichment in DHA and EPA (P < 0.05). The expression of placental peroxisome proliferator–activated receptor γ (r = −0.39, P = 0.04) and its target genes DGAT1 (r = −0.37, P = 0.02) and PLIN2 (r = −0.38, P = 0.04) significantly decreased, with an increasing maternal n–3:n–6 ratio (representing the n–3 status) near the end of pregnancy. The expression of genes that regulate FA oxidation or uptake was not changed. Birth weight and length were significantly higher in the offspring of n–3-supplemented women than in those in the placebo group (P < 0.05), but no differences in the ponderal index were observed. Supplementation of n–3 significantly decreased FA esterification in isolated trophoblasts without affecting FA oxidation. CONCLUSION Supplementing overweight and obese women with n–3 FAs during pregnancy inhibited the ability of the placenta to esterify and store lipids. This trial was registered at clinicaltrials.gov as NCT00957476.

Background Less than one-half of women with gestational diabetes mellitus are screened for type 2 diabetes postpartum. Other approaches to postpartum screening need to be evaluated, including the role of screening during the delivery hospitalization. Objective To assess the performance of an oral glucose tolerance test administered during the delivery hospitalization compared with the oral glucose tolerance test administered at a 4- to 12-week postpartum visit. Study Design We conducted a combined analysis of patient-level data from 4 centers (6 clinical sites) assessing the utility of an immediate postpartum 75-g oral glucose tolerance test during the delivery hospitalization (PP1) for the diagnosis of type 2 diabetes compared with a routine 4- to 12-week postpartum oral glucose tolerance test (PP2). Eligible women underwent a 75-g oral glucose tolerance test at both PP1 and PP2. Sensitivity, specificity, and negative and positive predictive values of the PP1 test were estimated for diagnosis of type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Results In total, 319 women completed a PP1 screening, with 152 (47.6%) lost to follow-up for the PP2 oral glucose tolerance test. None of the women with a normal PP1 oral glucose tolerance test (n=73) later tested as having type 2 diabetes at PP2. Overall, 12.6% of subjects (n=21) had a change from normal to impaired fasting glucose/impaired glucose tolerance or a change from impaired fasting glucose/impaired glucose tolerance to type 2 diabetes. The PP1 oral glucose tolerance test had 50% sensitivity (11.8–88.2), 95.7% specificity (91.3–98.2%) with a 98.1% (94.5–99.6%) negative predictive value and a 30% (95% confidence interval, 6.7–65.3) positive predictive value for type 2 diabetes vs normal/impaired fasting glucose/impaired glucose tolerance result. The negative predictive value of having type 2 diabetes at PP2 compared with a normal oral glucose tolerance test (excluding impaired fasting glucose/impaired glucose tolerance) at PP1 was 100% (95% confidence interval, 93.5–100) with a specificity of 96.5% (95% confidence interval, 87.9–99.6). Conclusion A normal oral glucose tolerance test during the delivery hospitalization appears to exclude postpartum type 2 diabetes mellitus. However, the results of the immediate postpartum oral glucose tolerance test were mixed when including impaired fasting glucose or impaired glucose tolerance. As a majority of women do not return for postpartum diabetic screening, an oral glucose tolerance test during the delivery hospitalization may be of use in certain circumstances in which postpartum follow-up is challenging and resources could be focused on women with an abnormal screening immediately after the delivery hospitalization.

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.

