Validity of self-reported hysterectomy and oophorectomy in a population-based cohort: The HUNT study.

OBJECTIVE: To validate self-reported hysterectomy and bilateral oophorectomy. DESIGN: Validation study. SETTING: Large population-based cohort study in Norway: The Trøndelag Health Study (HUNT). POPULATION: The Trøndelag Health Study 2 and 3 (HUNT2 and HUNT3) included questions on gynaecological history. Women who answered questions regarding hysterectomy and/or oophorectomy were included. In total, 30 263 women were included from HUNT2 (1995-1997) and 23 138 from HUNT3 (2006-2008), of which 16 261 attended both HUNT2 and HUNT3. METHODS: We compared self-reported hysterectomy and bilateral oophorectomy with electronic hospital procedure codes. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value and negative predictive value of self-reported hysterectomy and bilateral oophorectomy, by comparing with hospital procedure codes. RESULTS: Self-reported hysterectomy and bilateral oophorectomy in HUNT2 and/or HUNT3 both had specificity and negative predictive value above 99%. Self-reported hysterectomy had a sensitivity of 95.9%, and for bilateral oophorectomy sensitivity was 91.2%. Positive predictive value of self-reported hysterectomy was 85.8%, but for self-reported bilateral oophorectomy it was 65.4%. CONCLUSIONS: Self-reported hysterectomy corresponded quite well with hospital data and can be used in epidemiological studies. Self-reported bilateral oophorectomy, on the other hand, had low positive predictive value, and results based on such data should be interpreted with caution. Women who report no previous hysterectomy or bilateral oophorectomy can safely be classified as unexposed to these surgeries.

Maternal prenatal cholesterol levels predict offspring weight trajectories during childhood in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Numerous intrauterine factors may affect the offspring's growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. METHODS: This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). RESULTS: Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99). CONCLUSIONS: Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

Maternal body mass index, birthweight, and placental glucose metabolism: evidence for a role of placental hexokinase.

BACKGROUND: The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose-6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown. OBJECTIVE: This study aimed to test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birthweight. STUDY DESIGN: Overall, 67 healthy pregnant participants at term were included in this study at Oslo University Hospital, Oslo, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arteriovenous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptakes. The Spearman rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (milliunit per milligram of protein) with prepregnancy body mass index, maternal glucose and insulin, birthweight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (micromole per minute). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight. RESULTS: Hexokinase activity was detectable in all placental tissue samples. The mean activity was 19.6 (standard deviation, 4.64) mU/mg protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman rho=0.33; P=.006). On controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=.01) and insulin (r=0.28; P=.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (Spearman rho=0.31; P=.01) and consumption (Spearman rho=0.28; P=.02). Hexokinase activity did not correlate with fetal glucose uptake. On controlling for placental weight, hexokinase activity showed a positive correlation with birthweight (r=0.31; P=.01). CONCLUSION: Our findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for disposition, is related to both maternal body mass index and birthweight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.

All-cause and cardiovascular mortality after hysterectomy and oophorectomy in a large cohort (HUNT2).

INTRODUCTION: Hysterectomy and bilateral oophorectomy are common major surgical procedures that have been associated with increased mortality risk. We aimed to assess the association of hysterectomy and/or bilateral oophorectomy with all-cause and cardiovascular mortality in a Norwegian population. MATERIAL AND METHODS: Cohort study with data from The Trøndelag Health Study (HUNT2) linked to the Norwegian Cause of Death Registry, with follow-up from 1996 until 2014 or death. The unexposed group (n = 18 673) included women with both their ovaries and uterus intact, while the two exposed groups included women with hysterectomy alone (n = 1199), or bilateral oophorectomy with or without hysterectomy (n = 907). We compared mortality in exposed vs unexposed groups and adjusted for relevant covariates by Cox regression. Further, we performed analyses stratified by age at surgery (≤39, 40-52, ≥53 years) and subgroup analyses among women ≤52 years of age at inclusion. RESULTS: Among the 47 312 women in HUNT2 (1995-1997), 20 779 provided complete information regarding gynecological surgery and previous health. The hysterectomy group had increased all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06-1.58) and cardiovascular mortality (HR 1.47, 95% CI 1.09-1.97). We found no significant association between bilateral oophorectomy and all-cause or cardiovascular mortality in the total population. However, among women ≤52 years at inclusion, cardiovascular mortality was increased in the hysterectomy group (HR 2.71, 95% CI 1.19-6.17) with a similar, but less precise estimate in the bilateral oophorectomy group (HR 2.42, 95% CI 0.84-6.93). CONCLUSIONS: Hysterectomy was associated with increased all-cause and cardiovascular mortality, whereas bilateral salpingo-oophorectomy was not. Among women ≤52 years at inclusion, both hysterectomy and bilateral oophorectomy were associated with a twofold increased risk of cardiovascular mortality, but the results were imprecise. Women after hysterectomy and/or bilateral salpingo-oophorectomy constitute a group with increased cardiovascular mortality that may need closer attention to cardiovascular disease risk from the healthcare system to ensure timely and effective preventive interventions.

