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

Background: Air-displacement plethysmography is a good candidate for monitoring body composition in new-borns and young infants, but reference centile curves are lacking that allow for assessment at birth and across the first six months of life. Objective: Using pooled data from four studies, we aimed to produce new charts for assessment according to gestational age at birth (30+1 to 41+6 weeks) and postnatal age at measurement (1 to 27 weeks). Design: The sample comprised 222 preterm infants born in the United States of America (USA) who were measured at birth; 1029 term infants born in Ireland who were measured at birth; 149 term infants born in the USA and 57 term infants born in Italy who were measured at birth, 1 & 2 weeks and 1, 2, 3, 4, 5, & 6 months of age. Infants whose birth weights were 97th centile of the INTERGROWTH-21st standard were excluded, thereby ensuring that the charts depict body composition of infants whose birth weights did not indicate suboptimal fetal growth. Sex-specific centiles for fat mass (kg), fat-free mass (kg), and percentage body fat were estimated using the lambda-mu-sigma (LMS) method. Results: For each sex and measure (e.g., fat mass), the new charts comprise two panels. The first shows centiles according to gestational age, allowing term infants to be assessed at birth and preterm infants to be monitored until they reach term. The second shows centiles according to postnatal age, allowing all infants to be monitored to age 27 weeks. The LMS values underlying these charts are presented, enabling researchers and clinicians to convert measurements to centiles and Z-scores. Conclusions: These charts provide a single tool for the assessment of body composition, according to air-displacement plethysmography, in infants across the first six months of life and will help enhance early-life nutritional management.

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.

Objective Increased subcutaneous adipose tissue is a well known characteristic of diabetic fetopathy. Prenatal estimation of adipose tissue can be performed by ultrasound, while postnatally skinfold measurements are performed using a Holtain caliper. The aim of this study was to compare these methods in the same patients. Methods This was a prospective study of 172 pregnant patients (142 controls and 30 with gestational diabetes) at ≥ 37 gestational weeks. In addition to fetal weight estimation, fetal subcutaneous tissue was measured at the anterior abdomen lateral to the umbilicus (SonoSfAbd) and at the middle of the femur (SonoSfFem). Within 72 h after delivery, a Holtain caliper was used to measure neonatal skinfold thickness at the left anterior iliac spine (SfAbd), at the lower angle of the left scapula (SfSca), at the middle of the femur, above the left quadriceps femoris (SfFem) and at the middle of the left triceps (SfHum). Ultrasound and mechanical measurements were correlated. Results The sonographic and mechanical methods showed good correlation with each other. Linear regression analysis gave the following equations: SfAbd (mm) = SonoSfAbd (mm) × 0.489 + 1.988 (r2 = 0.34, P < 0.001); SfSca (mm) = SonoSfAbd (mm) 0.457 + 2.043 (r2 = 0.40, P < 0.001); SfFem (mm) = SonoSfFem (mm) × 0.714 + 1.763 (r2 = 0.41, P < 0.001); SfHum (mm) = SonoSfFem (mm) 0.564 + 2.09 (r2 = 0.39, P < 0.001). Conclusions Ultrasound examination is a reliable method for non-invasive intrauterine measurement of fetal subcutaneous tissue and can be used to predict mechanical neonatal skinfold thickness measurements. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

OBJECTIVE Offspring of obese mothers have an increased risk for obesity and diabetes. The purpose of this study was to determine whether fetuses of obese women have increased obesity, insulin resistance, and markers of inflammation, supporting the concept of fetal programming. RESEARCH DESIGN AND METHODS Fifty-three lean and 68 obese women with singleton term pregnancies were evaluated at elective cesarean delivery. Maternal and umbilical cord blood was obtained for measures of insulin resistance and cytokines. Neonatal body composition was estimated using anthropometric measurements within 24 h of delivery. RESULTS The fetuses of obese mothers had greater percent body fat (13.1 ± 3.4 vs. 11.6 ± 2.9%, P = 0.02), homeostasis model assessment of insulin resistance (1.51 ± 0.86 vs. 1.06 ± 0.70, P = 0.003), cord leptin (14.5 ± 13.5 vs. 8.2 ± 4.7 ng/ml, P = 0.001), and interleukin-6 (3.5 ± 2.3 vs. 2.4 ± 1.4 pg/ml, P = 0.02) than fetuses of lean women. There was a strong positive correlation between fetal adiposity and insulin resistance (r = 0.32, P = 0.0008) as well as maternal pregravid BMI and fetal insulin resistance (r = 0.31, P = 0.007) even with adjustment for potential confounders. Cord leptin had a significant correlation with fetal insulin resistance (r = 0.30, P = 0.001), but there was no significant correlation between any other umbilical cord cytokines and fetal insulin resistance. CONCLUSIONS These data suggest that maternal obesity creates a significant risk for the next generations with metabolic compromise already apparent at birth. Therefore, if prevention of obesity is the goal rather than treatment, the perinatal period may be an important focus of future research.

