Maternal elevated inflammation impairs placental fatty acids ß-oxidation in women with gestational diabetes mellitus.

Introduction: An adverse proinflammatory milieu contributes to abnormal cellular energy metabolism response. Gestational diabetes mellitus (GDM) is closely related to an altered maternal inflammatory status. However, its role on lipid metabolism regulation in human placenta has not yet been assessed. The aim of this study was to examine the impact of maternal circulating inflammatory mediators ([TNF]-α, [IL]-6, and Leptin) on placental fatty acid metabolism in GDM pregnancies. Methods: Fasting maternal blood and placental tissues were collected at term deliveries from 37 pregnant women (17 control and 20 GDM). Molecular approach techniques as radiolabeled lipid tracers, ELISAs, immunohistochemistry and multianalyte immunoassay quantitative analysis, were used to quantify serum inflammatory factors' levels, to measure lipid metabolic parameters in placental villous samples (mitochondrial fatty acid oxidation [FAO] rate and lipid content [Triglycerides]), and to analyze their possible relationships. The effect of potential candidate cytokines on fatty acid metabolism in ex vivo placental explants culture following C-section a term was also examined. Results: Maternal serum IL-6, TNF-α and leptin levels were significantly increased in GDM patients compared with control pregnant women (9,9±4,5 vs. 3,00±1,7; 4,5±2,8 vs. 2,1±1,3; and 10026,7±5628,8 vs. 5360,2±2499,9 pg/ml, respectively). Placental FAO capacity was significantly diminished (~30%; p<0.01), whereas triglyceride levels were three-fold higher (p<0.01) in full-term GDM placentas. Uniquely the maternal IL-6 levels showed an inverse and positive correlation with the ability to oxidize fatty acids and triglyceride amount in placenta, respectively (r= -0,602, p=0.005; r= 0,707, p=0.001). Additionally, an inverse correlation between placental FAO and triglycerides was also found (r=-0.683; p=0.001). Interestingly, we ex vivo demonstrated by using placental explant cultures that a prolonged exposure with IL-6 (10 ng/mL) resulted in a decline in the fatty acid oxidation rate (~25%; p=0.001), along to acute increase (2-fold times) in triglycerides accumulation (p=0.001), and in lipid neutral and lipid droplets deposits. Conclusions: Enhanced maternal proinflammatory cytokines levels (essentially IL-6) is closely associated with an altered placental fatty acid metabolism in pregnancies with GDM, which may interfere with adequate delivery of maternal fat across the placenta to the fetus.

First Trimester Evaluation of Maternal Visceral Fat and Its Relationship with Adverse Pregnancy Outcomes.

Obese women are more likely to experience pregnancy complications. The distribution of fat, and more particularly the rise in visceral fat, is well established to be more closely linked to the onset of cardiovascular disease and metabolic syndrome than obesity itself. We aim to examine the relationship between maternal visceral fat assessment in the first trimester and the appearance of adverse pregnancy outcomes. A prospective cohort study including 416 pregnant women was conducted. During the first trimester scan (11-13 + 6 weeks), all individuals had their visceral fat and subcutaneous thicknesses measured by ultrasonography. Blood samples were obtained, and maternal demographics and clinical information were documented. After delivery, the obstetric outcomes were evaluated. We contrasted two groups: one with healthy pregnancies and the other with adverse pregnancy outcomes (APO), defined as the development of at least one of the following complications: gestational diabetes mellitus, hypertensive disorders of pregnancy, abnormal fetal growth, preterm delivery or preterm premature rupture of membranes. Median maternal age was 33 and 34 years old for the uncomplicated and adverse pregnancy outcomes groups, respectively. We found that women with adverse pregnancy outcomes had higher VFT (median 30 vs. 26.5 mm, p = 0.001) and SFT (median 18.9 vs. 17.1 mm, p = 0.03). However, the visceral/subcutaneous fat ratio was not statistically different between groups. Finally, we performed a subanalysis for metabolic and placental vascular dysfunction complications. After performing a multivariate logistic regression analysis adjusted for maternal age, smoking, and mean arterial pressure, both the VFT (aOR 1.03, p < 0.001) and the ratio of visceral/subcutaneous fat (aOR 1.37, p = 0.04) were significantly associated with the development of adverse pregnancy outcomes; however, the associations of VFT and the VFT-to-SFT ratio were higher for the occurrence of gestational diabetes (aOR 1.07, p < 0.001; aOR 2.09, p = 0.001; respectively) and showed no relationships with placental complications. When conducting a first-trimester ultrasound assessment, sonographers may measure VFT without additional time or cost involved. Identification of pregnant women with increased VFT (>37 mm) may benefit from a close follow-up, especially for the development of gestational diabetes, independent of BMI.