Metabolic profiling of pregnancies complicated by preeclampsia: A longitudinal study.

INTRODUCTION: Preeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures. MATERIAL AND METHODS: We measured 91 metabolites by high-throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14-16, 22-24, 30-32 and 36-38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia (n = 38) and healthy controls (n = 70). RESULTS: Among women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid-related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very-low-density lipoprotein particles, the smallest high-density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4. CONCLUSIONS: In early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre-pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia-specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very-low-density lipoprotein, triglycerides, and total fatty acids.

Lipid and lipoprotein concentrations during pregnancy and associations with ethnicity.

BACKGROUND: To describe ethnic differences in concentrations of lipids and lipoproteins, and their changes, during pregnancy to postpartum. METHODS: This was a population-based cohort study conducted in primary antenatal care in Norway. The participants (n = 806) were healthy, pregnant women, 59% were ethnic minorities. Outcomes were triglycerides, total cholesterol, HDL- and LDL-cholesterol, analysed from fasting blood samples drawn at gestational age (weeks) 15, 28 and 14 weeks postpartum. We performed linear regression models and linear mixed models to explore the total effect of ethnicity on the outcomes, adjusting for gestational age /week postpartum, maternal age and education. The analyses are corrected for multiple testing using the Bonferroni correction. RESULTS: At gestational age 15, triglyceride concentrations were lower in women of African origin (1.03 mmol/mol (95% CI: 0.90, 1.16)) and higher in women of South Asian (primarily Pakistan and Sri Lanka) origin (1.42 mmol/mol (1.35, 1.49)) and East Asian (primarily Vietnam, Philippines and Thailand) origin (1.58 mmol/mol (1.43, 1.73)) compared with Western Europeans (1.26 mmol/mol (1.20, 1.32)). Women of Asian and African origin had a smaller increase in triglycerides, LDL- and total cholesterol from gestational age 15 to 28. At gestational age 28, LDL-cholesterol levels were lowest among East Asians (3.03 mmol/mol (2.72, 3.34)) compared with Western Europeans (3.62 mmol/mol (3.50, 3.74)). Triglycerides and HDL-cholesterol were lower postpartum than at gestational age 15 in all groups, but the concentration of LDL-cholesterol was higher, except in Africans. South and East Asian women had lower HDL-cholesterol and higher triglycerides postpartum, while African women had lower triglycerides than Western Europeans. CONCLUSION: We found significant differences in the concentrations of lipids and lipoproteins and their changes during pregnancy and the early postpartum period related to ethnic origin.

Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring's cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. METHODS: This study is based on 710 mother-father-newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. RESULTS: Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. CONCLUSIONS: Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring's long-term cardiovascular disease risk.

The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling.

We sought to identify proteins secreted by the human placenta into the maternal and fetal circulations. Blood samples from the maternal radial artery and uterine vein and umbilical artery and vein were obtained during cesarean section in 35 healthy women with term pregnancy. Slow off-rate modified aptamer (SOMA) protein-binding technology was used to quantify 1310 known proteins. The uteroplacental and umbilical venoarterial concentration differences were calculated. Thirty-four proteins were significantly secreted by the placenta into the maternal circulation, including placental growth factor, growth/differentiation factor 15, and matrix metalloproteinase 12. There were 341 proteins significantly secreted by the placenta into the fetal circulation. Only 7 proteins were secreted into both the fetal and maternal circulations, suggesting a distinct directionality in placental protein release. We examined changes across gestation in the proteins found to be significantly secreted by the placenta into the maternal circulation using serial blood samples from healthy women. Among the 34 proteins secreted into the maternal circulation, 8 changed significantly across gestation. The identified profiles of secreted placental proteins will allow us to identify novel minimally invasive biomarkers for human placental function across gestation and discover previously unknown proteins secreted by the human placenta that regulate maternal physiology and fetal development.-Michelsen, T. M., Henriksen, T., Reinhold, D., Powell, T. L., Jansson, T. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling.