The incidence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years and is paralleling the obesity epidemic. GDM carries long-term implications for the subsequent development of type 2 diabetes in the mother and increased risk for obesity and glucose intolerance in the offspring. Insulin resistance exists before pregnancy in women with a history of GDM but worsens during gestation. Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy. Thus, chronic insulin resistance is a central component of the pathophysiology of GDM. Human pregnancy is characterized by a series of metabolic changes that promote adipose tissue accretion in early gestation, followed by insulin resistance and facilitated lipolysis in late pregnancy. In early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase (1,2). However, in late gestation, maternal adipose tissue depots decline, while postprandial free fatty acid (FFA) levels increase and insulin-mediated glucose disposal worsens by 40–60% compared with prepregnancy (2). The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy (3), and this is further reduced in GDM subjects (4), contributing to greater postprandial increases in FFAs, increased hepatic glucose production, and severe insulin resistance (2,5–7). Although various placental hormones have been suggested to reprogram maternal physiology to meet fetal needs, the cellular mechanisms for this complex transition remain obscure (8). Further, the critical molecular mechanisms involved in increasing maternal lipid flux in obese women throughout pregnancy that may underlie skeletal muscle insulin resistance and increased fetal fuels are just beginning to be investigated. Skeletal muscle is the principal site of whole-body glucose disposal, and along with adipose tissue, becomes severely insulin resistant during the latter half of pregnancy. Normal …

Objective Long-chain omega 3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) exert potent anti-inflammatory properties in humans. This study characterized the effects of omega-3 ω-3 fatty acids supplements (ω-3 FA) on the inflammatory status in the placenta and adipose tissue of overweight/obese pregnant women. Study Design A randomized, double-masked controlled trial was conducted in overweight/obese pregnant women that were randomly assigned to receive DHA plus EPA (2g/day) or the equivalent of a placebo twice a day from week 10–16 to term. Inflammatory pathways were characterized in: 1) adipose tissue and placenta of treated vs. untreated women; and 2) adipose and trophoblast cells cultured with long chain FAs. Results The sum of plasma DHA and EPA increased by 5.8 fold and ω-3 FA/ ω-6 FA ratio was 1.5 in treated vs. untreated women (p< 0.005). Plasma CRP concentrations were reduced (p25 weeks reduced inflammation in maternal adipose and the placental tissue. TLR4 appears as a central target of the anti-inflammatory effects at the cellular level. Trial Registration ClinicalTrials.gov NCT00957476

Objective Because offspring of women with gestational diabetes mellitus have an increased risk of obesity and diabetes mellitus as young adults, our purpose was to characterize body composition at birth in infants of women with gestational diabetes mellitus and normal glucose tolerance. Study design One hundred ninety-five infants of women with gestational diabetes mellitus and 220 infants of women with normal glucose tolerance had anthropometric measurements and total body electrical conductivity body composition evaluations at birth. Parental demographic, anthropometric, medical and family history data, and diagnostic glucose values were used to develop a stepwise regression model that related to fetal growth and body composition. Results There was no significant difference in birth weight (gestational diabetes mellitus [3398±550 g] vs normal glucose tolerance [3337±549 g], P = .26) or fat-free mass (gestational diabetes mellitus [2962±405 g] vs normal glucose tolerance [2975±408 g], P = .74) between groups. However, infants of women with gestational diabetes mellitus had significantly greater skinfold measures (P = .0001) and fat mass (gestational diabetes mellitus [436±206 g] vs normal glucose tolerance [362±198 g], P = .0002) compared with infants of women with normal glucose tolerance. In the gestational diabetes mellitus group, although gestational age had the strongest correlation with birth weight and fat-free mass, fasting glucose level had the strongest correlation with neonatal adiposity. Conclusion Infants of women with gestational diabetes mellitus, even when they are average weight for gestational age, have increased body fat compared with infants of women with normal glucose tolerance. Maternal fasting glucose level was the strongest predictor of fat mass in infants of women with gestational diabetes mellitus. This increase in body fat may be a significant risk factor for obesity in early childhood and possibly in later life.

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

Adiponectin (adpN) production is down-regulated in several situations associated with insulin resistance. The hypoadiponectinemia, which develops in late pregnancy, suggests a role of adpN in pregnancy-induced insulin resistance.In obese pregnancy there is a decreased systemic adpN, which results from down-regulation of gene expression in adipose tissue.One hundred and thirty-three women with uncomplicated pregnancies and a wide range in pre-gravid body mass index (18-62 kg/m(2)) were recruited at term for a scheduled cesarean delivery. Maternal blood, placenta, and sc abdominal adipose tissue were obtained in the fasting state. DNA methylation was analyzed by MBD-based genome-wide methylation sequencing and methyl-specific PCR of placenta and maternal adipose tissue. mRNA and protein expression were characterized by real-time RT-PCR and immunodetection. Plasma adpN, leptin, and insulin were assayed by ELISA.Maternal adipose tissue was the prominent site of adpN gene expression with no detectable mRNA or protein in placenta. In obese women, adipose tissue adpN mRNA was significantly decreased (P.01) whereas DNA methylation was significantly increased (P.001) compared with lean women. The decreased adipose tissue expression resulted in normal-weight women having significantly greater plasma adpN compared with the severely obese (12.8 ± 4.3 ng/mL vs 8.6 ± 3.1, P.001). Plasma adpN was negatively correlated with maternal body mass index (r = -0.28, P.001) and homeostasis model assessment indices of insulin sensitivity (r = -0.32, P.001) but not with gestational weight gain.Maternal adipose tissue is the primary source of circulating adpN during pregnancy. Further, based on our results, the placenta does not synthesize adiponectin at term. Obesity in pregnancy is associated with negative regulation of adpN adipose expression with increase in adpN DNA methylation associated with lower mRNA concentrations and hypoadiponectinemia. Maternal hypoadiponectinemia may have functional consequences in down-regulating biological signals transmitted by adpN receptors in various tissues, including the placenta.