Fetal cerebral three-dimensional power Doppler vascularization indices and their relationships with maternal glucose levels in pregnancies complicated with gestational diabetes.

OBJECTIVES: We aimed to evaluate fetal cerebral circulation using three-dimensional power Doppler (3DPD) vascular indices and to study their relationships with maternal lipid and glycaemic profiles. METHODS: Case-control study in women with and without gestational diabetes mellitus (GDM) at 28-32 weeks in which feto-maternal Doppler study and 3DPD cerebral vascularization indices (FI, VI and VFI) were determined. Maternal lipid and glycaemic profiles were also analysed. Both groups were compared and the correlations of the 3DPD indices with studied variables were analysed. RESULTS: There were significant differences between groups in cerebral FI (p= 0.02), mean maternal Uterine artery PI (p= 0.009) and glucose levels (p= 0.001), being higher in the GDM group. Significant negative correlations were found in GDM group between VFI and MCA PI (p = 0.02) and between VI and MCA PI (p= 0.01). In the GDM group we found a negative significant correlation between FI, VI, VFI and maternal glucose (r= -0.52, p<0.001; r= -0.32, p=0.03 and r= -0.36, p= 0.01, respectively). CONCLUSIONS: Fetal cerebral FI values were higher in GDM pregnancies. All 3DPD vascular indices showed an inverse correlation with maternal glucose levels. These findings support the view that GDM may also represent a fetal vascular disorder influencing fetal neurodevelopment.

INTERGROWTH-21st versus a customized method for the prediction of neonatal nutritional status in hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) generate complications and are one of the principal causes of maternal, foetal, and neonatal mortality worldwide. It has been observed that in pregnancies with HDP, the incidence of foetuses small for their gestational age (SGA) is twice as high as that in noncomplicated pregnancies. In women with HDP, the identification of foetuses (SGA) is substantially important, as management and follow-up are determined by this information. OBJECTIVE: The objective of this study was to evaluate whether the INTERGROWTH-21st method or customized birthweight references better identify newborns with an abnormal nutritional status resulting from HDP. METHOD: A comparative analysis study was designed with two diagnostic methods for the prediction of neonatal nutritional status in pregnancies with HDP. The performance of both methods in identifying neonatal malnutrition (defined by a neonatal body mass index < 10th centile or a ponderal index < 10th centile) was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, diagnostic odds ratio, Youden's index and probability ratios. RESULTS: The study included 226 pregnant women diagnosed with HDP. The customized method identified 45 foetuses as small for gestational age (19.9%), while the INTERGROWTH-21st method identified 27 newborns with SGA (11.9%). The difference between proportions was statistically significant (p < 0.01). Using body mass index (< 10th centile) as a measure of nutritional status, newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR: 4.87 (95% CI: 1.86-12.77) vs. 3.75 (95% CI: 1.49-9.43)) (DOR: 5.56 (95% CI: 1.82-16.98) vs. 4.84 (95% CI: 1.51-15.54)) Even when using Ponderal index (< 10th centile), newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR 2.37 (95% CI: 1.11-5.05) vs. 1.68 (95% CI: 0.70-4.03))(DOR 2.62 (95% CI: 1.00-6.87) vs. 1.90 (95% CI: 0.61-5.92)). CONCLUSION: In pregnant women with HDP, the predictive ability of the customized foetal growth curves to identify neonatal malnutrition appears to surpass that of INTERGROWTH-21st.

Neuroapoptosis in newborns with respiratory acidosis at birth.