Use of hormone replacement therapy after risk-reducing salpingo-oophorectomy.

INTRODUCTION: After premenopausal risk-reducing salpingo-oophorectomy (RRSO) to prevent ovarian cancer, the non-cancer-related morbidity and mortality may be increased if sex hormones are not replaced. Several guidelines recommend systemic hormone replacement therapy (HRT) to these women until the expected age of menopause. We aimed to study the use of HRT after RRSO. MATERIAL AND METHODS: Participants were 324 women after RRSO and 11 160 postmenopausal controls. A subsample of 950 controls had undergone bilateral salpingo-oophorectomy (BSO). All participants completed the same questionnaire regarding HRT use. We compared HRT use in the RRSO group with the BSO controls using logistic regression. RESULTS: Among the women aged ≤52 years without a history of breast cancer, 51.7% of the RRSO group and 48.7% of the BSO controls reported current use of systemic HRT (odds ratio 1.13, 95% confidence interval 0.72-1.76). Among the HRT users, systemic estrogen was used by 35.1% and 58.7% in the RRSO and BSO control groups, respectively (p = 0.001). Among the women aged >52 years, 16.8% of the RRSO group and 38.4% of the BSO controls (p < 0.001) used systemic HRT. CONCLUSIONS: Among the RRSO women and BSO controls ≤52 years old without a history of breast cancer, relatively few were current users. If there are no contraindications, these women would benefit from systemic HRT. Additionally, almost 40% of the BSO controls >52 years used systemic HRT. Doctors should be aware of this practice and prescribe systemic HRT when indicated.

Sexual activity and functioning after risk-reducing salpingo-oophorectomy: Impact of hormone replacement therapy.

OBJECTIVE: To examine sexual activity and functioning in women after risk-reducing salpingo-oophorectomy (RRSO) compared with the general population (NORM). METHODS: Retrospective cohort study. 294 women who underwent RRSO and 1228 women from the NORM group provided written information based on mailed questionnaires. Sexual pleasure and discomfort scores and frequency of sexual activity were evaluated using the Sexual Activity Questionnaire. RESULTS: The RRSO group reported less sexual pleasure (10.5 vs. 11.9, P=0.009), more discomfort (1.9 vs. 0.83, P<0.001), and less frequent sex than did the controls. Significant associations were observed between a lower pleasure score and being in the RRSO group, older age, history of cancer, low body image, high level of role functioning, and low level of global quality of life (QoL). Further, significant associations were detected between more discomfort and being in the RRSO group, older age, history of cancer, poor body image, and low level of global QoL. Hormone replacement therapy (HRT) use had no impact on pleasure or discomfort score in regression analyses among all the sexually active women. However, in subanalyses of the RRSO group, users of systemic HRT reported less discomfort (1.2 vs. 2.4, P=0.001) than did the nonusers. CONCLUSIONS: After RRSO, women reported significantly less sexual pleasure, more discomfort, and less frequent sex compared with the controls. In the RRSO group, systemic HRT users reported less discomfort than did the nonusers. Health care providers should be attentive to these issues when counseling before and after prophylactic surgery.

In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies.

