Reduced Insulin Receptor Expression and Altered DNA Methylation in Fat Tissues and Blood of Women With GDM and Offspring.

Context: Altered expression of the insulin receptor (IR) in adipose tissue (AT) could contribute to gestational diabetes mellitus (GDM) etiopathogenesis. Transcriptional regulation via epigenetic mechanisms (e.g., DNA methylation) may play a critical role. However, the human IR promoter DNA methylation patterns and involvement in gene expression are unknown. Objective: We evaluated IR mRNA and protein expression accompanied by targeted DNA methylation analyses in AT and blood cells of women with GDM and their offspring. Design: Prospective observational study. Setting: Academic clinic and research unit. Participants: GDM-affected (n = 25) and matched control (n = 30) mother-child dyads. Main Outcome Measures: Maternal IR gene and protein expression in paired subcutaneous (SAT) and visceral adipose tissue samples (VAT). DNA methylation levels in IR promoter and intronic regions in maternal AT and blood cells of mother-offspring pairs. Results: In SAT and VAT, IR mRNA/protein expressions were significantly reduced in women with GDMs (P < 0.05). The decrease in VAT was more pronounced and independent of maternal body mass index. VAT IR protein levels were inversely associated with key maternal and neonatal anthropometric and metabolic parameters (P < 0.05). DNA methylation patterns were similar across tissues, with significant yet small size alterations between groups in mothers and offspring (P < 0.05). Conclusion: Decreased IR levels in AT may be a relevant pathogenic factor in GDM, affecting materno-fetal metabolism. Further investigation of causal factors for IR dysregulation is necessary, especially in VAT. Potential functional and/or clinical roles of altered DNA methylation also should be evaluated.

Alterations of adiponectin gene expression and DNA methylation in adipose tissues and blood cells are associated with gestational diabetes and neonatal outcome.

BACKGROUND: Adiponectin critically contributes to metabolic homeostasis, especially by insulin-sensitizing action. Gestational diabetes mellitus (GDM) is characterized by insulin resistance leading to materno-fetal hyperglycemia and detrimental birth outcomes. By investigating paired subcutaneous (SAT) and visceral adipose tissue (VAT) as well as blood (cell) samples of GDM-affected (n = 25) vs. matched control (n = 30) mother-child dyads of the prospective "EaCH" cohort study, we addressed whether alterations of adiponectin plasma, mRNA, and DNA methylation levels are associated with GDM and offspring characteristics. RESULTS: Hypoadiponectinemia was present in women with GDM, even after adjustment for body mass index (BMI). This was accompanied by significantly decreased mRNA levels in both SAT and VAT (P < 0.05), independent of BMI. Maternal plasma adiponectin showed inverse relations with glucose and homeostatic model assessment of insulin resistance (both P < 0.01). In parallel to reduced mRNA expression in GDM, significant (P < 0.05) yet small alterations in locus-specific DNA methylation were observed in maternal fat (~ 2%) and blood cells (~ 1%). While newborn adiponectin levels were similar between groups, DNA methylation in GDM offspring was variously altered (~ 1-4%; P < 0.05). CONCLUSIONS: Reduced adiponectin seems to be a pathogenic co-factor in GDM, even independent of BMI, affecting materno-fetal metabolism. While altered maternal DNA methylation patterns appear rather marginally involved, functional, diagnostic, and/or predictive implications of cord blood DNA methylation should be further evaluated.

Maternal overweight is not an independent risk factor for increased birth weight, leptin and insulin in newborns of gestational diabetic women: observations from the prospective 'EaCH' cohort study.