Objective: This study seeks to determine which parental demographic and metabolic factors best correlate with fetal growth and body composition as estimated by ultrasound. Study Design: Thirty-one gravid patients had ultrasound estimates of fetal anthropometry in mid-third trimester. These measurements included estimated fetal weight, abdominal subcutaneous fat, and/or thigh subcutaneous fat thickness. Independent variables included diagnosis of gestational diabetes, parental demographic factors, neonatal sex, and late gestation estimates of carbohydrate metabolism. Results: In the multivariate stepwise model the strongest predictor of ultrasound estimated fetal weight was basal hepatic glucose production, followed by late gestation insulin sensitivity (total R 2 = 0.27). The strongest predictors of abdominal subcutaneous fat thickness were weight gain and presence of gestational diabetes (total R 2 = 0.25). Conclusion: Measures of maternal carbohydrate metabolism, rather than fat mass, explain sonographic measurements of fetal weight. We speculate that factors other than maternal carbohydrate metabolism further explain the variances of fetal adiposity. (Am J Obstet Gynecol 2001;185:1416-20.)

These data are a review of previously published data. Initially, body composition was estimated in 186 neonates. Fat- free mass (FFM), which constituted 86% of birth weight, accounted for 83% of the variance in birth weight; fat mass (FM), which constituted 14% of birth weight, accounted for 46% of the variance in birth weight. Male neonates were an average of 175 g heavier than females. FFM was greater among males compared with females (P = 0.0001). Using stepwise logistic regression, 29% of the variance in birth weight, 30% in FFM, and 17% in FM was accounted for. Independent variables included maternal height, pregravid weight, weight gain during pregnancy, education, parity, paternal height and weight, neonatal sex, and gestational age. Including maternal insulin sensitivity explained 48% of the variance in birth weight, 53% in FFM, and 46% in FM. There was a positive correlation between weight gain and birth weight in control subjects but a negative correlation in subjects with gestational diabetes mellitus. Lastly, the roles of insulin, insulin-like growth factors, and leptin were examined in relation to fetoplacental growth and body composition. The assessment of fetal/neonatal body composition may improve the understanding of the effect of differential factors on fetal growth. Factors associated with accretion of fetal adipose tissue in late gestation are less well understood compared with birth weight and FFM. Additional studies of maternal glucose and lipid metabolism are needed to better evaluate fetal growth.

To examine changes in skinfolds in late gestation in healthy women. Skinfold measures were performed in 39 women at 30.8 (mean) and 37.7 weeks gestation. Fat mass (kg) and sum of three skinfolds were calculated. A decrease in skinfold thickness was observed in 21 women (−3.1±2.1 mm) in late gestation, whereas 18 women had an increase (4.3±3.2 mm), P

OBJECTIVE To evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women. RESEARCH DESIGN AND METHODS We performed anthropometric measurements and collected blood samples at 1st (6–13 weeks) and 2nd (24–28 weeks) trimesters. Diagnosis of GDM was made at 2nd trimester based on a 75-g oral glucose tolerance test (International Association of the Diabetes and Pregnancy Study Groups criteria). Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCinsulin/glucose), and β-cell compensation (insulin secretion sensitivity index-2). Adiponectin was measured by radioimmunoassay. RESULTS Among the 445 participants included in this study, 38 women developed GDM. Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance). Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA1c at 1st trimester). Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = −0.22, P < 0.0001) and Matsuda index (r = 0.28, P < 0.0001, and r = 0.29, P < 0.0001). After adjustment for confounding factors, we found no significant association with HOMA-B and AUCinsulin/glucose. CONCLUSIONS Pregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements.

OBJECTIVE: Our purpose was to correlate maternal carbohydrate metabolism and parental morphometric measurements with neonatal birth weight, body composition, and placental weight. STUDY DESIGN: Sixteen singleton (six control and 10 abnormal glucose tolerance) infants had placental weight, birth weight, and estimates of body composition performed within 24 hours of birth. Independent variables considered were (1) maternal and paternal demographic and morphometric measures, (2) neonatal sex and gestational age, and (3) estimates of maternal carbohydrate metabolism, including basal hepatic glucose production, insulin response, and insulin sensitivity. All metabolic measurements were performed before conception and in early (12 to 14 weeks) and late (34 to 35 weeks) gestation. Best-fit stepwise regression analysis was used to relate the independent variables with placental weight, neonatal birth weight, fat-free mass, and fat mass. RESULTS: Insulin sensitivity in late gestation had the strongest correlation with placental weight ( R 2 = 0.28), neonatal birth weight ( R 2 = 0.28), and fat-free mass ( R 2 = 0.33). In contrast, insulin sensitivity before conception had the best correlation with neonatal fat mass ( R 2 = 0.15). Including all significant independent variables in the model improved the correlations for placental weight ( R 2 = 0.58), birth weight ( R 2 = 0.48) fat-free mass ( R 2 = 0.53), and fat mass ( R 2 = 0.46). CONCLUSION: Maternal insulin sensitivity had stronger correlations with fetoplacental growth in comparison with maternal demographic or mophometric factors.

