Increased ferroptosis in leukocytes from preeclamptic women involving the long non-coding taurine upregulated gene 1 (TUG1).

BACKGROUND: Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non-coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells. METHODS: We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE. RESULTS: We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti-ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti-inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22-24 weeks were strongly associated with the development of PE. CONCLUSIONS: Our findings suggest that maternal leukocytes in PE show decreased anti-ferroptotic activity that correlates with anti-inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE.

The long non-coding RPPH1 is decreased in leukocytes and increased in plasma from women developing pre-eclampsia.

Previous studies show differentially expressed long non-coding RNA present in the placenta from women with pre-eclampsia, potentially playing a vital role in the pathogenesis of the complication. In a published microarray study, Ribonuclease P RNA Component H1 (RPPH1), was decreased in leukocytes from women that later developed pre-eclampsia. We hypothesized that RPPH1 decreased during pregnancy in women developing pre-eclampsia and important for the development of the complication. We isolated RNA from extracellular vesicles, leukocytes and plasma using blood samples taken at week 22-24 and 36-38 in women who subsequently developed pre-eclampsia and from healthy pregnancy. The expression of RPPH1 was quantified using qPCR. Expression of RPPH1 at 22-24 week was further examined to investigate its discriminatory potential of subsequent pre-eclampsia and association with clinical markers. We found lower expression of RPPH1 in leukocytes at 22-24 and 36-38 weeks amongst women who subsequent developed pre-eclampsia compared to those who did not, while increased RPPH1 expression was found in plasma at 36-38 weeks. Pre-eclampsia risk factors could not account for this difference in the RPPH1 expression. Prediction of pre-eclampsia at 22-24 weeks using RPPH1 expression in leukocytes in addition to the screening algorithm used today had a significantly better performance. In conclusion, RPPH1 expression in leukocytes was significantly decreased in women with pre-eclampsia, and the expression at 22-24 weeks associated with the subsequent development of pre-eclampsia. RPPH1 in leukocytes may be a useful biomarker for prediction and/or early detection of pre-eclampsia and an unknown regulator of the signaling affecting immune cells.

Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia.

BACKGROUND: Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels. OBJECTIVE: We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1-3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations. STUDY DESIGN: Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins. RESULTS: The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower. CONCLUSION: An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins' involvement in the pathophysiology and as treatment targets is warranted.

Maternal metabolic profiling across body mass index groups: An exploratory longitudinal study.

INTRODUCTION: Increased BMI has been identified as a risk factor for most pregnancy complications, but the underlying metabolic factors mediating the detrimental effects of BMI are largely unknown. We aimed to compare metabolic profiles in overweight/obese women (body mass index [BMI] ≥ 25 kg/m2 ) and normal weight/underweight women (BMI < 25 kg/m2 ) across gestation. We also explored how gestational weight gain (GWG) affected maternal metabolic profiles. MATERIAL AND METHODS: Exploratory nested case-control study based on a prospective longitudinal cohort of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002 to 2008. The sample consisted of 48 women who were overweight/obese and 59 normal-weight/underweight women. Plasma samples from four time points in pregnancy (weeks 14-16, 22-24, 30-32 and 36-38) were analyzed by nuclear magnetic resonance spectroscopy and 91 metabolites were measured. Linear regression models were fitted for each of the metabolites at each time point. RESULTS: Overweight or obese women had higher levels of lipids in very-low-density lipoprotein (VLDL), total triglycerides, triglycerides in VLDL, total fatty acids, monounsaturated fatty acids, saturated fatty acids, leucine, valine, and total branched-chain amino acids in pregnancy weeks 14-16 compared to underweight and normal-weight women. Docosahexaenoic acid and degree of unsaturation were significantly lower in overweight/obese women in pregnancy weeks 36-38. In addition, overweight or obese women had higher particle concentration of XXL-VLDL and glycoprotein acetyls (GlycA) at weeks 14-16 and 30-32. GWG did not seem to affect the metabolic profile, regardless of BMI group when BMI was treated as a dichotomous variable, ≥25 kg/m2 (yes/no). CONCLUSIONS: Overweight or obese women had smaller pregnancy-related metabolic alterations than normal-weight/underweight women. There was a trend toward higher triglyceride and VLDL particle concentration in overweight/obese women. As this was a hypothesis-generating study, the similarities with late-onset pre-eclampsia warrant further investigation. The unfavorable development of fatty acid composition in overweight/obese women, with possible implication for the offspring, should also be studied further in the future.