BACKGROUND: Both gestational diabetes mellitus (GDM) as well as overweight/obesity during pregnancy are risk factors for detrimental anthropometric and hormonal neonatal outcomes, identified to 'program' adverse health predispositions later on. While overweight/obesity are major determinants of GDM, independent effects on critical birth outcomes remain unclear. Thus, the aim of the present study was to evaluate, in women with GDM, the relative/independent impact of overweight/obesity vs. altered glucose metabolism on newborn parameters. METHODS: The prospective observational 'Early CHARITÉ (EaCH)' cohort study primarily focuses on early developmental origins of unfavorable health outcomes through pre- and/or early postnatal exposure to a 'diabetogenic/adipogenic' environment. It includes 205 mother-child dyads, recruited between 2007 and 2010, from women with treated GDM and delivery at the Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Germany. Recruitment, therapy, metabolite/hormone analyses, and data evaluation were performed according to standardized guidelines and protocols. This report specifically aimed to identify maternal anthropometric and metabolic determinants of anthropometric and critical hormonal birth outcomes in 'EaCH'. RESULTS: Group comparisons, Spearman's correlations and unadjusted linear regression analyses initially confirmed that increased maternal prepregnancy body-mass-index (BMI) is a significant factor for elevated birth weight, cord-blood insulin and leptin (all P < 0.05). However, consideration of and adjustment for maternal glucose during late pregnancy showed that no maternal anthropometric parameter (weight, BMI, gestational weight gain) remained significant (all n.s.). In contrast, even after adjustment for maternal anthropometrics, third trimester glucose values (fasting and postprandial glucose at 32nd and 36th weeks' gestation, HbA1c in 3rd trimester and at delivery), were clearly positively associated with critical birth outcomes (all P < 0.05). CONCLUSIONS: Neither overweight/obesity nor gestational weight gain appear to be independent determinants of increased birth weight, insulin and leptin. Rather, 3rd trimester glycemia seems to be crucial for respective neonatal outcomes. Thus, gestational care and future research studies should greatly consider late pregnancy glucose in overweight/obese women with or without GDM, for evaluation of critical causes and interventional strategies against 'perinatal programming of diabesity' in the offspring.

Early postnatal life as a critical time window for determination of long-term metabolic health.

Epidemiological studies demonstrated a clear phenomenological association between low birth weight and increased cardiometabolic risk later in life, very similar to that in high birth weight subjects. Pre- and/or neonatal overfeeding appears to be an etiological clue. In animal studies, irrespective of birth weight neonatal over-nutrition leads to later overweight, impaired glucose tolerance and cardiometabolic alterations. Probably, perinatally acquired alterations of DNA methylation patterns of gene promoters of central nervous regulators of body weight and metabolism play a key role in mediating these relationships. In humans, the long-term impact of neonatal nutrition is conclusively demonstrated by studies on the consequences of breastfeeding vs. formula-feeding. Taken together, the quantity and quality of nutrition during neonatal life plays a critical role, beyond prenatal development, in the long-term programming of health and disease. This opens a variety of opportunities and challenges to primarily prevent chronic diseases, e.g. the metabolic syndrome.

Emergency cerclage versus bed rest for amniotic sac prolapse before 27 gestational weeks. A retrospective, comparative study of 161 women.

OBJECTIVE: The objective of the study is to compare outcomes after conservative management alone versus conservative management with cerclage in the treatment of amniotic sac prolapse in the second trimester. STUDY DESIGN: Retrospective, comparative study at a university hospital/tertiary referral centre. The medical data was provided by the files of 182 women who were in-patients between December 1989 and June 2005 as a result of prolapse of the amniotic sac during live pregnancies between the 17+0 and 26+0 weeks of gestation. The women were assigned to different groups on the basis of the type of treatment received (Group I: operative procedure=emergency cerclage or Group II: conservative procedure=bed rest, tocolysis, administration of antibiotics). Specified level of significance: p<0.05. MAIN OUTCOME MEASURES: prolongation of pregnancy, pregnancy outcome/infant mortality, and birth weight. RESULTS: The investigation covered 161 women with amniotic sac prolapse (operative management: n=89, conservative procedure: n=72). With operative procedures it was possible to prolong the pregnancy by 41 days (from the day of admission), compared with 3 days when conservative therapy was used (p<0.001, median values). In the group that received operative treatment, live births occurred in 72% of cases as opposed to 25% of cases in the group of women that received conservative therapy (p<0.001). There was also a significant difference in the median weight at birth of all live-born children: 1340g with operative therapy, 750g by conservative procedures (p<0.001). CONCLUSIONS: In the second trimester operative management of the amniotic sac was associated with improved perinatal outcomes including improved live-born rate, increased birth weight and prolonged pregnancy.