Reference %fat and total fat-free mass data is necessary for evaluating growth in infants. We aimed to develop longitudinal %fat and total fat-free mass data in infants from birth to 6 months of age. An observational, multicenter, prospective cohort study was conducted with assessments at birth, 1 week, 2 weeks, 1, 2, 3, 4, 5, and 6 months of age. Subjects were exclusively breast-fed and were enrolled at three centers. Whole-body composition (i.e., % fat and total fat-free mass) were assessed using air-displacement plethysmography (ADP) (PEA POD; Life Measurement, Concord, CA). Maternal prepregnancy BMI, gestational weight gain, and infant anthropometric data were collected. A total of 160 infants (boys = 84) were assessed from birth to 4 months of age. Mean birth weight was 3.46 ± 0.39 kg % fat and fat-free mass significantly increased from birth to 4 months of age (P < 0.0001). Gender-specific %fat and total fat-free mass curves for infants from birth to 4 months of age were created. This study will be beneficial to health-care professionals in evaluating normal growth and nutritional patterns in the first months of life.

Obese pregnant women develop severe insulin resistance and enhanced systemic and placental inflammation, suggesting associated modifications of endocrine and immune functions. Activation of innate immunity by endotoxins/lipopolysaccharides (LPS) has been proposed as a mechanism for enhancing metabolic alterations in disorders with insulin resistance. The aim of this study was to characterize the immune responses developed by the adipose tissue (AT) and their potential links to maternal endotoxemia in pregnancy with obesity. Blood and subcutaneous abdominal AT were obtained from 120 lean and obese women (term pregnancy) recruited at delivery. Gene expression was assessed in AT and stromal vascular cells isolated from a subset of 24 subjects from the same cohort. Doubling of plasma endotoxin concentrations indicated subclinical endotoxemia in obese compared with lean women. This was associated with significant increase in systemic C-reactive protein and interleukin-6 (IL-6) but not tumor necrosis factor-α (TNF-α) concentrations. AT inflammation was characterized by accumulation of CD68(+) macrophages with a threefold increased gene expression of the macrophage markers CD68, EMR1, and CD14. Gene expression for cytokines IL-6, TNF-α, IL-8, and monocyte chemotactic protein-1 (MCP1) and for LPS-sensing CD14, toll-like receptor 4 (TLR4), translocating chain-associated membrane protein 2 was 2.5-5-fold higher in stromal cells of obese compared to lean. LPS-treated cultured stromal cells of obese women expressed a 5-16-fold stimulation of the same cytokines upregulated in vivo. Our data demonstrate that subclinical endotoxemia is associated with systemic and AT inflammation in obese pregnant women. Recognition of bacterial pathogens may contribute to the combined dysfunction of innate immunity and the metabolic systems in AT.

OBJECTIVE The objective of this study was to determine maternal hormonal and metabolic factors associated with insulin sensitivity in human pregnancy. RESEARCH DESIGN AND METHODS This was a prospective observational cross-sectional study of 180 normal pregnant women, using samples collected at the time of a blinded oral glucose tolerance test (OGTT) between 24 and 32 weeks' gestation as an ancillary to the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The study was conducted at two public university teaching hospitals, Cleveland, Ohio, and Brisbane, Australia. Fasting maternal serum cholesterol, triglycerides, free fatty acids, insulin, leptin, tumor necrosis factor-α, placental growth hormone (PGH), insulin-like growth factors (IGFs) 1 and 2, and insulin-like growth factor binding proteins (IGFBPs) 1 and 3 were assayed. Correlation and multiple regression analyses were used to determine factors associated with maternal insulin sensitivity (IS) estimated using both OGTT-derived (ISOGTT) and fasting (using the homeostasis model assessment [HOMA]; ISHOMA) insulin and glucose concentrations. RESULTS Insulin sensitivity correlated (r = x and y for ISOGTT and ISHOMA, respectively) with fasting maternal serum leptin (−0.44 and −0.52), IGFBP1 (0.42 and 0.39), and triglycerides (−0.31 and −0.27). These factors were significantly associated with insulin sensitivity in multiple regression analyses (adjusted R2 0.44 for ISOGTT and ISHOMA). These variables explained more than 40% of the variance in estimates of insulin sensitivity. CONCLUSIONS Maternal hormonal and metabolic factors related to the placenta, adipose tissue, and the growth hormone axis are associated with the variation in insulin sensitivity seen during normal human pregnancy.