BACKGROUND: Preeclampsia is characterized by maternal endothelial dysfunction, which underlies a highly diverse clinical presentation. The pathophysiologic condition remains to be unraveled fully, but interplay between factors that are released from the placenta and maternal vascular vulnerability is likely. An imbalance in circulating angiogenic factors is a prominent feature of preeclampsia; placental growth factor and soluble Fms-like tyrosine kinase 1 have been implemented as biomarkers of placental function and preeclampsia. Their test accuracies are limited in a clinical setting, which urges better insight into their production and removal. Current data suggest that placental growth factor and soluble Fms-like tyrosine kinase 1 are released from the placenta. Both the circulating levels and the placental expression are altered in preeclamptic pregnancies. However, in vivo placental release has not been determined in human pregnancies. Moreover, there is evidence that extra-placental tissues might contribute to the circulating levels placental growth factor and soluble Fms-like tyrosine kinase 1 in normal and preeclamptic pregnancies. OBJECTIVES: We aimed to study the in vivo placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 by determining the uteroplacental arteriovenous differences in human pregnancies. Further, we investigated whether this release was altered in early-onset preeclampsia compared with control subjects and whether there was a release of placental growth factor and soluble Fms-like tyrosine kinase 1 from maternal systemic endothelium. STUDY DESIGN: We conducted a case-control study at Oslo University Hospital and included 23 women with preeclampsia (diagnosis <34 weeks) and 20 control subjects. During cesarean delivery, we sampled blood from 3 vessels simultaneously (uterine vein, radial artery, and antecubital vein). We determined concentrations of placental growth factor and soluble Fms-like tyrosine kinase 1 and calculated the arteriovenous differences. A possible net placental and extra-placental release was evaluated with the use of a Wilcoxon signed rank test. Differences between groups were compared by a Mann-Whitney U-test. RESULTS: The median gestational age at delivery was 33.4 weeks (Q1, 28.3; Q3, 34.4 weeks) in the preeclamptic group and 39.3 weeks (Q1, 39.0; Q3, 39.6 weeks) in the control subjects. Women with preeclampsia had lower plasma concentrations of placental growth factor and higher concentrations of soluble Fms-like tyrosine kinase 1 compared with control subjects (P<.001). There were significant uteroplacental arteriovenous differences of soluble Fms-like tyrosine kinase 1 in preeclampsia (P<.001), but not in the control subjects. The uteroplacental arteriovenous differences of placental growth factor were significant in both groups (P<.001). Despite lower concentrations of plasma placental growth factor in women with preeclampsia, the arteriovenous differences were not significantly different from normal pregnancies (P=.53), even when we corrected for placental weight (P=.79). We found no placental growth factor or soluble Fms-like tyrosine kinase 1 concentration differences between the radial artery and the antecubital vein. CONCLUSION: Our findings are consistent with a net release of soluble Fms-like tyrosine kinase 1 from the placenta in early-onset preeclampsia. This study demonstrated a placental release of placental growth factor to the maternal circulation but could not demonstrate that this release was impaired in the preeclamptic group. We could not find evidence of systemic endothelial release of placental growth factor and soluble Fms-like tyrosine kinase 1 by analyzing the arteriovenous differences in the forearm. This study contributes to the pathophysiologic understanding of preeclampsia by the use of the clinical setting to test current concepts in vivo and underscores that studies of in vivo degradation rates of placentally released compounds are needed.

Pregnancy outcomes following maternal kidney transplantation: a national cohort study.

INTRODUCTION: Internal design flaws in previous reports of pregnancies following kidney transplantation have been outlined, and the need for a validation has been stated. The aim of this study was to collect information about obstetrical and neonatal outcomes in all Norwegian pregnancies following maternal kidney transplantation, and to compare these data with the general Norwegian population. MATERIAL AND METHODS: A retrospective cohort study based on 1 272 000 deliveries in Norway between 1969 and 2013. All data were collected from medical records. From the source population, we compared 119 first deliveries in kidney transplanted women with 238 first deliveries in nontransplanted women. An explanatory strategy was used in the analysis. RESULTS: The risk of preeclampsia was significantly increased in kidney-transplanted women compared with nontransplanted women (adjusted incidence rate ratio: 6.06, 95% confidence interval 3.18-11.55). Additionally, preeclampsia in kidney-transplanted women was early onset (diagnosed <34 gestational weeks) in half of the cases. There were also persistent risks of cesarean delivery (adjusted incidence rate ratio 4.14, 95% confidence interval 2.56-6.66), preterm delivery (adjusted incidence rate ratio 4.45, 95% confidence interval 2.13-9.30) and a birthweight below the 10th centile (22.7% vs. 9.7%) in the kidney-transplanted group. A high proportion (63%) of the kidney-transplanted women with chronic hypertension developed preeclampsia. CONCLUSIONS: Using consistent diagnostic criteria, this study shows high rates of maternal and neonatal complications in pregnancies following kidney transplantation. In particular, we reveal a high rate of early-onset preeclampsia requiring operative preterm delivery, conferring long-term risks on both the mother and child.

Placental energy metabolism: Evidence for a placental-maternal lactate-ketone trade in the human.