During pregnancy, progesterone is exclusively produced by the placenta. As in all steroidogenic tissues, the first and rate-limiting step for the biosynthesis of placental progesterone is the import of cholesterol into the mitochondria via specific transporters. Plasma progesterone is 20% lower in pregnant obese women despite increased cholesterol availability suggesting an impairment in cholesterol import mechanisms. We investigated the role of the outer mitochondrial translocator protein (TSPO), the placental analog of StAR, as a potential regulator of placental progesterone production. Study design: Villous fragments of placentas were collected at term scheduled Cesarean delivery of lean and obese women with normal glucose tolerance. Trophoblast cells were isolated and plated for primary culture. In vitro silencing of TSPO was performed by transfecting primary trophoblast cells with siRNA. Progesterone production was measured in lysates of trophoblast cells before and after TSPO silencing. Results and Discussion: TSPO mRNA and protein expression were 2 to 3-fold lower in placentas of obese vs. lean women. TSPO siRNA silencing in trophoblast cells induced a 90% (p Disclosure M. Haghiac: None. J. Minium: None. Y. Skomorovska-Prokvolit: None. P. Catalano: None. S. Hauguel de Mouzon: None.

While overt diabetes during pregnancy is associated with a higher childhood risk of altered glucose metabolism, the contribution of GDM to this disorder is less clear. Using data from HAPO FUS, we examined associations of maternal GDM not confounded by treatment with childhood glucose metabolism. Maternal glycemic status was based on a 75 g oral glucose tolerance test (OGTT) at ∼28 weeks gestation. Offspring disorders of glucose metabolism (impaired glucose tolerance or type 2 diabetes using American Diabetes Association criteria) were assessed at the HAPO FUS visit using an OGTT in 41children at mean age 11.4 (range 7.9-15.5) years. Insulin sensitivity (IS) was calculated using the Matsuda index and insulin secretion using the insulinogenic index. GDM was defined by International Association of Diabetes in Pregnancy Study Groups criteria. Among offspring of mothers with and without GDM, 10.6% and 5.2%, respectively, had a disorder of glucose metabolism. After adjusting for field center, maternal pregnancy variables and child age, Tanner stage and family history of diabetes at HAPO FUS, the odds ratio and 95% confidence interval (CI) for a disorder of glucose metabolism was 1.98 (1.44-2.74), p=3.1 x 10-5. Adjusting for maternal BMI at OGTT, child’s BMI z score, or both did not attenuate risk. Offspring of GDM mothers had lower IS (29.7 ± 12.5, mean ± SD) compared to offspring of non-GDM mothers (33.7 ± 13.8) with a mean difference of -2.1 (95% CI -3.2 - -1.0), p= 1.9 x 10-4 after adjusting for field center, maternal pregnancy variables and child age, Tanner stage and family history of diabetes at HAPO FUS. The association was attenuated but still significant after adjusting for maternal BMI and/or child BMI z score. Maternal GDM was not associated with insulinogenic index. In summary, exposure to untreated GDM in utero is significantly and independently associated with childhood disorders of glucose metabolism, in part through insulin resistance. Disclosure W. Brickman: None. P. Catalano: None. P.E. Clayton: None. C. Deerochanawong: None. J. Hamilton: None. P.M. Lashley: None. J.M. Lawrence: None. Y. Lebenthal: Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Kamada. D.R. McCance: None. W.H. Tam: None. A. Kuang: None. L.P. Lowe: None. B.E. Metzger: None. D. Scholtens: None. W. Lowe: None.