Circulating adiponectin reflects the degree of energy homeostasis and insulin sensitivity of adult individuals. Low abundance of the high molecular weight (HMW) multimers, the most active forms mediating the insulin-sensitizing effects of adiponectin, is indicative of impaired metabolic status. The increase in fetal adiponectin HMW compared with adults is a distinctive features of human neonates. To further understand the functional properties of adiponectin during fetal life, we have evaluated the associations of adiponectin with insulin sensitivity, body composition, and gender. Umbilical cord adiponectin, adiponectin complexes, and metabolic parameters were measured at term by elective cesarean delivery. The associations between adiponectin, measures of body composition, and insulin sensitivity were evaluated in relation to fetal gender in 121 singleton neonates. Higher total adiponectin concentrations in female compared with male fetuses (34.3 ± 9.5 vs. 24.9 ± 8.6, P < 0.001) were associated with a 3.2-fold greater abundance in circulating HMW complexes (0.20 ± 0.03 vs. 0.08 ± 0.03, P < 0.001, n = 9). Adiponectin was positively correlated with neonatal fat mass (r = 0.27, P < 0.04) and percent body fat in female fetuses (r = 0.28, P < 0.03) and with lean mass in males (r = 0.28, P < 0.03). There was no significant correlation between cord adiponectin and fasting insulin concentrations or fetal insulin sensitivity as estimated by homeostasis model assessment of insulin resistance (HOMA-IR). The gender dimorphism for plasma adiponectin concentration and complex distribution first appears in utero. In sharp contrast to the inverse correlation found in adults, the positive relationship between adiponectin and body fat is a specific feature of the fetus.

High plasma adiponectin concentrations in human fetuses and neonates are unique features of early developmental stages. Yet, the origins of the high adiponectin concentrations in the perinatal period remain elusive.This study was undertaken to identify the sources and functional properties of adiponectin in utero.Tissue specimens were obtained at autopsy from 21- to 39-wk-old stillborn human fetuses. Adipose tissue and placenta were obtained at term elective cesarean section. Adiponectin complexes and expression were measured by immunodetection and real-time PCR.Adiponectin mRNA transcripts were detected in fetal sc and omental adipose depots at lower concentrations than in maternal adipose tissue. Immunoreactive adiponectin was also observed in vascular endothelial cells of fetal organs, including skeletal muscle, kidney, and brain. The absence of adiponectin in all placental cell types and lack of correlation between maternal and umbilical adiponectin indicate that umbilical adiponectin reflects its exclusive production by fetal tissues. The most prominent forms of adiponectin in fetal plasma were high and low molecular mass (HMW and LMW) multimers of 340 and 160 kDa, respectively. The proportion of the HMW complexes was 5-fold (P0.001) higher in umbilical plasma than in adult. The high HMW and total adiponectin levels were associated with lower insulin concentration and lower homeostasis model of assessment of insulin resistance indices in umbilical plasma, reflecting higher insulin sensitivity of the fetus compared with adult.The abundance of HMW adiponectin and its vascular expression are characteristics of human fetal adiponectin. Combined with high insulin sensitivity, fetal adiponectin may be a critical determinant of in utero growth.

Obesity and pregnancy are associated with a combination of insulin resistance and inflammatory changes which exacerbate in combination. Based on the similarity between the inflammatory transcriptomes of adipose tissue and placenta, we hypothesized that the placenta develops exaggerated inflammation in response to obesity. The aim of this study was to characterize placental inflammatory mediators and macrophage accumulation in relation to peripheral inflammation in obesity. Placental macrophages and maternal peripheral blood mononuclear cells (PBMC) from 20 obese and 15 lean women were functionally and phenotypically characterized using immunohistochemistry, flow cytometry and expression for macrophage markers and inflammatory cytokines. The number of resident CD68+ and CD14+ cells was increased 2–3 fold in the placenta of obese as compared to lean women. The macrophage population was characterized by a marked phenotypic heterogeneity with complex subsets of CD14+, CD68+ and CD11b+ (mac-1) cells and by an increased expression of the pro-inflammatory cytokines IL-1, TNF-alpha, IL-6. Placental inflammation was associated with an activation of PBMC gene expression with an increase in the monocyte differentiation and maturation markers CD14 and CD68 in maternal but not fetal PBMC. The inflammatory changes were associated with higher plasma concentrations of C-reactive protein and IL-6 in obese compared to lean women. In conclusion, the chronic inflammation state of pre-gravid obesity is extending to in utero life with accumulation of a heterogeneous macrophage population and pro-inflammatory mediators in the placenta. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short and long term programming of obesity.

To determine the relationship between body mass index (BMI) and percent body fat in overweight/obese pregnant women (BMI25) before and during pregnancy.Thirteen overweight women were evaluated longitudinally (prospective cohort study design) before conception, in early gestation (12-22 weeks) and in late gestation (31-36 weeks). BMI was calculated as weight (kg)/height (m)2, and percent body fat was estimated using hydrodensitometry with correction for residual lung volume.The correlation between BMI and percent body fat before conception was r2 = 0.86 (p = 0.001). Furthermore, the correlation remained strong in early pregnancy, r2 = 0.84 (p = 0.001), but was less strong yet significant, r2 = 0.54 (p = 0.004), in late gestation.In overweight women, the correlation between BMI and percent body fat remained significant during pregnancy. However, the correlation weakened as the pregnancy advanced.