BACKGROUND: S100B protein is one of the most accurate biomarkers for diagnosis of neuroapoptosis and brain damage. The aim was to evaluate the lactate concentration and acid-base balance (pH, pCO2, pO2, HCO3c and BEb) in umbilical cord blood to predict high risk of neuroapoptosis and analyze the relationship between the levels of these biomarkers and umbilical cord blood S100B protein concentration at birth. METHODS: Apparently healthy newborns were included. S100B protein and blood gas test (lactate and acid-base balance) were determined in umbilical cord blood at birth. Newborns were classified into two groups: with and without high risk of neuroapoptosis. Newborns with high umbilical cord blood S100B protein concentration were considered newborns at high risk of neuroapoptosis. RESULTS: Sixty-one newborns were included, 12 had high risk of neuroapoptosis and 49 did not. S100B protein concentration correlate directly with pCO2 levels (Rho: 0.286, p = .0321) and lactate concentration (Rho: 0.278, p = .0315); and indirectly with pH (Rho: -0.332, p = .01). The analysis of the ROC curves yielded significant curves for pH and pCO2 to predict high risk of neuroapoptosis, pH optimal cutoff value was 7.19 (sensitivity: 50%, specificity: 83.7%, AUC: 0.708); and pCO2 optimal cutoff value was 60 mmHg (sensitivity: 30%, specificity: 85.4%, AUC: 0.705). CONCLUSIONS: Respiratory acidosis is associated to high concentrations of S100B protein in umbilical cord blood at birth. Umbilical cord blood pH and pCO2 may be useful in differentiating newborns at high risk of neuroapoptosis. Umbilical cord blood gas test may be valuable as risk indicator for neuroapoptosis at birth.

The Influence of Lipid and Proinflammatory Status on Maternal Uterine Blood Flow in Women With Late Onset Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with increased proinflammatory cytokines and is also associated with adverse cardiovascular disease (CVD) outcomes later in life. We aim to evaluate the relationships between uterine arteries vascularization and endothelial dysfunction markers, proinflammatory cytokines, and glycemic and lipid profile in women with GDM. METHODS: Fifty pregnant women were recruited at the third trimester of pregnancy for a prospective cohort study. They were classified into 2 groups: control and GDM. Comparisons of maternal plasma concentrations of endothelial dysfunction markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and plasminogen activator inhibitor 1), proinflammatory cytokines and mediators (interleukin 6 [IL-6], tumor necrosis factor α, vascular endothelial growth factor, placental growth factor, leptin, leukocyte count, and C-reactive protein), lipid profile, glucose, and glycosylated hemoglobin levels were performed. Mean uterine arteries Doppler pulsatility index (PI) was calculated and the relationships between the variables and PI were also analyzed. RESULTS: Women with GDM showed higher proinflammatory cytokines, however, endothelial dysfunction markers were similar in both groups. In the diabetic group, significant correlations were found between the mean uterine arteries PI and maternal IL-6 ( r = .56, P = .01), triglycerides ( r = .49; P = .03), total cholesterol/high-density lipoprotein cholesterol (HDL-c) ratio ( r = .61; P = .006), glucose (r = .62, P = .005), and glycosylated hemoglobin ( r = .48; P = .03). A negative significant correlation between mean uterine arteries PI and HDLc ( r = -.58; P = .02) was also found. CONCLUSION: The proinflammatory status, hyperlipidemia, and metabolic control correlate with uterine blood flow velocity waveforms in women with gestational diabetes.

Prepregnancy body mass index influences lipid oxidation rate during pregnancy.