Obesity prevalence during pregnancy (PG), a significant risk factor for metabolic inflammation and subsequent increase in insulin resistance (IR), has increased ∼ 35% in the last 20 years. Offspring of obese (OB) women are at a higher risk of metabolic dysfunction. Omega-3 fatty acids such as DHA have been shown to decrease IR in animals, though the effects of DHA in PG women are unclear. We hypothesize that high plasma DHA levels are associated with lower IR in PG women in an environment of high omega-3 intake (Hawaii), but differ in metabolic effect in OB vs. lean (LN) women. We evaluated 54 healthy, normal glucose tolerant women and their offspring at term elective C-section in Honolulu. We grouped subjects according to their pre-PG BMI into LN and OB. We measured maternal plasma insulin, glucose, C-reactive protein (CRP), and DHA concentration (gas chromatography/mass spectrophotometry) and calculated the homeostatic model assessment for IR (HOMA-IR). As expected, IR was higher in OB women (Table 1). Maternal DHA was negatively correlated with maternal HOMA-IR (R2= 0.25 p = 0.001), and CRP (R2=0.15 p= 0.004) among all women. These correlations persisted for OB women: HOMA-IR (R2=38 p=0.0007), CRP (R2=0.20 p=0.01); but not for LN women. High maternal DHA is associated with lower inflammation and IR in OB PG women at term. We speculate that high pre-PG omega-3 intake has a significant metabolic impact on insulin sensitivity, especially in OB women.Table 1Lean (BMI: 16-24.9 kg/m2 n=29)Obese (BMI>30, n=26)P.valueGestational Age at delivery (wks)38.8 ± 0.639.1 ± 0.40.088Pre-Pregnancy BMI (kg/m2)21.1 ± 2.236.8 ± 6.9 Disclosure F. Alvarado: None. P. Tsai: None. J. Minium: None. P. Catalano: None. P. O'Tierney-Ginn: None.

GDM have decreased glucose insulin sensitivity vs. NGT. However, there are less data on the impact of GDM on AA metabolism or relationship to fetal growth. Ten NGT and 8 GDM (≥ 1 abnormal value, 3 hour OGTT) were evaluated at 18-22 and 32-36 weeks for 2 potent amino acid secretogogues, Phenylalanine (PHE) and Leucine (LEU). PHE and LEU turnover was estimated (D5 PHE and 13C LEU) under basal and euglycemic hyperinsulinemic clamp conditions. Neonatal body composition was estimated using anthropometrics. There were no significant difference in maternal age, race, education, tobacco use, weight or body composition between GDM and NGT at 18-22 weeks. The was a higher family hx of diabetes in GDM (p=0.05). Basal LEU but not PHE turnover increased over time and was greater in GDM, Table. Glucose disposal decreased over time and was lower in GDM. During the clamp LEU but not PHE turnover increased over time and was greater in GDM. Clamp PHE turnover (µmol/kg/hour) at 18-22 weeks correlated with neonatal lean mass (r=0.48, p=0.048) and there was a trend for fat mass (r=0.47, p=0.058). Omitting 1 outlier there remained a trend for PHE turnover and neonatal lean mass (r=0.43, p=0.09). Leu turnover increased over time and was greater in GDM vs. NGT. In contrast, there were no significant changes in PHE turnover over time or between groups but PHE turnover in early pregnancy was related to fetal lean mass.Metabolic ResultsNGT (n=10)GDM (n=8)ANOVABasal Leucine turnover (umol/kg*ffm/hr)12-16 weeks129.8 ± 19.8155.6 ± 20.1p=0.00532-36 weeks134.1 ± 20.8157.0 ± 22.9pgroup = 0.001Leucine turnover (umol/kg*ffm/hr)12-16 weeks108.5 ± 18.5126.8 ± 20.8p=0.0232-36 weeks123.0 ± 19.8136.2 ± 21.8pgroup = 0.03mean ± SDpgroup difference between NGT & GDM Disclosure P. Catalano: None. L. Presley: None. S. Hauguel de Mouzon: None. S. Kalhan: None.