Objective The purpose of this study was to determine whether there is a difference in body composition and the factors that are associated with fat mass in the large-for-gestational-age infants of women with gestational diabetes mellitus compared with the large-for-gestational-age infants of women with normal glucose tolerance levels. Study design Large for gestational age was defined as weight >90th percentile for gestational age, race, and sex on the basis of our population's normative data. Anthropometric measurements and/or total body electrical conductivity estimated body composition that included fat mass, percent body fat, and lean body mass were obtained. Multiple stepwise regression was used to determine factors correlating with fat mass. Results Fifty cases of women with gestational diabetes mellitus and 52 cases of women with normal glucose tolerance levels were evaluated. Infants of mothers with gestational diabetes mellitus had increased fat mass (662 vs 563 g; P =.02) and percent body fat (16.2% vs 13.5%; P =.002) but decreased lean body mass (3400 vs 3557 g; P =.0009), as compared with infants of mothers with normal glucose tolerance levels, despite similar birth weights. Stepwise regression on all 102 women showed gestational age and a diagnosis of gestational diabetes mellitus correlated with fat mass ( r 2 =0.11; P =.001). For gestational diabetes mellitus alone, both gestational age and fasting value of the oral glucose tolerance test correlated with fat mass and percent body fat ( r 2 =0.33 [ P =.0009] and r 2 =0.26 [ P =.005], respectively). Conclusion Large-for-gestational-age infants of mothers with gestational diabetes mellitus have increased fat mass and decreased lean body mass compared with infants of mothers with normal glucose tolerance levels. In gestational diabetes mellitus, gestational age and fasting value of the oral glucose tolerance test correlated best with fat mass.

The purpose of this study was to evaluate the effect of pregravid obesity and gestational diabetes mellitus (GDM) on the longitudinal accretion and distribution of adipose tissue in pregnancy.Women with normal glucose tolerance and GDM were evaluated before conception, early (12-14 weeks) and late (33-36 weeks) in gestation. Fat mass, lean body mass, and percent body fat were assessed longitudinally with hydrodensitometry. Serial biceps, triceps, subscapular, iliac, costal, mid thigh, and lower thigh skinfold measurements quantified the changes in fat mass distribution. Pregravid obesity was defined as25% body fat.Subjects included 19 patients with GDM (5 lean women, 14 obese women), and 33 patients with normal glucose tolerance (controls; 12 lean women, 21 obese women). GDM and control subjects were similar in pregravid percent body fat (29.6% vs 27.9%, P=.47) and fat mass (20.8 kg vs 18.2 kg, P=.37). Values for subjects with GDM and controls were also similar in terms of percent body fat, fat mass, and weight gained (change in percent body fat, -0.7% vs 1.9% [P=.07]; change in fat mass, 3.8 kg vs 5.0 kg [P=.08]; change in weight, 12.0 kg vs 13.2 kg [P=.35]). Lean subjects gained more percent body fat compared with obese subjects (change in percent body fat, 3.3% vs 0.1% [P=.004]) but gained similar amounts of fat mass (change in fat mass, 4.7 kg vs 4.2 kg [P=.58]), lean body mass (7.6 kg vs 8.8 kg [P=.18]), and weight (change in weight, 12.3kg vs 13.0 kg [P=.61]) The distribution of adipose tissue that was accumulated as estimated with skinfold measurements was similar between patients with GDM and glucose tolerance (P.05 for all changes in skinfolds), but significantly different between lean and obese patients (P.05 for all changes in skinfolds). Lean women gained a predominance of adipose tissue peripherally over that in obese women.Lean women accrue significantly more fat mass than obese women, regardless of glucose tolerance. Pregestational obesity rather than GDM influences the distribution of adipose accretion.

The objective of the study is to evaluate neonatal body composition determined by the isotope dilution method compared with the total-body electrical conductivity (TOBEC) method. An oral dose of 18O- and 2H-labeled water was given to 40 healthy term newborns, and 26 infants successfully completed the protocol. The isotope concentrations in urine samples were measured by gas-isotope ratio mass spectrometry. Fat and percent body fat (%F) estimated by isotope dilution were correlated with fat and %F estimated. Total body water measured by isotope dilution of 18O and 2H was 2.44 ± 0.36 and 2.49 ± 0.35 kg, respectively (p < 0.001). Fat and %F estimated by 18O, 2H, and TOBEC were 0.48 ± 0.20 kg and 13.7 ± 5.1%, 0.48 ± 0.19 kg and 13.7 ± 4.6%, and 0.38 ± 0.21 kg and 10.9 ± 5.0%, respectively. Neither fat nor %F estimates by isotope dilution showed good correlation with the TOBEC estimates (r = 0.22–0.57). Because of the wide variation of water content in individuals, the isotope dilution method may not be the optimal way of assessing body composition, and specifically body fat, in newborns.

Gestational diabetes mellitus (GDM) is associated with elevated postprandial free fatty acids (FFA) and insulin resistance; however, little is known about the cellular mechanisms underlying insulin resistance to suppress lipolysis during gestation. We evaluated the longitudinal changes in insulin suppression of FFA before pregnancy and in early (12–14 wk) and late (34–36 wk) gestation in obese subjects with normal glucose tolerance and in obese GDM subjects. Abdominal subcutaneous adipose tissue biopsies were also obtained during cesarean delivery from normal obese pregnant (Preg-Con), GDM, and nonpregnant obese control (Non-Preg-Con) subjects during gynecological surgery. GDM subjects had higher basal plasma FFA before pregnancy ( P = 0.055). Insulin's ability to suppress FFA levels declined from early to late gestation in both GDM and Preg-Con subjects and was significantly less in GDM subjects compared with Preg-Con subjects over time ( P = 0.025). Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower ( P = 0.02) and p85α subunit of phosphatidylinositol 3-kinase was twofold higher ( P = 0.03) in GDM compared with Preg-Con subjects. The levels of peroxisome proliferator-activated receptor-γ (PPARγ) mRNA and protein were lower by 38% in Preg-Con ( P = 0.006) and by 48% in GDM subjects ( P = 0.005) compared with Non-Preg controls. Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects ( P < 0.002). Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. Decreased PPARγ and its target genes may be part of the molecular mechanism to accelerate fat catabolism to meet fetal nutrient demand in late gestation.