INTRODUCTION: The influence of maternal body mass index (BMI) on respiratory quotient during pregnancy is not clear. We aim to evaluate longitudinal changes in energy expenditure, respiratory quotient, and substrate oxidation rates in normal and overweight women with uncomplicated pregnancies. We hypothesized that the threshold period in switching from a predominantly carbohydrate to a predominantly lipid metabolism may be different in normal and overweight women. MATERIAL AND METHODS: Forty healthy pregnant women were recruited for a prospective cohort study. They were divided into two groups, normal and overweight (BMI <25 kg/m2 or ≥25 kg/m2 ). Comparisons of indirect calorimetry data were performed monthly throughout pregnancy. The relationships between energy and substrate metabolism variables and maternal BMI were also analyzed. RESULTS: There was a significant increase in oxygen consumption (Vo2 ), carbon dioxide production (Vco2 ) and resting energy expenditure during pregnancy in both normal and overweight women. In the normal weight group, respiratory quotient decreased during the second trimester and increased in the last trimester. Respiratory quotient was lower in the overweight group in the second trimester and decreased in the last trimester; between-group differences being significant at 20 and 36 weeks (0.85 ± 0.06 vs. 0.81 ± 0.01, p = 0.009; 0.87 ± 0.05 vs. 0.80 ± 0.03, p = 0.01, respectively). Lipid oxidation was significantly higher in overweight women at both 20 and 36 weeks (36.8 ± 19.7% vs. 55.2 ± 5.6%, p = 0.003 and 33.6 ± 18.2% vs. 59.6 ± 12.7%, p = 0.007, for normal and overweight group, respectively). CONCLUSION: Prepregnancy maternal BMI influences lipid oxidation rate and respiratory quotient during pregnancy.

The influence of placental perfusion on birthweight in women with gestational diabetes.

OBJECTIVE: To evaluate the influence of both uterine and umbilical arteries Doppler pulsatility indexes (PI) and metabolic control on birthweight in pregnant women with gestational diabetes mellitus. METHODS: One hundred sixty-nine women with gestational diabetes were evaluated. Doppler measurements of umbilical artery and mean uterine arteries PI were recorded and the corresponding Z-score values by gestational age calculated. Maternal pregestational body mass index (BMI) and the levels of glycosylated hemoglobin were also recorded. The relationships between these studied variables and customised birthweight centiles according to sex and gestational age were analyzed using Spearman's correlation coefficient and linear regression. RESULTS: There was a significant correlation between birthweight centiles and Z-score values of the umbilical artery PI (r = -0.25, p = 0.001), but not with the Z-score values of the uterine artery PI (r = -0.12, p = 0.43). Third trimester maternal glycosylated hemoglobin was also positively correlated to birthweight (r = 0.29, p = 0.01). When using stepwise linear regression both maternal glycosylated hemoglobin and the Z-score of umbilical artery PI were included as independent variables in the predictive model of birthweight centile (p = 0.0002, p = 0.001 respectively, R(2)( )= 0.27). CONCLUSIONS: Umbilical artery PI predicts birthweight in women with gestational diabetes. However, metabolic control is the only important determinant of fetal macrosomia in these mothers.

Glucose and Fatty Acid Metabolism in Placental Explants From Pregnancies Complicated With Gestational Diabetes Mellitus.

Placental metabolism is an important mechanism for the regulation of fetal growth and long-term health of the newborns. In this study, we investigated the effects of maternal metabolic environment on human placental fatty acid and glucose metabolism. We used placental explants from uncomplicated pregnancies or pregnancies complicated with gestational diabetes mellitus (GDM), undergoing vaginal delivery (VD) or cesarean section (CS). Fatty acid oxidation (FAO) and glucose uptake (2-DOG) were similar in both modes of delivery in normal and GDM pregnancies. However, placental explants from GDM exhibited 40% to 50% reduced FAO capacity compared to control placentas in women undergoing VD or CS. In contrast, 2-DOG uptake was 2- to 3-fold higher in placental explants from GDM compared to control placentas in women undergoing VD or CS, respectively. In conclusion, ex vivo placental fuel selection is influenced by maternal GDM, but placental metabolic characteristics are not altered by the mode of delivery.

Heterotopic triplets: tubal ectopic and twin intrauterine pregnancy. A review of obstetric outcomes with a case report.

INTRODUCTION: Heterotopic triplets hardly take place, but nowadays the extended use of assisted reproductive technologies is increasing the ectopic pregnancies rate and subsequently the heterotopic pregnancies, leading to a potentially dangerous condition for the woman and the intrauterine pregnancy. MATERIAL AND METHODS: Fourteen cases previously reported in the literature of patients presenting an intrauterine twin pregnancy which became complicated by a tubal ectopic pregnancy have been reviewed. The case of a patient following a homologous intrauterine insemination treatment, resulting in live birth of both twins, is also described. CONCLUSION: Although the diagnosis of heterotopic triplets with tubal ectopic is challenging, a timely surgical treatment will preserve intrauterine gestation with a great chance of a successful obstetric outcome for both twins.