INTRODUCTION: Glucose from placenta is the predominant energy source for the fetus. Individual placentas exhibit a range of glucose handling from apparent net production to high consumption, presumably reflecting an ability of placenta to secure both own and fetal energy needs. A dependency of placenta on glucose as the main energy source could impede fetal supply. Placenta seems to release lactate to maternal side implying loss of energy. Whether placenta takes up ketones is unclear. Our main hypothesis was that the human placenta can release lactate to the maternal side but take up maternal ketones. METHODS: An in vivo study of term uncomplicated pregnancies including 56 women delivered by cesarean section. We measured uterine and umbilical blood flow by Doppler ultrasonography, combined with blood sampling from maternal radial artery, uterine vein, umbilical artery and vein. Lactate and ketones were determined by quantitative nuclear magnetic resonance. RESULTS: Placenta released lactate to the maternal side (median -36.65 µmol/min. Q1, Q3: 78.53, 13.29), p < 0.001), but not to the fetal side. A net uptake of maternal ketones was found (median (Q1, Q3): 59.12 (30.64, 131.46) µmol acetate equivalents/min, p < 0.001) which largely was metabolized by the uteroplacenta. The uptake of ketones was comparable in energy to the loss of lactate. DISCUSSION: Placenta may release lactate to the maternal side. The energy lost by lactate may be compensated by uptake of maternal ketones. This lactate-ketone trade could benefit both placenta and the fetus by providing lactate for maternal gluconeogenesis and ketones for uteroplacental oxidative energy production.

Placental weight, surface area, shape and thickness - Relations with maternal ethnicity and cardio-metabolic factors during pregnancy.

INTRODUCTION: A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. METHODS: A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks' gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. RESULTS: Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (-51 g (95% CI: 75, -27) and -55 g (-95, -14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. DISCUSSION: Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness.

Association between hysterectomy with ovarian preservation and cardiovascular disease in a Norwegian population-based sample.

BACKGROUND/AIMS: Some previous studies have reported that hysterectomy predicts increased prevalence of cardiovascular diseases, but the findings are disputed. We aimed to examine associations between hysterectomy and cardiovascular disease in a Norwegian cross-sectional health study. METHODS: The data were obtained from the population-based cross-sectional Nord-Trøndelag Health Study (The HUNT-2 Study). Of 46,709 invited females, 35,280 (76%) participated; 939 (3%) reported hysterectomy without oophorectomy (exposed women). Each exposed woman was age-matched with four randomly chosen women (n = 3,756) without hysterectomy or oophorectomy. Oophorectomy and hysterectomy status was self-reported by the women. Hazard ratio for cardiovascular diseases was calculated by Cox regression analyses with hysterectomy as a time-dependent covariate. RESULTS: Median time since hysterectomy was 14 years (range 0-56 years). We calculated a significantly larger cumulative probability of cardiovascular diseases after hysterectomy with a hazard ratio of 1.92, 95% CI (1.51-2.38) after adjustments for cardiovascular risk factors (diabetes, age, use of hormonal replacement therapy and positive family history of myocardial infarction). CONCLUSION: Women had a significantly increased risk of cardiovascular diseases after hysterectomy compared to age-matched controls. Studies with longitudinal design and confirmed medical outcome data are needed.

Uteroplacental versus fetal use of glucose in healthy pregnancies at term. A human in vivo study.

INTRODUCTION: Fetal glucose is thought to originate from maternal glucose driven across the placenta by a maternal-fetal glucose gradient. Still, there is no correlation between the mass of glucose taken up by the uteroplacenta and the fetal uptake. We propose a hypothesis that the uteroplacenta's own treatment of glucose affects the net mass of glucose taken up by the fetus, independent of the maternal-fetal gradient. METHODS: We performed a human in vivo study of term uncomplicated pregnancies including seventy healthy women delivered by scheduled cesarean delivery. We measured uterine and umbilical blood flow by Doppler ultrasonography, and glucose concentrations in the maternal radial artery, uterine vein, umbilical artery and vein. We calculated Spearman's correlations between uteroplacental and fetal glucose uptake within tertiles of placental glucose consumption. RESULTS: There were significant correlations between uteroplacental uptake and fetal uptake of glucose when determined within each tertile (Spearman's rho 0.76, (p < 0.001); 0.94 (p < 0.001) and 0.49 (p = 0.029) from lowest to highest tertile, respectively). The median (Q1, Q3) uteroplacental glucose consumption in each tertile was -88.8 (-140.3, 56.7), 29.7 (9.2, 47.4) and 174.7 (87.8, 226.1) (µmol/min). The corresponding median (Q1, Q3) fetal glucose uptake was 152.9 (94.2, 162.7), 110.8 (54.7, 167.2) and 66.6 (8.5, 122.1) (µmol/min). DISCUSSION: The maternal fetal glucose gradients were similar in the tertiles of placental glucose consumption. Still, the net mass of glucose taken up by the fetus was markedly different between the tertiles. Placental treatment of glucose exhibited a large variation from apparent production to consumption.