We sought to evaluate the longitudinal changes in maternal serum leptin concentrations, body composition, and resting metabolic rate during pregnancy.Ten women were evaluated before pregnancy, in early pregnancy (12 to 14 weeks), and in late pregnancy (34 to 36 weeks). Leptin concentrations were measured by radioimmunoassay, body composition with hydrodensitometry with adjustment for total body water, and resting metabolic rate by use of indirect calorimetry.Using analysis of variance with repeated measures from pregravid to late pregnancy, a 66% increase (mean +/- SD) was found in leptin concentrations (in nanograms per milliliter) (before pregnancy, 25.4 +/- 19.9; in early pregnancy, 37.5 +/- 26.2; and in late pregnancy, 38.4 +/- 27.3, p = 0.003); a 9% increase in body fat (in kilograms) (before pregnancy, 29.4 +/- 15.7; in early pregnancy, 28.7 +/- 14.0; in late pregnancy, 31.4 +/- 14.6; p = 0.04); a 28% increase in oxygen consumption (in milliliters of oxygen per minute) (before pregnancy, 221.2 +/- 29.5; in early pregnancy, 230.4 +/- 42.9; in late pregnancy, 285.3 +/- 51.9; p0.0001); and a 9% increase in oxygen consumption (milliliters of oxygen per kilogram per minute) (before pregnancy, 3.02 +/- 0.43; in early pregnancy, 3.05 +/- 0.30; in late pregnancy, 3.31 +/- 0.37, p = 0.002) with advancing gestation. A significant positive correlation was present between leptin and body fat before pregnancy (r = 0.90, p0.0001), in early pregnancy (r = 0.91, p0.0001), and in late pregnancy (r = 0.87, p = 0.0005) and between leptin and oxygen consumption before pregnancy (r = 0.80, p = 0.004), in early pregnancy (r = 0.92, p0.0001), and in late pregnancy (r = 0.62, p = 0.06). When oxygen consumption was adjusted for maternal and fetal tissue mass, a significant negative correlation was found between leptin and oxygen consumption before pregnancy (r = -0.96, p0.0001), in early pregnancy (r = -0.80, p = 0.0034), and in late pregnancy (r = -0.70, p = 0.02).We conclude that leptin increases significantly during early pregnancy before any major changes in body fat and resting metabolic rate. These data suggest that pregnancy represents a leptin-resistant state.

To determine the longitudinal relationship between body mass index (BMI) and percent body fat in women before and during pregnancy.Twenty-seven healthy, nonobese women were evaluated before conception, in early gestation (12-17 weeks), and in late gestation (33-36 weeks). Height and weight were measured and BMI was calculated. Percent body fat was estimated using hydrodensitometry with correction for residual lung volume.The correlation between BMI and percent body fat before conception was r = 0.693 (P.005); in early gestation it was r = 0.723 (P.005) and in late gestation r = 0.633 (P.005). The mean pregravid BMI was 21.54 and the 95% predictive confidence interval (CI) for percent body fat was 18.2, 26.5%. For the mean BMI of 22.26 in early gestation, the predictive 95% CI for percent body fat was 20.0, 29.0%. In late gestation, the mean BMI was 26.04 with a predictive 95% CI for percent body fat 22.5, 30.8%.In nonobese women the correlation between BMI and percent body fat remains significant during pregnancy, although the 95% CI for predicting percent body fat from the mean BMI ranges widely.

OBJECTIVE: Our purpose was to examine the pattern of growth of both fetal lean body mass incorporating bone, brain, and muscle and subcutaneous fat mass during the course of normal pregnancy. We hypothesized that there are detectable differences in the accretion of fat versus lean body mass. STUDY DESIGN: To establish our method we correlated standardized cross-sectional ultrasonographic images of the fetal extremities with anthropometric assessment of neonatal body composition in 25 subjects. Subsequently 36 nonsmoking women with normal prepregnancy body mass index, normal glucose screening results, and no medical or obstetric complications were recruited. We performed 135 ultrasonographic examinations between 19 and 40 weeks' gestation (mean 3.8 scans per fetus, range 2 to 6) at 4-week intervals. Lean body mass measures included biparietal diameter, head circumference, and femur length. Fetal subcutaneous fat and lean body mass were examined both in the mid upper arm and midthigh by standardized cross-sectional images. All neonates were born between 37 and 42 weeks' gestation and had normal birth weight distribution. Stepwise regression analysis established best-fit equations for fetal measurements obtained ultrasonographically. Independent variables included gestational age, maternal age, weight gain in pregnancy, parity, fetal gender, and maternal prepregnancy weight. RESULTS: Fetal bone growth was best described by a second-order quadratic equation demonstrating deceleration with advancing gestational age ( p R 2 0.92 to 0.96). A quadratic equation that accelerates with advancing gestation best described lean body mass accretion in the extremities ( p R 2 = 0.85 to 0.86). Fetal fat deposition in the extremities was characterized by an accelerating quadratic equation when plotted against gestational age with maternal age and prepregnancy weight contributing significantly ( p R 2 = 0.80 to 0.81). CONCLUSION: Consistent with our hypothesis, fetal fat and lean body mass demonstrate unique growth profiles. We speculate that, as a result of an accelerated rate of growth in late gestation, the measurement of fetal fat will provide a more sensitive and specific marker of abnormal fetal growth when compared with index values of lean body mass. (Am J Obstet Gynecol 1997;176:28-32.)