Platelet and mitochondrial RNA is decreased in plasma-derived extracellular vesicles in women with preeclampsia-an exploratory study.

BACKGROUND: Circulating extracellular vesicles (EVs) are increased in preeclampsia (PE) and are associated with severity and progression. We examined in this exploratory cohort study if the mRNAs and long noncoding RNAs (lncRNAs) in plasma-derived EVs were dysregulated in PE compared to normal pregnancy and display different temporal patterns during gestation. METHODS: We isolated EVs from plasma at weeks 22-24 and 36-38 in women with and without PE (n=7 in each group) and performed RNA-seq, focusing on mRNAs and lncRNAs. We validated highly expressed mitochondrial and platelet-derived RNAs discovered from central pathways in 60 women with/without PE. We examined further one of the regulated RNAs, noncoding mitochondrially encoded tRNA alanine (MT-TA), in leukocytes and plasma to investigate its biomarker potential and association with clinical markers of PE. RESULTS: We found abundant levels of platelet-derived and mitochondrial RNAs in EVs. Expression of these RNAs were decreased and lncRNAs increased in EVs from PE compared to without PE. These findings were further validated by qPCR for mitochondrial RNAs MT-TA, MT-ND2, MT-CYB and platelet-derived RNAs PPBP, PF4, CLU in EVs. Decreased expression of mitochondrial tRNA MT-TA in leukocytes at 22-24 weeks was strongly associated with the subsequent development of PE. CONCLUSIONS: Platelet-derived and mitochondrial RNA were highly expressed in plasma EVs and were decreased in EVs isolated from women with PE compared to without PE. LncRNAs were mostly increased in PE. The MT-TA in leukocytes may be a useful biomarker for prediction and/or early detection of PE.

Placenta-derived proteins across gestation in healthy pregnancies-a novel approach to assess placental function?

BACKGROUND: Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function. METHODS: We analyzed proteins in plasma samples collected in two cohorts using the Somalogic 5000-plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14-16, 22-24, and 30-32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function. RESULTS: Among the nearly 5000 measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a "placental proteomic clock." CONCLUSIONS: Together, these data may serve as a first step towards a reference for the healthy placenta-derived proteome that can be measured in the systemic maternal circulation and potentially serve as biomarkers of placental function. The "placental proteomic clock" represents a novel concept that warrants further investigation. Deviations in the proteomic pattern across gestation of such proteomic clock proteins may serve as an indication of placental dysfunction.

Third trimester fetal lung volume, thoracic circumference, and early infant lung function.

BACKGROUND: We aimed to investigate the relationship between fetal third trimester lung volume (LV), thoracic circumference (TC), fetal weight, as well as fetal thoracic and weight growth, and early infant lung function. METHODS: Fetal LV, TC and estimated weight were measured with ultrasound at 30 gestational weeks in 257 fetuses from the general population-based prospective cohort study Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL). Fetal thoracic growth rate and weight increase were calculated using TC and estimated fetal weight measured by ultrasound during pregnancy, and TC and birthweight of the newborn. Lung function was assessed by tidal flow-volume measurement in awake infants at 3 months of age. The associations between fetal size (LV, TC, and estimated weight) and growth (thoracic growth rate and fetal weight increase) measures and the time to peak tidal expiratory flow to expiratory time ratio (tPTEF /tE ) as well as tidal volume standardized for body weight (VT /kg) were analyzed using linear and logistic regression models. RESULTS: We observed no associations between fetal LV, TC or estimated fetal weight and tPTEF /tE as a continuous variable, tPTEF /tE < 25th percentile, or VT /kg. Similarly, fetal thoracic growth and weight increase were not associated with infant lung function. Analyses stratified for sex showed a significant inverse association between fetal weight increase and VT /kg (p = 0.02) in girls. CONCLUSION: Overall, fetal third trimester LV, TC, estimated fetal weight, thoracic growth rate and weight increase were not associated with infant lung function at 3 months of age.