Fetal scalp pH and ST analysis of the fetal ECG as an adjunct to cardiotocography to predict fetal acidosis in labor--a multi-center, case controlled study.

OBJECTIVE: To assess the relationship between scalp pH (FBS) and ST analysis in situations of acidosis with special emphasis on the timing of cardiotocography (CTG), FBS and ST changes during labor. STUDY DESIGN: From a European Union multicenter study on clinical implementation of the STAN methodology, 911 cases were identified where a scalp-pH had been obtained. In 53 cases, marked cord artery acidosis was found (cord artery pH<7.06) and 44 cases showed moderate acidemia at birth (pH 7.06-7.09). Comparisons were made with 97 control cases (pH>or=7.20). RESULTS: Of those cases with FHR+ST events recorded within 16 min of delivery, 61% (17/28) had a cord artery pH>or=7.20. The corresponding figure for cases where STAN indications occurred for more than 16 min was 19% (13/69) (OR 6.66, 2.53-17.55, P<0.001). Out of the 121 cases with an abnormal CTG, 84 (69%) showed a cord artery pH of <7.10. STAN indicated abnormality in 83% (70 out of 84). The corresponding figure for scalp pH<7.20 was 43% (36/84). In the case of CTG changes at the start of an adequate recording STAN guidelines provided information on developing acidosis in all cases but one (16 out of 17) in the marked acidosis group. STAN guidelines indicated abnormality prior to an abnormal FBS in 14 out of 17 cases. The median duration between STAN indications to intervention and an abnormal FBS was 29 (95% CI 11-74) min. CONCLUSIONS: ST analysis, as an adjunct to CTG, identifies adverse fetal conditions during labor similar to that of FBS but on a more consistent basis. The timing of CTG+ST changes relates to the level of acidosis at birth.

Actinomycotic inflammatory disease and misdiagnosis of ovarian cancer. A case report.

Actinomycosis in the pelvic region is an uncommon diagnosis. This infection is caused by Actinomyces israelii, a gram-positive anerobic saprophyte bacterium that is a normal inhabitant of the upper intestinal tract in humans. Pelvic actinomycosis is difficult to diagnose pre-operatively and is diagnosed, in most cases, accidentally. Actinomycosis can mimic pelvic and abdominal malignancies. A case report of a 35-year-old female patient with a fixed pelvic mass is presented and the diagnosis and treatment of pelvic actinomycotic inflammatory disease in relation to ovarian cancer are discussed. Clinicians should be aware of this rare infection to spare women potential morbidity from excessive surgical procedures.

Fetal scalp pH and ST analysis of the fetal ECG as an adjunct to CTG. A multi-center, observational study.

OBJECTIVE: To evaluate the relationships between scalp-pH and CTG plus ST waveform analysis of the fetal ECG (STAN) clinical guidelines as indicators of intrapartum hypoxia in term fetuses born with cord artery acidemia. STUDY DESIGN: Data from 6999 term deliveries monitored by the STAN (R) S 21 as part of an EU multi-center study on clinical implementation of the STAN methodology for intrapartum fetal surveillance were analyzed. We identified 911 cases where a scalp-pH was obtained, including 53 cases with cord artery acidemia (pH < 7.06). Lag times between ST events and scalp-pH and time to delivery were related to cord artery metabolic and respiratory acidosis and neonatal outcome. RESULTS: 43 fetuses were identified by CTG plus ST as being in need of intervention 31 (25-46) minutes before delivery (median, 95% Cl). In five, no indications were given and in another five there were inadequate data. Fifteen cases with metabolic acidosis required special neonatal care, all 14 cases adequately monitored on STAN had indications to intervene for 19 minutes or more. In 30 adequately recorded cases, fetal blood sampling (FBS) was obtained within the last hour of labor. In 22 cases, FBS was obtained 13 (7-24) minutes after STAN guidelines had indicated abnormality and in eight no ST changes had occurred at time of FBS. The corresponding FBS data were pH 7.10 (7.01-7.15) and pH 7.21 (7.08-7.31), respectively, P = 0.01. In cases of metabolic acidosis, scalp-pH fell 0.01 units per minute after a baseline T/QRS rise was recorded during the second stage of labor. Apart from one newborn that died at 2 h from E. Coli septicemia, none of the neonates were affected neurologically. CONCLUSION: Cardiotocography plus ST analysis provides accurate information about intrapartum hypoxia similar to that obtained by scalp-pH.