OBJECTIVE: Estimation of neonatal body composition can be useful in the understanding of fetal growth. However, body composition methods such as total body water and total body electric conductivity are expensive and not readily available. Our primary purpose was to develop an anthropometric model to estimate neonatal body composition and prospectively validate the model against total body electric conductivity and secondarily tocompare our anthropometric model and a previously published anthropometric formula with total body electric conductivity. STUDY DESIGN: A total of 194 neonates had estimates of body composition according to total body electric conductivity (group 1). Parental morphometrics, gestational age, race, sex, parity, and neonatal measurements including birth weight, length, head circumference, and skinfolds (triceps, subscapular, flank, and thigh) were correlated with body fat by use of stepwise regression analysis. The model was validated in a second group of 65 neonates (group 2). RESULTS: There were no significant differences in any of the parental or neonatal measurements between groups 1 and 2. In group 1, 78% of the variance in body fat with the use of total body electric conductivity was explained by birth weight, length, and flank skifold ( R 2 = 0.78, p = 0.0001). When prospectively validated by the subjects in group 2, the model had significant and stronger correlation ( R 2 = 0.84, p = 0.0001) with body fat estimated by total body electric conductivity as compared with the other anthropometric model ( R 2 = 0.54, p = 0.0001). There was no significant ( p = 0.11) difference between our anthropometric estimate of body fat and total body electric conductivity. CONCLUSIONS: The anthropometric model developed can be used to reasonably predict neonatal body fat mass at birth.

hypothesis. STUDY DESIGN: This open-label multicentre randomised controlled trial took place at 13 French university hospitals and included women with singleton pregnancies admitted at 24 0 through 31 6 weeks of gestation with a cervical length 25 mm for an episode of preterm labour that was then successfully arrested by tocolytic treatment. A course of betamethasone 12 mg, repeated after 24 hours, was given intramuscularly in all patients. Women were randomly assigned (by a centralised, computer-generated randomisation process) in a 1:1 ratio to receive either 500 mg of intramuscular 17 alpha-hydroxyprogesterone caproate (17P), started after tocolysis ended and repeated twice weekly until 36 weeks or until preterm delivery, or no treatment with 17P. Additional management in the two arms was left to the discretion of the attending physician, except that progesterone was not allowed in the control group. The primary outcome was time from randomisation to delivery, assessed according to the intention-totreat principle. RESULTS: A total of 188 women were randomised. The two groups were similar with respect to baseline characteristics. Outcome data were available for 184 women. There was no significant difference between the 17P and control groups in median [Q1-Q3] time to delivery (64 [42-79] and 67 [46-83] days, respectively; mean difference, -2; 95% confidence interval, -9 to 6) or in the rates of delivery before 37 (39% and 38%, p 0.99), 34 (16% and 20%, p 0.57), or 32 (9% vs 14%, p 0.35) weeks of gestation. Finally, rates of adverse perinatal outcomes did not differ significantly between the groups. CONCLUSION: Biweekly injections of 500 mg of 17P did not prolong pregnancy significantly in women with an episode of preterm labour successfully arrested by tocolytic treatment.

OBJECTIVE: Changes in metabolic homeostasis in pregnant diabetic women are potential determinants of increased adiposity of the fetus. The aim of this study was to characterize diabetes mellitus-induced changes in genes for fetoplacental energy metabolism in relation to fetal adiposity. STUDY DESIGN: Placentas of women with type 1 diabetes mellitus, gestational diabetes mellitus (GDM), or no complications were analyzed by microarray profiling. The pattern of gene expression was assessed in primary placental cell cultures. RESULTS: Diabetes mellitus was associated with 49 alterations in gene expression at key steps in placental energy metabolism, with 67% of the alterations related to lipid pathways and 9% of the alterations related to glucose pathways. Preferential activation of lipid genes was observed in pregnancy with GDM. Type 1 diabetes mellitus induced fewer lipid modifications but an enhancement of glycosylation and acylation pathways. Oleate enhanced expression of genes for fatty acid esterification and the formation of lipid droplets 3 times as much as glucose in cultured placental cells. CONCLUSION: These results point to fatty acids as preferential lipogenic substrates for placental cells and suggest that genes for fetoplacental lipid metabolism are enhanced selectively in GDM. The recruited genes may be instrumental in increasing transplacental lipid fluxes and the delivery of lipid substrates for fetal use.