Low CETP activity and unique composition of large VLDL and small HDL in women giving birth to small-for-gestational age infants.

Cholesteryl ester transfer protein (CETP) regulates high density lipoproteins (HDL)-cholesterol (C) and HDL-C is essential for fetal development. We hypothesized that women giving birth to large-for-gestational-age (LGA) and small-for-gestational age (SGA) infants differed in longitudinal changes in lipoproteins, CETP activity and HDL-C and that placentas from women with higher or lower circulating HDL-C displayed differential expression of mRNAs involved in cholesterol/nutrient transport, insulin signaling, inflammation/ extracellular matrix (ECM) remodeling. Circulating lipids and CETP activity was measured during pregnancy, NMR lipidomics in late pregnancy, and associations with LGA and SGA infants investigated. RNA sequencing was performed in 28 placentas according to higher and lower maternal HDL-C levels. Lipidomics revealed high triglycerides in large VLDL and lipids/cholesterol/cholesteryl esters in small HDL in women giving birth to SGA infants. Placentas from women with higher HDL-C had decreased levels of CETP expression which was associated with mRNAs involved in cholesterol/nutrient transport, insulin signaling and inflammation/ECM remodeling. Both placental and circulating CETP levels were associated with growth of the fetus. Low circulating CETP activity at 36-38 weeks was associated with giving birth to SGA infants. Our findings suggest a link between increased maternal HDL-C levels, low CETP levels both in circulation and placenta, and SGA infants.

Dysregulated non-coding telomerase RNA component and associated exonuclease XRN1 in leucocytes from women developing preeclampsia-possible link to enhanced senescence.

Senescence in placenta/fetal membranes is a normal phenomenon linked to term parturition. However, excessive senescence which may be induced by telomere attrition, has been associated with preeclampsia (PE). We hypothesized that the telomerase complex in peripheral blood mononuclear cells (PBMC) and circulating telomere associated senescence markers would be dysregulated in women with PE. We measured long non-coding (nc) RNA telomerase RNA component (TERC) and RNAs involved in the maturation of TERC in PBMC, and the expression of TERC and 5'-3' Exoribonuclease 1 (XRN1) in extracellular vesicles at 22-24 weeks, 36-38 weeks and, 5-year follow-up in controls and PE. We also measured telomere length at 22-24 weeks and 5-year follow-up. The circulating senescence markers cathelicidin antimicrobial peptide (CAMP), ß-galactosidase, stathmin 1 (STMN1) and chitotriosidase/CHIT1 were measured at 14-16, 22-24, 36-38 weeks and at 5-year follow-up in the STORK study and before delivery and 6 months post-partum in the ACUTE PE study. We found decreased expression of TERC in PBMC early in pregnant women who subsequently developed PE. XRN1 involved in the maturation of TERC was also reduced in pregnancy and 5-year follow-up. Further, we found that the senescence markers CAMP and ß-galactosidase were increased in PE pregnancies, and CAMP remained higher at 5-year follow-up. ß-galactosidase was associated with atherogenic lipid ratios during pregnancy and at 5-year follow-up, in PE particularly. This study suggests a potential involvement of dysfunctional telomerase biology in the pathophysiology of PE, which is not restricted to the placenta.

Changes in maternal blood glucose and lipid concentrations during pregnancy differ by maternal body mass index and are related to birthweight: A prospective, longitudinal study of healthy pregnancies.