Maternal metabolic alterations are essential to achieve healthy pregnancy outcomes, but increasing maternal parity may be associated with long-term metabolic dysfunction risk. As existing data are limited by study design, our aim was to employ robust metabolic measures to determine whether or not physiological pregnancy alterations in maternal metabolic function persist at 1 year postpartum.We evaluated 21 healthy women, of whom 11 had an interval pregnancy (IP) and assessment at preconception, during pregnancy and 1 year postpartum, and 10 had no IP and assessment at baseline and a 1 year interval. Assessment measures included body composition, insulin sensitivity and response, and basal metabolic rate. For each measure, IP vs no IP and time intervals within each group were compared using nonparametric analyses, reporting median (IQR).IP and no IP women were similar at enrolment, and no IP women had similar metabolic profiles at enrolment and the 1 year interval. IP women exhibited expected metabolic changes during pregnancy compared with preconception. In IP women, preconception and postpartum measures, including fat mass (20.7 [13.7-37.4] kg vs 18.4 [13.8-41.3] kg; p = 0.2), total insulin response (AUC 11,459 [9,230-13,696] pmol/ml × min vs 11,522 [5,882-17,404] pmol/ml × min; p = 0.9), insulin sensitivity (0.12 [0.06-0.13] mg [kg fat-free mass (FFM)](-1) min(-1) vs 0.11 [0.10-0.15] mg [kg FFM](-1) min(-1); p = 0.1) and basal metabolic rate (0.092 [0.092-0.105] kJ min(-1) FFM vs 0.096 [0.088-0.096] kJ min(-1) FFM; p = 0.5), were similar.Our findings suggest pregnancy might not irreversibly alter maternal metabolic profile, measured at preconception through to 1 year postpartum. This result might be explained by a return to pre-pregnancy weight.

Low concentrations of estradiol and progesterone are hallmarks of adverse pregnancy outcomes as is maternal obesity. During pregnancy, placental cholesterol is the sole source of sex steroids. Cholesterol trafficking is the limiting step in sex steroid biosynthesis and is mainly mediated by the translocator protein (TSPO), present in the mitochondrial outer membrane.The objective of the study was to investigate the effects of maternal obesity in placental sex steroid biosynthesis and TSPO regulation.One hundred forty-four obese (body mass index 30-35 kg/m(2)) and 90 lean (body mass index 19-25 kg/m(2)) pregnant women (OP and LP, respectively) recruited at scheduled term cesarean delivery. Placenta and maternal blood were collected.This study was conducted at MetroHealth Medical Center (Cleveland, Ohio).Maternal metabolic components (fasting glucose, insulin, leptin, estradiol, progesterone, and total cholesterol) and placental weight were measured. Placenta (mitochondria and membranes separated) and cord blood cholesterol values were verified. The expression and regulation of TSPO and mitochondrial function were analyzed.Plasma estradiol and progesterone concentrations were significantly lower (P.04) in OP as compared with LP women. Maternal and cord plasma cholesterol were not different between groups. Placental citrate synthase activity and mitochondrial DNA, markers of mitochondrial density, were unchanged, but the mitochondrial cholesterol concentrations were 40% lower in the placenta of OP. TSPO gene and protein expressions were decreased 2-fold in the placenta of OP. In vitro trophoblast activation of the innate immune pathways with lipopolysaccharide and long-chain saturated fatty acids reduced TSPO expression by 2- to 3-fold (P.05).These data indicate that obesity in pregnancy impairs mitochondrial steroidogenic function through the negative regulation of mitochondrial TSPO.

Objective The aim of the article is to determine whether maternal body mass index (BMI) influences the beneficial effects of diabetes treatment in women with gestational diabetes mellitus (GDM). Study Design Secondary analysis of a multicenter randomized treatment trial of women with GDM. Outcomes of interest were elevated umbilical cord c-peptide levels (> 90th percentile 1.77 ng/mL), large for gestational age (LGA) birth weight (> 90th percentile), and neonatal fat mass (g). Women were grouped into five BMI categories adapted from the World Health Organization International Classification of normal, overweight, and obese adults. Outcomes were analyzed according to treatment group assignment. Results A total of 958 women were enrolled (485 treated and 473 controls). Maternal BMI at enrollment was not related to umbilical cord c-peptide levels. However, treatment of women in the overweight, Class I, and Class II obese categories was associated with a reduction in both LGA birth weight and neonatal fat mass. Neither measure of excess fetal growth was reduced with treatment in normal weight (BMI Conclusion There was a beneficial effect of treatment on fetal growth in women with mild GDM who were overweight or Class I and Class II obese. These effects were not apparent for normal weight and very obese women.

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.

