Do variations in insulin sensitivity and insulin secretion in pregnancy predict differences in obstetric and neonatal outcomes?

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

Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

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) (ß = 1.388; 95% CI 0.870, 1.906; p < 0.001; ß = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (ß = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (ß = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. CONCLUSIONS/INTERPRETATION: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

Reliability of routine anthropometric measurements to estimate body composition in term infants.

BACKGROUND: Birth weight percentiles provide limited information on qualitative infant growth. Body composition provides estimates of fat mass, fat-free mass, and body fat percentage (adiposity). We sought to implement assessment of body composition at birth into clinical practice using a validated anthropometric equation and to evaluate measurement reliability. METHODS: Body composition was incorporated into newborn nursery admission procedure. Body fat percentage derived from skinfold measurements performed by clinical nurses were compared to a historical database of similar measurements performed on newborns by experienced research staff. Body Mass Index (BMI) and Ponderal Index (PI) were used as surrogates for adiposity. Comparison of correlations between groups assessed measurement reliability. P < 0.05 was considered significant. RESULTS: Nine hundred and ninety-one infants had body composition evaluated. Correlations were similar between BMI and %BF for measurements performed by research and clinical nurses (r2 = 0.82 versus r2 = 0.80; P = 0.142 for the difference between correlation coefficients) demonstrating good reliability. Similar results were found using PI (r2 = 0.58 versus r2 0.53; P = 0.105). CONCLUSIONS: Body composition can be assessed at birth using a validated anthropometric equation. Measurements performed by clinical RNs were found to be reliable, allowing for a qualitative measure of growth beyond birth weight. IMPACT: Assessment of neonatal body composition at birth can be implemented into routine clinical practice using an anthropometric equation to estimate fat free-mass, fat mass, and percentage body fat. It provides a detailed, reproducible protocol to incorporate into routine practice. Assessment of fat mass, fat-free mass, and adiposity at birth allows for a qualitative measure of intrauterine growth beyond birth weight. Routine assessment of body composition provides a foundation for longitudinal follow-up of metabolic health in infancy and childhood.

Longitudinal changes in glucose metabolism in women with gestational diabetes, from late pregnancy to the postpartum period.

AIMS/HYPOTHESIS: This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), 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 ISOGTT, insulin response and DI. METHODS: ISOGTT, 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 ISOGTT, 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, ISOGTT 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 ISOGTT, 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.

Augmented insulin secretory response in early pregnancy.

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

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes.

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

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

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.

Causal relationship between obesity-related traits and TLR4-driven responses at the maternal-fetal interface.

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

Maternal fat, but not lean, mass is increased among overweight/obese women with excess gestational weight gain.

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

Comparison of 2- and 3-Dimensional Sonography for Estimation of Birth Weight and Neonatal Adiposity in the Setting of Suspected Fetal Macrosomia.

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

First Trimester Detection of Placental Disease: Challenges and Opportunities.

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

Are the metabolic changes of pregnancy reversible in the first year postpartum?

AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts.

STUDY QUESTION: What are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)? SUMMARY ANSWER: Exogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways. WHAT IS KNOWN ALREADY: The placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis. STUDY DESIGN, SIZE, DURATION: Trophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action. PARTICIPANTS/MATERIALS, SETTING, METHODS: General approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots. MAIN RESULTS AND THE ROLE OF CHANCE: The long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P < 0.001). In contrast, the unsaturated (palmitoleic, oleic, linoleic) acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation. LIMITATIONS, REASONS FOR CAUTION: TNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA. WIDER IMPLICATIONS OF THE FINDINGS: These mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status. STUDY FUNDING/COMPETING INTERESTS: X.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing else to disclose. TRIAL REGISTRATION NUMBER: None.

Identification of early transcriptome signatures in placenta exposed to insulin and obesity.

OBJECTIVE: The purpose of this study was to investigate the effects of insulin on human placental transcriptome and biological processes in first-trimester pregnancy. STUDY DESIGN: Maternal plasma and placenta villous tissue were obtained at the time of voluntary termination of pregnancy (7-12 weeks) from 17 lean (body mass index, 20.9±1.5 kg/m2) and 18 obese (body mass index, 33.5±2.6 kg/m2) women. Trophoblast cells were immediately isolated for in vitro treatment with insulin or vehicle. Patterns of global gene expression were analyzed using genome microarray profiling after hybridization to Human Gene 1.1 ST and real time reverse transcription-polymerase chain reaction. RESULTS: The global trophoblast transcriptome was qualitatively separated in insulin-treated vs untreated trophoblasts of lean women. The number of insulin-sensitive genes detected in the trophoblasts of lean women was 2875 (P<.001). Maternal obesity reduced the number of insulin-sensitive genes recovered by 30-fold. Insulin significantly impaired several gene networks regulating cell cycle and cholesterol homeostasis but did not modify pathways related to glucose transport. Obesity associated with high insulin and insulin resistance, but not maternal hyperinsulinemia alone, impaired the global gene profiling of early gestation placenta, highlighting mitochondrial dysfunction and decreased energy metabolism. CONCLUSION: We report for the first time that human trophoblast cells are highly sensitive to insulin regulation in early gestation. Maternal obesity associated with insulin resistance programs the placental transcriptome toward refractoriness to insulin with potential adverse consequences for placental structure and function.

A retrospective cohort study of factors relating to the longitudinal change in birth weight.

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