BACKGROUND: Maternal obesity is increasing worldwide but the consequences for maternal physiology and fetal growth are not fully understood. OBJECTIVE: To study whether changes in glucose and lipid metabolism during pregnancy differ between women with normal weight and overweight/obesity, and investigate which of these metabolic factors are associated with birthweight. DESIGN: Prospective, longitudinal study. SETTING: Department of Obstetrics, Oslo University Hospital, Rikshospitalet. POPULATION: 1031 healthy pregnant women with singleton pregnancies. METHODS: Blood samples from early and late pregnancy were analyzed for fasting glucose, insulin and lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides). Associations between metabolic factors and birthweight (z-scores) were explored by linear regression models. Main Outcome Measures: Group-dependent longitudinal changes in glucose and lipids and their association with birthweight (z-scores). RESULTS: Compared to women with normal weight (BMI < 25), women with overweight (BMI 25-29.9) and obesity (BMI > 30) had significantly higher fasting glucose (4.54, 4.68 and 4.84 mmol/l), insulin (23, 33 and 50 pmol/l), total cholesterol (4.85, 4.99 and 5.14 mmol/l), LDL-C (2.49, 2.66 and 2.88 mmol/l) and triglycerides (1.10, 1.28 and 1.57 mmol/l), but lower HDL-C (1.86, 1.75 and 1.55 mmol/l). BMI (B 0.05, 95% CI 0.03-0.06, p<0.001), gestational weight gain (GWG) (B 0.06, 0.05-0.08, p<0.001) and an increase in fasting glucose (B 0.30, 0.16-0.43, p<0.001) were positively associated with birthweight, whereas a decrease in HDL-C (B -0.72, -0.96- -0.53, p<0.001) had a negative association with birthweight. CONCLUSIONS: Overweight/obesity was associated with an unfavorable metabolic profile in early pregnancy which was associated with increased birthweight. However, modifiable factors like gestational weight gain and an increase in fasting glucose were identified and can be targeted for interventions.

Elevated Cholesteryl Ester Transfer Protein Activity Early in Pregnancy Predicts Prediabetes 5 Years Later.

CONTEXT: Cholesteryl ester transfer protein (CETP) regulates high-density lipoprotein (HDL) cholesterol levels and interaction between glucose, and HDL metabolism is central in the development of diabetes. OBJECTIVE: We hypothesized that CETP levels would be regulated in diabetic pregnancies. We tested the hypothesis by evaluating CETP activity measured multiple times during pregnancy and at 5 years' follow-up in a prospective cohort (STORK) and investigated its association with gestational diabetes mellitus (GDM) during pregnancy or development of prediabetes 5 years after pregnancy. We also evaluated the strongest correlation of CETP activity among measures of adipocity and glucose metabolism, lipoproteins, adipokines, and monocyte/macrophage activation markers. DESIGN: A population-based longitudinal cohort study was conducted from 2001 to 2013. SETTING: The study setting was Oslo University Hospital. PATIENTS OR OTHER PARTICIPANTS: A total of 300 women during pregnancy and at 5 years postpartum participated in this study. MAIN OUTCOME MEASURES: CETP activity was measured at 14 to 16, 22 to 24, 30 to 32, and 36 to 38 weeks' gestation, and at 5 years' follow-up. RESULTS: We found higher CETP activity in pregnancy in women developing prediabetes but no association with GDM. CETP activity decreased throughout pregnancy and remained low at follow-up. High CETP activity was associated with sCD14 levels, in particular in women who developed prediabetes. These data show that enhanced CETP activity during pregnancy is associated with systemic indices of monocyte/macrophage activation, in particular in women who develop prediabetes later in life. CONCLUSIONS: CETP activity during pregnancy identifies women at risk for later diabetes development.

Maternal-fetal cholesterol transfer in human term pregnancies.

OBJECTIVES: The extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive. Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol. METHODS: A cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically. RESULTS: We found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) µmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) µmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p < 0.001). CONCLUSION: Fetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term.

Prediction of Gestational Diabetes Mellitus and Pre-diabetes 5 Years Postpartum using 75 g Oral Glucose Tolerance Test at 14-16 Weeks' Gestation.