Pulse oximetry during labour--does it give rise to hope? Value of saturation monitoring in comparison to fetal blood gas status.

OBJECTIVE: Purpose of this presentation is to show the diagnostic power of fetal pulse oximetry in comparison to the other blood gas parameters from fetal blood samplings (FBS). The distribution of saturation readings in acidotic fetuses and normally oxygenated fetuses should be established. STUDY DESIGN: A fetal pulse oximetry system (N400, FS14) was evaluated in a strictly observational study design based on blinded saturation display and on continuous data storing. The investigation was performed on 170 fetuses with non-reassuring fetal heart rate (FHR)-tracings. Since pulse oximetry readings were not available for decision finding, the clinical management was based on electronic fetal monitoring and fetal blood samplings. The oxygen saturation from FBS or umbilical cord blood was measured by blood gas analysers with an integrated hemoximeter (Bayer 865; ABL 625, Radiometer) and biosensors measuring lactate as metabolic component. Out of the 170 cases 17 cases were defined as group of acidemia (pH(umb.art.) < 7.16 + BD<-9.4). The distribution of saturation readings and the duration of desaturation periods (in minutes and percentage of total monitoring time SPO2 below 30%) were determined. ROC curve analysis from FBS preceding delivery compared the diagnostic power of other blood gas parameters with oxygen saturation. The Wilcoxon test for uneven pairs was used. RESULTS: The distribution of oxygen saturation in the normal group of fetuses differs significantly from the acidemic group. The correlation coefficient between both methods to determine oxygen saturation was r=0.66. A specific evaluation of the distribution of SPO2 shows an overestimation of pulse oximetry in the low range and an underestimation in the high range of saturation. ROC-curve analysis showed a good diagnostic power of lactate in comparison to the oxygen saturation measured by pulse oximetry or by hemoximetry. CONCLUSIONS: The advantage of continuous fetal pulse oximetry surveilling the fetus under suspicion of hypoxia appears limited by the poor diagnostic power of the respiratory parameter saturation itself and by the impairment of the precision of the technology.

Feasibility of simultaneous application of fetal electrocardiography and fetal pulse oximetry.

BACKGROUND: Fetal pulse oximetry measures arterial oxygen saturation during delivery. The fetal electrocardiogram STAN S21 analyzes the repolarisation segment of ECG (ST) waveform, which is altered by the intramyocardial potassium release resulting from metabolic acidemia. This study aimed to evaluate the feasibility of a simultaneous application of pulse oximetry and fetal electrocardiography and to estimate any agreement between both methods indicating fetal compromise. METHODS: In an observational trial 35 fetuses were simultaneously monitored by pulse oximetry (OBS-500) and electrocardiography. The evaluation focused on signal output and on the coincidence of desaturation in fetal pulse oximetry and on ST events. Desaturation was defined as a drop of at least 20% of oxygen saturation from base line level occurring within 1 min (steep desaturation) or duration of time (s) with oxygen saturation below the threshold of 30%. Statistical analysis was performed with the Mann-Whitney U-test for continuous variables. RESULTS: Signal output of the simultaneous application of both sensors was not significantly reduced in the electrocardiogram and in pulse oximetry (8% vs. 12% reduction). In 15 of the 35 fetuses, ST events indicating fetal hypoxia occurred. In these cases, pulse oximetry showed significantly more episodes of desaturation in comparison with fetuses without ST events. Median saturation during the ST events was significantly lower than in the recordings without ST events (60% vs. 74%, p < 0.05). In the umbilical artery these neonates showed significantly lower pH (7.19 vs. 7.33, p < 0.001), significantly higher lactate (5.1 vs. 3.4 mmol/l, p < 0.05) and significantly lower base deficit (-9.4mmol/l vs. -4.0 mmol/l, p < 0.001) levels. CONCLUSIONS: The combination of fetal pulse oximetry and fetal electrocardiography appears feasible and indicates signs of intermittent hypoxia. These findings may encourage the development of technology that combines these different methods of monitoring.