Insulin Increases Adipose Adiponectin in Pregnancy by Inhibiting Ubiquitination and Degradation: Impact of Obesity.

CONTEXT: Circulating adiponectin levels are decreased in pregnant women with obesity or gestational diabetes, and this is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms regulating adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. OBJECTIVE: We tested the hypothesis that obesity in pregnancy is associated with adipose tissue insulin resistance and increased adiponectin ubiquitination and degradation, caused by inflammation and endoplasmic reticulum (ER) stress. METHODS: Visceral adipose tissues were collected from lean and obese pregnant humans and mice. Total and ubiquitinated adiponectin, and markers of inflammation, ER stress, and insulin resistance were examined in adipose tissues. The role of insulin, inflammation, and ER stress in mediating adiponectin ubiquitination and degradation was examined using 3T3L-1 adipocytes. RESULTS: Obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination, and decreased total abundance of adiponectin. Adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. CONCLUSION: We have identified adiponectin ubiquitination as a key mechanism by which obesity diminishes adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.

Gynecologic oncology training systems in Europe: a report from the European network of young gynaecological oncologists.

OBJECTIVE: The objectives of the study were to highlight some of the differences in training systems and opportunities for training in gynecologic oncology across Europe and to draw attention to steps that can be taken to improve training prospects and experiences of European trainees in gynecologic oncology. METHODS: The European Network of Young Gynaecological Oncologists national representatives from 34 countries were asked to review and summarize the training system in their countries of origin and fulfill a mini-questionnaire evaluating different aspects of training. We report analysis of outcomes of the mini-questionnaire and subsequent discussion at the European Network of Young Gynaecological Oncologists national representatives Asian Pacific Organization for Cancer Prevention meeting in Istanbul (April 2010). RESULTS: Training fellowships in gynecologic oncology are offered by 18 countries (53%). The median duration of training is 2.5 years (interquartile range, 2.0-3.0 years). Chemotherapy administration is part of training in 70.5% (24/34) countries. Most of the countries (26/34) do not have a dedicated national gynecologic-oncology journal. All trainees reported some or good access to training in advanced laparoscopic surgical techniques, whereas 41% indicated no access, and 59% some access to training opportunities in robotic surgery. European countries were grouped into 3 different categories on the basis of available training opportunities in gynecologic oncology: well-structured, moderately structured, and loosely structured training systems. CONCLUSIONS: There is a need for further harmonization and standardization of training programs and structures in gynecologic oncology across Europe. This is of particular relevance for loosely structured countries that lag behind the moderately structured and well-structured ones.

Characterization of the Primary Human Trophoblast Cell Secretome Using Stable Isotope Labeling With Amino Acids in Cell Culture.

The placental villus syncytiotrophoblast, the nutrient-transporting and hormone-producing epithelium of the human placenta, is a critical regulator of fetal development and maternal physiology. However, the identities of the proteins synthesized and secreted by primary human trophoblast (PHT) cells remain unknown. Stable Isotope Labeling with Amino Acids in Cell Culture followed by mass spectrometry analysis of the conditioned media was used to identify secreted proteins and obtain information about their relative rates of synthesis in syncytialized multinucleated PHT cells isolated from normal term placental villus tissue (n = 4/independent placenta). A total of 1,344 proteins were identified, most of which have not previously been reported to be secreted by the human placenta or trophoblast. The majority of secreted proteins are involved in energy and carbon metabolism, glycolysis, biosynthesis of amino acids, purine metabolism, and fatty acid degradation. Histone family proteins and mitochondrial proteins were among proteins with the slowest synthesis rate whereas proteins associated with signaling and the plasma membrane were synthesized rapidly. There was a significant overlap between the PHT secretome and proteins known be secreted to the fetal circulation by the human placenta in vivo. The generated data will guide future experiments to determine the function of individual secreted proteins and will help us better understand how the placenta controls maternal and fetal physiology.