Early detection and treatment of women at risk for gestational diabetes mellitus (GDM) could improve perinatal and long-term outcomes in GDM women and their offspring. We explored if a 75 g oral glucose tolerance test (OGTT) at 14-16 weeks of gestation could identify women who will (1) develop GDM or give birth to large-for-gestational-age (LGA) babies in 1031 pregnant women from the STORK study using different diagnostic criteria (WHO1999, IADPSG2010, WHO2013, NORWAY2017) and (2) develop pre-diabetes 5 years postpartum focusing on first trimester ß-cell function in a separate study of 300 women from the STORK cohort. The sensitivity of the 14-16 week OGTT to identify women who would develop GDM or have LGA babies was low, and we could not identify alternative cut-offs to exclude women not at risk or identify women that could benefit from early intervention. First trimester ß-cell function was a stronger determinant than third trimester ß-cell function of predicting maternal pre-diabetes. In conclusion, in our normal low-risk population, the 75 g OGTT at 14-16 weeks is insufficient to identify candidates for early treatment of GDM or identify women not likely to develop GDM or have LGA babies. First trimester ß-cell function may predict pre-diabetes 5 years postpartum.

[A 33-year old pregnant woman with nausea, itching and fatigue]. / En 33 år gammel gravid kvinne med kvalme, kløe og slapphet.

Acute fatty liver of pregnancy (AFLP) is a serious, but rare condition with substantial maternal and perinatal mortality and morbidity. It occurs in the third trimester or early postpartum period. The medical history, physical examination and laboratory tests are often sufficient to make the diagnosis, and liver biopsy is rarely indicated. We present a 33-year-old woman with the diagnosis AFLP. Her case is presented to draw attention to AFLP as a differential diagnosis to liver diseases in pregnancy, especially the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets). Appropriate diagnosis and prompt delivery is essential to optimal maternal and fetal outcome in both the AFLP and HELLP syndromes, and this should be followed by intensive care treatment of the dysfunctional maternal multiorgan system.

Large Reduction in Adiponectin During Pregnancy Is Associated With Large-for-Gestational-Age Newborns.

Context: Fetuses exposed to an obese intrauterine environment are more likely to be born large-for-gestational age (LGA) and are at increased risk of obesity in childhood and cardiovascular disease and/or type 2 diabetes mellitus as adults, but which factors that influence the intrauterine environment is less clear. Objective: To investigate the association between circulating levels of leptin and adiponectin, measured multiple times during pregnancy, and birth weight and prevalence of LGA or small-for-gestational-age infants. The association between birth weight and messenger RNA (mRNA) expression of adiponectin receptors and genes involved in nutrient transport in the placenta was also investigated. Design: Population-based prospective cohort [substudy of the STORK study (STORe barn og Komplikasjoner, translated as Large Babies and Complications)] from 2001 to 2008. Setting: University hospital. Patients or other participants: 300 women. Main Outcome Measures: Oral glucose tolerance test was performed twice along with adiponectin and leptin levels measured four times during pregnancy. Results: Circulating adiponectin was lower in mothers who gave birth to LGA offspring or had fetuses with high intrauterine abdominal circumference late in pregnancy. Adiponectin decreased most from early to late pregnancy in mothers who gave birth to LGA offspring, and the decrease was an independent predictor of birth weight. Adiponectin receptor 2 and system A amino acid transporter mRNA expression in placentas was negatively correlated with birth weight and was lower in placentas from LGA infants. Conclusions: Our findings suggest that maternal adiponectin may be an important predictor of fetal growth and birth weight, independent of body mass index and insulin resistance.

Gene expression in term placentas is regulated more by spinal or epidural anesthesia than by late-onset preeclampsia or gestational diabetes mellitus.

Pre-eclampsia (PE) and gestational diabetes mellitus (GDM) are common complications of pregnancy, but the mechanisms underlying these disorders remain unclear. The aim was to identify the extent of altered gene expression in term placentas from pregnant women with late-onset PE and GDM compared to controls. RNAseq identified few significantly differentially regulated genes in placental biopsies between PE, GDM, or uncomplicated pregnancy (n = 10 each group). Five genes were altered in placentas from PE including 4 non-coding genes and Angiopoietin 2 (ANGPT2). No genes were significantly regulated by GDM. In contrast, many genes were significantly regulated by fetal, maternal and delivery-specific variables, particularly spinal and epidural anesthesia. We selected ANGPT2 and Chemokine (C-X-C motif) ligand 14 (CXCL14) to test with qPCR in a larger set of placentas (n = 475) and found no differences between the groups. However, regression analysis revealed a stronger association between placental ANGPT2 and CXCL14 mRNA expression and fetal, maternal and delivery-specific variables than diagnostic group. To conclude, the gene expression in term placentas are highly affected by fetal, maternal and delivery specific variables. Few regulated genes were found in late-onset PE and GDM placentas, which may suggest that these conditions could be more affected by maternal factors.

LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors.

BACKGROUND: Vast amounts of data show associations between maternal obesity, dysglycemia, diabetes, and undernutrition during pregnancy and increased cardiovascular disease risk in offspring. However, elevated maternal LDL cholesterol (LDL-C) in pregnancy and offspring cardiovascular disease (CVD) risk has scarcely been studied. OBJECTIVE: Our objective was to investigate the associations between elevated maternal LDL-C in pregnancy and CVD risk factors in 6-to-13-year-old offspring. METHODS: We recruited 6-to-13-year-old children whose mothers attended a pregnancy cohort and who had high or low cholesterol in pregnancy, defined as LDL-C over the 90th percentile or below the 10th percentile within the pregnancy cohort, respectively. We measured CVD risk factors in the children in the 2 groups. RESULTS: Maternal plasma LDL-C at gestational week 14 to 16 was 4.0 and 1.4 mmol/L in the hypercholesterolemic (n = 27) and hypocholesterolemic (n = 34) groups, respectively (P < .001). Interestingly, offspring plasma LDL-C was 0.4 mmol/L higher in children whose mothers had hypercholesterolemia during pregnancy (P < .01). We found no difference in birthweight or any other clinical or biochemical CVD risk factors or dietary intake between the children at 6-13 years. CONCLUSIONS: Women with elevated LDL-C during early pregnancy have offspring with higher LDL-C already at the age of 6-13 years. Unless cholesterol-reducing measures are successfully implemented, the affected children may be at increased cardiovascular risk.

[Postpartum dyspnea, edema and fever]. / Dyspné, ødem og feber i barseltiden.

BACKGROUND: Cardiomyopathy is a condition with heart failure caused by a reduction in the contractility of the heart. Peripartum cardiomyopathy is a rare, but serious condition, characterised by development of heart failure during the last month of pregnancy or the first five months after delivery. MATERIAL AND METHODS: We present a case in which a woman pregnant with twins developed heart failure a few days after giving birth. We give a short report of symptoms, clinical signs, diagnosis, treatment and prognosis for subsequent pregnancies. RESULTS AND INTERPRETATION: The condition was initially diagnosed and treated as pneumonia, but despite treatment and improvement in her laboratory tests, her condition worsened. The symptoms were dyspnoea, peripheral oedemas and pulmonary oedema. Peripartum cardiomyopathy was diagnosed after echocardiography. Treatment of heart failure with diuretics, nitroglycerine, angiotensin-converting enzyme inhibitor and beta blocker was given with good results. This case is presented in order to draw attention to a rare, but serious condition in pregnancy or the postnatal period which easily can be misjudged or mistreated.

ß-cell dysfunction in women with previous gestational diabetes is associated with visceral adipose tissue distribution.

CONTEXT: Glucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes. OBJECTIVE: The aim of the study was to evaluate glucose metabolism in women with and without gestational diabetes mellitus (GDM) at 5 years follow-up and identify risk factors associated with disturbed glucose metabolism post-partum. DESIGN: This follow-up study included 300 consecutively enrolled women from a previous population-based cohort study. The participants underwent oral glucose tolerance test under pregnancy and in the follow-up study, in addition to dual-energy X-ray absorptiometry in the follow-up study. RESULTS: Fifty-two women (17.7%) were found to have GDM in pregnancy with an odds ratio of 4.8 developing prediabetes 5 years later. ß-cell function, but not insulin resistance or sensitivity, was reduced in the follow-up study after adjusting for known risk factors. Furthermore, visceral fat content at follow-up was increased in GDM women compared to non-GDM women, and the ß-cell function declined with increasing visceral fat in both groups but was more pronounced in the women with previous GDM. CONCLUSIONS: Women with GDM are at increased risk of developing prediabetes and have a decreased ß-cell function 5 years post-partum that is associated with increased visceral fat mass.