Changes in adipose tissue metabolism are central to adaptation of whole body energy homeostasis to pregnancy. To gain insight into the molecular mechanisms supporting tissue remodeling, we have characterized the longitudinal changes of the adipose transcriptome in human pregnancy. Healthy nonobese women recruited pregravid were followed in early (8–12 wk) and in late (36–38 wk) pregnancy. Adipose tissue biopsies were obtained in the fasting state from the gluteal depot. The adipose transcriptome was examined via whole genome DNA microarray. Expression of immune-related genes and extracellular matrix components was measured using real-time RT-PCR. Adipose mass, adipocyte size, and cell number increased in late pregnancy compared with pregravid measurements ( P < 0.001) but remained unchanged in early pregnancy. The adipose transcriptome evolved during pregnancy with 10–15% of genes being differently expressed compared with pregravid. Functional gene cluster analysis revealed that the early molecular changes affected immune responses, angiogenesis, matrix remodeling, and lipid biosynthesis. Increased expression of macrophage markers (CD68, CD14, and the mannose-6 phosphate receptor) emphasized the recruitment of the immune network in both early and late pregnancy. The TLR4/NF-κB signaling pathway was enhanced specifically in relation to inflammatory adipokines and chemokines genes. We conclude that early recruitment of metabolic and immune molecular networks precedes the appearance of pregnancy-related physiological changes in adipose tissue. This biphasic pattern suggests that physiological inflammation is an early step preceding the development of insulin resistance, which peaks in late pregnancy.

In 2009, the Institute of Medicine (IOM) released revised pregnancy weight gain guidelines. There are limited data regarding the effect of maternal weight gain on newborn adiposity.The aim of this study was to estimate neonatal fat mass, lean body mass, and percentage body fat according to current Institute of Medicine (IOM) pregnancy weight gain guidelines.This is a secondary analysis of a prospective observational cohort study of neonates delivered at least 36 wk gestation and evaluated for fat mass, lean body mass, and percentage body fat. Women with abnormal glucose tolerance testing and other known medical disorders or pregnancies with known fetal anomalies were excluded. Pregravid body mass index (BMI) was categorized as normal weight (25 kg/m2), overweight (25-30 kg/m2), or obese (30 kg/m2). Maternal weight gain was quantified as less than, equal to, or greater than current IOM guidelines. Newborn body composition measurements were compared according to weight gain and BMI categories.A total of 439 maternal-newborn pairs were evaluated; 19.8% (n=87) of women gained less than IOM guidelines; 31.9% (n=140), equal to IOM guidelines; and 48.3% (n=212), greater than IOM guidelines. Significant differences for each component of body composition were found when evaluated by IOM weight gain categories (all ANOVA, P0.001). When controlling for pregravid BMI, only weight gain for women who were of normal weight before pregnancy remained significant.Maternal weight gain during pregnancy is a significant contributor to newborn body composition, particularly for women who are of normal weight before pregnancy.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study showed significant perinatal risks at levels of maternal hyperglycemia below values that are diagnostic for diabetes. A Consensus Panel of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) reviewed HAPO Study results and other work that examined associations of maternal glycemia with perinatal and long-term outcomes in offspring and published recommendations for diagnosis and classification of hyperglycemia in pregnancy in 2010. Subsequently, some commentaries and debate challenged the IADPSG recommendations. In this review, we provide details regarding some points that were considered by the IADPSG Consensus Panel but not published and address the following issues: 1) what should be the frequency of gestational diabetes mellitus (GDM); 2) were appropriate outcomes and odds ratios used to define diagnostic thresholds for GDM; 3) to improve perinatal outcome, should the focus be on GDM, obesity, or both; 4) should results of randomized controlled trials of treatment of mild GDM influence recommendations for diagnostic thresholds; and, 5) other issues related to diagnosis of GDM. Other groups are independently considering strategies for the diagnosis of GDM. However, after careful consideration of these issues, we affirm our support for the recommendations of the IADPSG Consensus Panel.